Medicine Science I International Medical Journal; E- Journal of March 2019; Volume 8, Issue 1 by Medicine Science

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ISSN 2147-0634

MEDICINE ISSN 2147-0634

SCIENCE International Medical Journal

Volume 8, Number 1, March 2019, Pages 1-259

photo by Serhat Karaman

E ditor-in-Chief Osman CELBIS

E ditors David O. CARPENTER Nevzat ERDIL Yuksel ERSOY Ədalət HƏSƏNOV Yunus KARAKOC Ronald S MacWALTER Selami Cagatay ONAL Ibrahim SAHIN

P ublishing E ditor Fatih BATI

Medicine Science International Medical Journal

EDITORIAL BOARD

Editor-in-Chief Osman CELBIS (MD, Professor), (editor.osmancelbis@gmail.com)

➢

Editors ➢

Yuksel ERSOY (MD, Professor) (editor.yukselersoy@gmail.com)

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Yunus KARAKOC (PhD, Professor) (editor.yunuskarakoc@gmail.com)

➢

Selami Cagatay ONAL (MD, Professor) (editor.cagatayonal@gmail.com)

➢

Ibrahim SAHIN (MD, Professor) (editor.ibrahimsahin@gmail.com)

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Nevzat ERDIL (MD, Professor) (editor.nevzaterdil@gmail.com)

➢

David O. CARPENTER (MD, Professor)

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Ronald S MacWalter (MD, FRCP)

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Ədalət Həsənov (MD, Professor)

Publishing Editor ➢

Fatih BATI (MD, Assistant Professor) (editor.fatihbati@gmail.com)

Medicine Science International Medical Journal

SCIENTIFIC ADVISORY BOARD (Alphabetical Order) •

Gökhan Akbulut, İzmir, Turkey

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Ferah Kızılay, MD, Antalya, Turkey

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Murat Alper, MD, Erzincan, Turkey

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Prakash Kinthada, PhD, Visakhapatnam, India

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Mustafa Altintas, MD, Antalya, Turkey

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Ozkan Kose, MD, Antalya, Turkey

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Sevil Atasoy, PhD, Istanbul, Turkey

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Zhiqiang Liu, MD, PhD, Houston, TX, USA

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Aysegul Atmaca, MD, Samsun, Turkey

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Liu Liu, MD, PhD, New Orleans, LA, USA

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Yasar Bayindir, MD, Malatya, Turkey

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Ronald S MacWalter, MD, Scotland, UK

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Turgay Bork, MD, Malatya,Turkey

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Bulent Mızrak, MD, Batumi, Georgia

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David O. Carpenter, MD, New York, USA

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Camal Musaev, MD, Azerbaycan

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Chang-Hwei Chen, PhD, New York, USA

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Musfiq Orucov, MD, Azerbaycan

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Gurkan Celebi, MD, Ankara, Turkey

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Ercument Olmez, MD, Manisa, Turkey

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Selcuk Cetin, MD, Tokat, Turkey

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Bedirhan Sezer Öner, MD, Malatya, Turkey

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Nefise Oztoprak Cuvalcı, MD, Antalya, Turkey

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Necdet Oz, MD, Antalya, Turkey

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Oguzhan Deyneli, MD, İstanbul, Turkey

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Abdullah Ozgonul, MD, Sanliurfa, Turkey

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Ahmet Hakan Dinc, Ankara, Turkey

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Hakan Parlakpinar, MD, Malatya, Turkey

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Ali Dogan, MD, Antalya, Turkey

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Erkan Pehlivan, PhD, Malatya, Turkey

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Teoman Dogru, MD, Balıkesir, Turkey

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Oguz Polat, MD, Cleveland , USA

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Nevzat Erdil, MD, Malatya, Turkey

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Nilufer Tulin Polat, PhD, Malatya, Turkey

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Bulent Eren, MD, Bursa, Turkey

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Nariman Safarli, MD, Baku, Azerbaijan

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Zerrin Erkol, MD, Bolu, Turkey

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Nusret Soylu, MD, Malatya, Turkey

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Kadir Ertem, MD, Malatya, Turkey

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Maryna Steyn, MD, South Africa

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Yasemin Ersoy, Malatya, Turkey

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Hülya Taskapan, MD, Malatya, Turkey

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Suraj K George, MD, USA

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Mehmet Tokdemir, MD, , Elazig, Turkey

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Mira R. Gökdoğan, PhD, Girne, North Cyprus

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Nilgun Ulutasdemir, PhD, Gaziantep, Turkey

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Ali Gunes, MD, Malatya, Turkey

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Ali Uzunkoy, MD, Sanliurfa, Turkey

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Hakan Gunen, MD, Istanbul, Turkey

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Yingjun Yan, MD, Nashville, TN 37232, USA

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Than Than Htwe, MD, Perak, Malaysia

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Dilek Yavuz, MD, İstanbul , Turkey

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S.Iqbal, MD, Kerala, India

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Ilhan Yetkin, MD, Ankara, Turkey

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Nur Efe Iris, MD, İstanbul, Turkey

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Tulay Öner Yıldırım, MD, Malatya, Turkey

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Servet Birgin Iritas, MD, Ankara, Turkey

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Oguzhan Yıldırım, MD, Malatya, Turkey

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Mehmet Yasar Işcan, PhD, Istanbul, Turkey

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Tuba Duygu Yılmaz, MD, Mersin, Turkey

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Om Prakash Jasuja, PhD, Patiala, India

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Eda Bengi Yılmaz, MD, Mersin, Turkey

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Kishore Kumar Jella, PhD, Atlanta GA, USA

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Saim Yologlu, PhD, Malatya, Turkey

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Mehmet Karaca, MD, Antalya, Turkey

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Menizibeya Osain Welcome, MD, Minsk, Belarus

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Abdullah Karaer, MD, Malatya, Turkey

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Ersoy Kekilli, MD, Malatya, Turkey

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Pavel Timonov, MD, Bulgaria

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Mehmet Kelles, MD, Malatya, Turkey

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Antoaneta Fasova, MD, Bulgaria

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Inam Danish Khan, MD, CH EC Kolkata, India

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Robert (Paweł) SUSŁO, MD, Poland

Ronald K Wright BS MD JD, FL , USA

Available online at www.medicinescience.org

ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):1-6

The evaluation of two different surgical approaches in total hip arthroplasty according to the patient satisfaction, plantar pressure distribution and trendelenburg sign Ahmet Yildirim1, Tacettin Ayanoglu2, Mustafa Ozer3, Erdinc Esen2, Ulunay Kanatli2, Selcuk Bolukbasi2 Selcuk University, Faculty of Medicine, Department of Orthopedics and Traumatology, Konya, Turkey Gazi University, Faculty of Medicine, Department of Orthopedics and Traumatology, Ankara, Turkey 3 Necmettin Erbakan University, Faculty of Medicine, Department of Orthopedics and Traumatology, Konya, Turkey 1

Received 07 September 2018; Accepted 21 September 2018 Available online 19.10.2018 with doi:10.5455/medscience.2018.07.8913 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The aim of this prospective study was to analyze the results of two different surgical aproaches for total hip arthroplasty as Trendelenburg sign, plantar pressure distribution with the help of dynamic pedobarography and clinical results by Harris Hip Score. A total of 28 patients who underwent unilateral total hip arthroplasty using two different types of lateral approach as conventional lateral Hardinge approach and intermuscular Hardinge approach described by Pai were included in this study. Plantar pressures have maesured by EMED-SF pedobarography device and analysed by the help of a commercial software; that seperates the foot to the four different parts which are called masks. Trendelenburg’s sign has been estimated as grade 1 and grade 2 by the method which was described by Hardcastle and Nade. Clinical outcome was measured by comparing Harris Hip Scores pre-operatively and postoperatively at last clinic visit. In both groups after the two years from the surgery; total contact time has increased at the operation side when the results were compared before the surgery at the same side and at the other side after the surgery. Also when we looked at the first and second masks which show the significant part of the stance phase; contact areas have similarly increased and the changes at the peak pressures were similar as contact areas. In both groups Harris Hip score was increased significantly after the operation. This is the first study to compare two different lateral approaches by pedobarographic analysis, clinical evaluation and functional scoring. The fuctional and clinical early results are similar in both lateral hip approaches for total hip arthroplasty when superior gluteal nerve protection, conjuant tendon repair and postoperative rehabilitation have done well. Keywords: Total hip arthroplasty, pedobarography, Trendelenburg’s sign, Harris hip score, gait analyses

Introduction The frequency of total hip arthroplasty treatment for the degenerative hip arthritis increases day by day. The main purpose of surgical treatment; to relieve the pain, provide functions to the joint and create a near normal hip range of motion. Many different surgical approaches have been described due to implant features and reasons of arthritis. Surgeon’s experience is the main criteria for selecting the approach type. Partial advantages such as preventing prosthesis dislocation, protecting the adductor muscle function and providing the best view of acetabulum effect the preference [1]. The biomechanics of the hip should be well known to better understanding of the complications as dislocation, corrosion, loosening and creating the anatomical and physiological features as near normal hip [2]. Protecting the strength and function *Coresponding Author: Ahmet Yildirim Selcuk University, Faculty of Medicine, Department of Orthopedics and Traumatology, Konya, Turkey E-mail: dr1907@gmail.com

of the abductor mechanism is extremely important in implant biomechanics. Traditionally isokinetic dynamometer is used in the assessment of quantitative abductor muscle strength. In recent years, gait analysis is said to be a easy and practical method in literature. Dynamic pedobarography may also be” an effective method to assessment of abductor muscle strenghth preoperatively and postoperatively. Stance phase, load distribution between hips and gait speed are based on the pedobarography [36]. Biomechanical concepts in hip, generally corresponding to the 16th phase of gait and the 31st phase (mid-stance phase) as described by O. Fischer and Braune in 1889. Pedobarography (plantar pressure measurement) provides to measure the ground reaction forces very precisely and pointwise during walking. It assess the dynamic pressure which created with contacting the ground. Analyzing plantar pressure has an important role in diagnosis, treatment and follow-up of the diseases which affecting the axial alingment of the lower extremity [7]. Osteoarthritis changes gait patern of the patients depending on pain, instability, neuromuscular disease, muscle weakness. They adapt in accordance with the current situation. Limited range 1

doi: 10.5455/medscience.2018.07.8913

of motion prevents the expected maximum extension during the stance phase. Patients try to tolorate the situation by increasing lomber lordosis or flexion of the pelvis [8]. Osteoarthritic patients after hip replacement surgery; show significant change in stance phase, especially in the mid stance phase, load distribution, range of motion, gait speed and postoperative gait can not be considered as normal [9,10]. Functional healing process and damage of hip abductor muscles and soft tissue are the most important reasons for these abnormal gait [11]. The forms of changes in foot-ground pressure are generally valuable to any pathological changes in gait, such as those characteristics of pain (“antalgic” or “painful” gait), loss of balance, disturbances in neuromuscular control. The pedobarograohy may be the easiest and cheapest way to understand the charecteristic changes after total hip arthroplasty. Abduction deficiency or trendelenburg gait pattern (or gluteus medius) is an abnormal gait caused by weakness of the abductor muscles of the lower limb, gluteus medius and gluteus minimus. During the stance phase, the weakened abductor muscles allow the pelvis to tilt down on the opposite side. To compensate, the trunk lurches to the weakened side to attempt to maintain pelvis throughout the gait cycle. And pelvic balance can be ensured with this way. Asymmetry in double assistance, decrease in gait speed and hip abductor moment in the stance phase and can be seen after total hip arthroplasty [12]. In the literature, there are few many reported articles about the gait analyses, Trendelenburg’s sign, and hip abductor muscle function after the total hip arthroplasty with the lateral approach. This is the first study to compare two different lateral approaches by pedobarographic analysis, clinical evaluation and functional scoring. In our study, we analyzed that the clinical results and the differences at the patients who had unilateral total hip arthroplasty surgery with two different surgical approaches as classical lateral Hardinge approach and modification of lateral intermuscular approach. The aim of this study was to assess the Trandelenburg sign, plantar pressure distribution with the help of dynamic pedobarography and clinical results by Harris Hip Score after two different surgical approaches. Materials and Methods This study protocol was approved by the Gazi University Faculty of Medicine Ethics Committee. (September 29 2010 / 167) We selected 28 patients (7 male, 21 female) who had been operated in our clinic because of the unilateral degenerative hip arthritis. Total hip arthroplasty was performed by the same surgeon to the patient. The cementless, standart off-set stem was used for whole the patients. The patients had been seperated by the bloc randomisation technique. The preferred approach for the first group is classical lateral Hardinge approach and 13 patients had been selected for this group. In the second group there were 15 patients and the preferred approach was modification of lateral intermuscular approach (Pai). The patients who had advanced stage of foot deformity, pes planus,

Med Science 2019;8(1):1-6

achilles tendon strain, generalized joint laxity, neuromuscular disease, peripheral neuropathy, spine problems that may lead to pelvic instability and surgical history of lower extremity were excluded from the study. Gait analysis was made preoperatively to the patients who planned total hip arthroplasty by the same researcher. Plantar pressures were maesured by EMED-SF pedobarography device and analysed by the help of a commercial software (Novel H, Munich, Germany). While patients were walking on a 7 meter treadmill, a static and two dynamic measurements are made for each feet. We requested each patient to step as minimum 3 phase on the board and the results were recorded 71 hz sample velocity for aquare. All patients were assessed with Harris Hip Score system to evaluate the patients satisfaction. According to this assessment, the patients were evaluated with pain score, function score (gait, stairs be able to walk up and down, to wear socks-shoes, sitting, to ride on public transport), the deformity score and move scores. Two years after the surgery, patients were called away control. And they were analyzed using the same technique. Trendelenburg’s sign of was investigated with physical examination and Harris hip score was applied. Patients were operated by the same surgeon, under general anesthesia and combined spinal and epidural anesthesia, in the supine position. In patients undergoing conventional Hardinge approach; incision was started from the spina iliaca anterior superior, ½ anterior part of gluteus medius fibers were removed from sticking area and has been reached to the joint; tendon-tendon repair was performed with 1.0 Vycril (Figure 3). In patients undergoing modified intermuscular Hardinge approach, direct lateral incision was passed from tip of trochanter major. 1/3 anterior part of muscle fibers were removed from sticking area with blunt approach. The surgeon has been reached to the joint by entering from cleavage which formed by tensor fasia lata, gluteus medius and minumus. After surgery tendon-bone repair was performed with 5.0 Ehtibond (Figure 4). Pedobarographic measurements were recorded with EMED-SF (44.4*22.5cm active area, 71 Hz sampling rate, two receiver in square centimeters) platform at the first and control admission by the same researcher. This platform covered with a thin leather surface and mounted on 7x1 meter wooden. Measurements were performed with barefoot and in a normal walking speed. Before coming to the measurement area, participants completed at least three times the normal gait cycle. Measurements were repeated three times for each foot. Assessment values were averaged for each of them by selecting the closest two measurements. A static and two dynamic measurements are made for each feet. Plantar pressures measurements that seperates the foot to the four different parts which are called masks. Each region were evaluated in terms of the contact area (cm²), the maximum force (N), the peak pressure (N / cm²), the maximum average pressure (N / cm²), a pressure-time integral of [(N/cm²)*s] and arch index. Recorded pressure images were transferred to Novel ortho (Novel GmbH) software for further analysis (Figure 2). A method as described by Cavanagh and Rodgers was used to the evaluation of medial longitudinal arch [13]. They have divided 2

doi: 10.5455/medscience.2018.07.8913

feet into three equal parts as front foot, midfoot, hind foot. Arch index is defined as the ratio of middle foot pressure area to all of the foot pressure area. In our method, plantar pressures measurements that seperates the foot to the four different parts which are called masks (Automask, Novel-ortho, Germany). These masks were divided as front foot, mid foot, hind foot and fingers. Lines were drawn from 50% and 69% of the length of all foot and thus the border of mask areas were identified. The border of fingers and front foot was identified by taking advantage of the difference in pressure in these areas. Abductor function was evaluated by correlating arch index and changes in foot contact time. Postoperative abductor forces in two different approach were evaluated by pedobarographic and plantar pressure changes. All the parameters were compared as preoperatively and postoperatively at the second year. Trendelenburg’s sign is used as an indicator of abduction dysfunction. This test is described by Friedrich Trendelenburg in 1895 [14]. Trendelenburg’s sign has been estimated as grade 1 and grade 2 by the method which was described by Hardcastle and Nade [15]. Clinical outcome was measured by comparing Harris Hip Scores pre-operatively and at last clinic visit. All the parameters were compared as preoperatively and postoperatively at the second year. The cases is considered over 100 points according to Harris Hip Score. Statistical analysis used the SPSS software (IBM corp version 21). Significance level was determined as p<0.05. Mean and standard deviation were calculated for all variables, with frequency values calculated with the same software.

The load-bearing parts of the foot are divided into three parts, as mask1, mask2 and mask3. Preoperatively, measurements in mask 1, 2, and 3 areas of opere and opposed sides do not differ from group to group (p>0.05). When the pedobarography results and the first three masks were analysed, we reached that; contact area, peak pressures and total contact time were less at the operation side preoperatively than the healthy side. Also at the second mask; which is the significance of the midstance phase, contact time was again less at the operation side (Table 1). In both groups after the two years from the surgery; total contact time has increased at the operation side when the results were compared before the surgery at the same side and at the other side after the surgery. Also when we looked at the first and second masks which show the significant part of the stance phase; contact areas

Med Science 2019;8(1):1-6

have similarly increased and the changes at the peak pressures were similar as contact areas. (Table 2,3). Table 1. Preoperative contact area of operated side according to the groups

Operated side, Preop Mask 1 Area Operated side, Preop Mask 2 Area Operated side, Preop Mask 3 Area

Group

Average (cm2)

Std. deviation

Hardinge

29.44

4.18

-1.709

0.107

Modified Hardinge

33.50

5.57

Hardinge

25.69

6.91

-1.177

0.256

Modified Hardinge

29.10

5.41

Hardinge

49.81

5.76

-0.222

0.827

50.50

7.09

Table 2. Postoperative contact area of operated side according to the groups

Non-operated side, Postop Mask 1 Area Non-operated side, Postop Mask 2 Area Non-operated side, Postop Mask 3 Area

Group

Average (cm2)

Std. deviation

Hardinge

32.13

4.47

-1.015

0.325

Modified Hardinge

34.30

4.55

Hardinge

26.19

5.31

-1.445

0.168

Modified Hardinge

31.40

8.99

Hardinge

47.06

10.10

-0.792

0.440

Modified Hardinge

50.60

8.85

Table 3. Preoperative and postoperative contact time of each two side according to the groups

Results The age ranges of the all patients varied between 30 and 77 years old and the average age for the whole patients was 54.78 years during the time of surgery. In the first group which were operated by classical lateral Hardinge approach; 10 (%76) of the 13 patients were women and 3 (%24) were men, and the average age was 57.62 years; in the second group 11 (%73) of the 15 patients were women and 4 patients (%27) were men and the average age was 52.33 years during the time of surgery. There was no significant difference between two groups in terms of age, gender and operated side (p>0.05).

Operated side, Preoperative total time Operated side, Postoerative total time Non-operated side, Preoperative total time Non-operated side, Postoperative total time

Group

Average (sn)

Std. deviation

Hardinge

1120.00

444.55

0.395

0.698

Modified Hardinge

1041.60

396.98

Hardinge

1155.78

540.32

-0.062

0.951

Modified Hardinge

1171.80

578.29

Hardinge

1151.50

454.25

0.403

0.692

Modified Hardinge

1064.00

459.61

Hardinge

1096,67

539.25

0.144

0.887

Modified Hardinge

1064,00

450.61

Before the surgery, Trendelenburg’s sign was positive in 3 patients in the first group and 1 patient in the second group; and there were no statistically differences for Trendelenburg’s sign between the two groups preoperatively. In the first group at the second year visit, 4 patients had Trendelenburg’s sign and 2 of them had also positive results before the surgery. In the second group only 1 new patient had Trendelenburg’s sign at the second year visit. After the analyse of the results by chi-square test; no significant differences were seen (p>0.05). For whole the patients the average preoperative Harris hip score was 41.50 (19-61) points. At the time of the last visit, the average Harris hip score was found as 86.68 (66-100) points. In the first group, the avarage preoperative Harris hip score was 39.46 (223

doi: 10.5455/medscience.2018.07.8913

56) points and at the postoperative second year visit, the average Harris Hip Score was found as 84,08 (67-100) points. In the second group, the avarage preoperative Harris hip score was 43.27 (19-61) points and at the postoperative second year visit, the average Harris Hip Score was found as 88.93 (66-100) points. There were no statistically differences for both groups (p>0.05). But, there was a significant difference between preoperative and postoperative Harris hip scores (p<0.01) (Figure 1).

Med Science 2019;8(1):1-6

Discussion Total hip arthroplasty, continues to be the most ideal method for hip surgical treatment of hip degenerative arthritis. In studies with large patient participation; male/female ratio is equal in some series, some series contain higher male/female rates. Male/female rates is 1 in Valle’s series, 0.37 in Kim’s series, 2.5 in Erdemli’s series [16,17]. In our study, there is no statistically significant difference between groups as similar publications. The average age is 57.6 in classic lateral Hardinge approach and 52.3 in modified intermuscular Hardinge approach. The average age of all patients in this study is 54.7. This average is 48.4 in Kim’s series [16], 58.0 in Pieringer’s series [17], 45.0 in Hellman series [18], 53.0 in Solak series [19]. In our study there were no significant differences between the two groups and similar publications in literature. Up to now, various approaches used for hip arthroplasty in the literature have been compared with gait analysis. Perron et al. compared posterior and anterolateral approaches [10], Klausmeier et al. compared anterior and anterolateral approaches, and Madsen et al. [20] compared the anterolateral and posterolateral approaches [21]. This is the first study to compare two different lateral approaches by pedobarographic analysis.

Figure 1. Postoperative increase of Harris Hip Score

Figure 2. Four- part pressure areas as called “mask” by EMED-SF system

Figure 3. Repair of tendons with 1.0 vicryl after Hardinge approach

Figure 4. Conjuant tendon repair after modified Hardinge approach

The modified Hardinge approach described by Pai shows some differences compared to the direct lateral approach described by Hardinge. In the direct lateral approach described by the Hardinge, approximately 1/2 of the gluteus medius muscle is pulled out from the trochanter major to reach the joint capsule; In Pai’s modified Hardinge method, the joint capsule is reached with blunt dissection among the muscle plans, minimal damage to the muscle. Only the front 1/3 of gluteus medius leaves. Another difference, while tendon-tendon repair method is used for repair of tendons removed in the Hardinge approach, gluteus-vastus flap is fixed to trochanter major, as tendon-bone method with nonabsorbable suture in the Hardinge approach modified by Pai. A variety of qualitative and quantitative methods are defined to evaluate the preoperative and postoperative hip circumference of muscle strength. Mechanical or digital dynamometer, electromyography and Trendelenburg sign in physical examination are some of the main methods [22,23]. In recent years, gait analysis is used for assessment of hip circumference muscle strength as a method that which can give quantitative parameters and kinematic analysis [24]. It is an effective method of evaluation both the results of hip arthroplasty and recognition of the complications as Trendelenburg gait [24-26]. In patients with hip osteoarthritis, limited joint mobility and shortened stance-phase can be seen. Asymmetry is observed in double-step and stance phase in patients with unilateral osteoarthritis [27]. Rantanen et al. have done dynomometric measurements and gait analysis to 75 years old participants who have no active complaints, can do daily work and climb stairs. Although there is no symptoms, the decline in isometric muscle strength have been identified by gait analysis [28]. Benedict et al., studied 30 patients with osteoarthritis of the hip as pedobarographic. They found that the total contact area, the peak pressure and the contact time during stance- phase decreased on the side of degenerative arthritis and tried to transfer the load 4

doi: 10.5455/medscience.2018.07.8913

Med Science 2019;8(1):1-6

distribution to the non-pathological side, especially during the mid-stance phase [29]. In our study, contact areas (table 1,2), peak pressure and total contact time (table 3) were found to be lower on osteoarthritic side similar to the literature, although it did not differ statistically as to be parallel to previous studies. At the time of the second mask which is thought to reflect the mid-stance phase, was found lower on osteoarthritic side.

the special areas of the foot, possibly associated with osteoarthritis of the hip or with the total hip arthroplasty itself. The results did not indicate any unequivocal differences in the characteristics of dynamic weight-bearing in the stance phase among the patients we studied.

There has not formed a consensus in the literature in terms of postoperative follow-up period. Klausmeier et al. emphasized that 6 week period was sufficient for healing and there was no difference between preoperative and postoperatve tissue quality at 16th weeks [20]. Bennett et al. argued that the former muscle strength is reached at 6 weeks after hip replacement [30]. Madsen and Nantel defined that the ideal time of healing in terms of muscle strenght after surgery was 6 months [31]. Considering these studies, we invited patients to control at the end of 6th months to be sure of soft tissue healing.

In conclusion, pedobarography is not really affective for grade 1 trendelenburg analyze. The functional and clinical early results are similar in both lateral hip approaches for unilateral total hip arthroplasty when superior gluteal nerve protection, conjuant tendon repair and postoperative rehabilitation have done well. The risk of insufficiency of hip abductors is rather low in both approaches. So that, two different surgical methods should be preferred easily. This is the first study to compare two different lateral approaches by pedobarographic analysis, clinical evaluation and functional scoring. We believe that the increased number of patients and prolonged follow-up can be more effective results in this issue.

Giving as little damage to the muscle plans and distinguishing the boundaries of safe zone on trochanter major are very important to avoid complications and ensure the ideal reconstruction after surgery [32]. Functional insufficiency ve Trandelenburg movement resulted from retracting anterior ½ fibers of gluteus medius fibers and after occuring reconstruction problems, besides of denervation of superior gluteal nerve, involved in literatüre [22]. For this reason, in lateral approach of their hip, modifications with less complication and hip muscles with better protection have been tried by various researchers Patients were performed with two different lateral total hip replacement approach have been analysed and no significant differences have been found from the point of pedobarographic and Trandelenburg sign. The most important reasons are thought as paying attention of safe zone for the inferior bundle of superior gluteal nerve during surgery in Hardinge approach applied group, both groups are taken care of proper and careful conjoint tendon repairment and both have been applied same rehabilitation programme of abductor muscle strengthening. All hips were classified in poor group preoperatively according to the Harris Hip Score. After 6 months follow up, in 28 hip, good and excellent clinical results (78.6%) and good scores with 86.8(on average) were obtained. In Kim and Pal’s 118 case series; Preoperative Harris hip score is reported as 48.8, after 9.8 years follow up score is reported as 92 and 112 cases’ (95%) results are reported as good and perfect [33]. Bojeskul [34] reported preoperative Harris Hip Score as 32 and postoperative 93; Archibeck [35] reported preoperative Harris Hip Score as 51 and after 10 follow up as 94; Aldinger [36] reported score after 10-15 years follow up as 84. Jerosch and Pal [37] reported that preoperative Harris score is 44, at the end of the third month 84.7, at the end of the first year 90 in 75 patients after lateral approach(early period results). When we compare our results with clinics in the literature, our results are low on the borderline, but seems parallel with literature. It is estimated that as the follow up time lengthen, functional outcomes will improve. Our procedure for the assessment of gait parameters was adopted based on a compilation of the methods explained in the literature [29]; we analyzed for characteristic changes in weight-bearing in

Conclusion

Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Before the study, permissions were obtained from local ethical committee. Ahmet Yildirim ORCID: 0000-0002-3953-091X Tacettin Ayanoglu ORCID: 0000-0002-3089-9913 Mustafa Ozer ORCID: 0000-0002-4199-836X Erdinc Esen ORCID: 0000-0003-0434-5850 Ulunay Kanatli ORCID: 0000-0002-9807-9305 Selcuk Bolukbasi ORCID: 0000-0002-9460-3368

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10. Perron M, Malouin F, Moffet H, et al. Three-dimensional gait analysis in women with a total hip arthroplasty. Clin Biomech. 2000;15:504-15. 11. Crenshaw A. Surgical approaches. In: Crenshaw AH, editor. Campbell’s Operative Orthopae-dics. 8th ed. St. Louis. MO: Mosby-Year Book, lnc; 1992.

doi: 10.5455/medscience.2018.07.8913 12. Whittle MW. Gait analysis: an introduction Oxford: Butterworth-Heinemann 1996. 13. Cavanagh PR, Rodgers MM. The arch index: a useful measure from footprints. J Biomech. 1987; 20:547-51. 14. Trendelenburg F. Dtsch Med Wochenschr. 1895;21:21. 15. Hardcastle P, Nade S. The significance of the Trendelenburg test, J Bone Joint Surg Br. 1985;67:741-6. 16. Kim HY, Kim SJ, Oh SH, et al. Comparison of porous coated titanium femoral stems with and without hydroxiapatite coating J Bone Joint Surg. 2003;85:1682-8. 17. Pieringer H, Auersperg V, Griebler W, et al. Long- term results with the Cementless alloclas-sic brand hip arthroplasty system. J.Arthroplasty. 2003;18:321-8. 18. Hellman EJ, Capello WN, Feinberg JR. Omnifit cementless total hip arthroplasty. A 10 year average follow up. Clin Orthop Relat Res. 1999;364:164-4. 19. Solak SA, Aydın E, Pestilci F. Hidroksiapatit kaplı total kalça protezleri ile kısa dönem takip sonuçlarımız. Turkish J. Arthroplasty Arthroscopic Surg. 1999;2:117-22. 20. Sevimli R, Aslanturk O, Ertem K, et al. An investigation of infection rate and seasonal effect level in total joint replacement cases. Med-Science. 2018;7:210-3. 21. Madsen MS, Ritter MA, Morris HH, et al. The effect of total hip arthroplasty surgical appro-ach on gait. J Orthop Res 2004;22:44-50. 22. Baker AS, Bitounis VC. Abductor function after total hip replacement. An electromyographic and clinical review J Bone Joint Surg Br. 1989;71:47-50. 23. Youdas JW, Madson TJ. Usefulness of the Trendelenburg test for identification of patients with hip joint osteoarthritis Physiother Theory Pract. 2010;26:184-94. 24. Sinha A, Twycross-Lewis R, Small C, et al. Motion analysis as an outcome measure for hip arthroplasty The Surgeon. 2011;9:284-91. 25. Madsen MS, Ritter MA, Morris HH, et al. The effect of total hip arthroplasty surgical appro-ach on gait Journal of Orthopaedic Research. 2004;22:44-50.

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26. Queen RM, Butler RJ, Watters TS, Kelley SS, Attarian DE, Bolognesi MP. The Effect of To-tal Hip Arthroplasty Surgical Approach on Postoperative Gait Mechanics The Journal of Arth-roplasty. 2011;26:66-71. 27. Özaras N, Yalçın S. Yürüme Analizi, Avrupa Tıp Kitapçılık, İstanbul, 2001 28. Rantanen T, Era P, Heikkinen E. Maximal isometric strength and mobility among 75-year-old men and women, Age Ageing. 1994;23:132-7. 29. Cichy B, Wilk M, Sliwiński Z. Changes in gait parameters in total hip arthroplasty patients be-fore and after surgery, Med Sci Monit. 2008;14:15969. 30. Bennett D, Ogonda L, Elliott D, et al. Comparison of gait kinematics in patients receiving mi-nimally invasive and traditional hip replacement surgery: a prospective blinded study. Gait Posture. 2006;23:374-82. 31. Nantel J, Termoz N, Vendittolo PA, et al. Gait patterns after total hip arthroplasty and surface replacement arthroplasty. Arch Phys Med Rehabil. 2009;90:463-9. 32. Siebenrock KA, Rösler KM, Gonzalez E, et al. Intraoperative electromyography of the supe-rior gluteal nerve during lateral approach to the hip for arthroplasty: a prospective study of 12 patients. J Arthroplasty. 2000;15:867-70. 33. Kim HY, Oh HS, Kim JS. Primary total hip arthroplasty with a secondgeneration cementless total hip prosthesisin patients younger than fifty years of age. J Bone Joint Surg. 2003; 85:109-14. 34. Bojeskul JA, Xenos JS, Callaghan JJ, et al. Results of porous coated anatomic total hip arth-roplasty without cement at fifteen years: a concise follow-up of a previous report. J Bone Joint Surg. 2003;85:1079-83. 35. Archibeck MJ, Berger RA, Jacobs JJ, et al. Second generation cementless total hip arthrop-lasty. Eight to eleven year results. J Bone Joint Surg. 2001;83-A11:1666-73. 36. Aldinger PR, Breusch SJ, Lukoschek M, et al. A ten to 15 year follow-up of the cementless spotorno stem. J Bone Joint Surg. Br. 2003;85-2:209-14. 37. Jerosch J, Theising C, Mohie E. Antero-lateral minimal invasive (almi) approach for total hip arthroplasty technique and early results, archives of orthopaedic and trauma surgery. 2006;136:164-73.

Available online at www.medicinescience.org

ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):7-10

Lower limb injuries secondary to hoeing machine accidents Ali Gulec, Fatih Durgut, Ali Ozdemir, Ahmet Yildirim, Bahattin Kerem Aydin Seluk University Faculty of Medicine, Department of Orthopaedics and Traumatology, Konya, Turkey Received 29 September 2018; Accepted 10 October2018 Available online 18.10.2018 with doi:10.5455/medscience.2018.07.8910 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Agricultural accidents are important for Turkey as more than 20 million people are involved in agriculture. The aim of this study was to evaluate orthopaedic lower limp injuries related to hoeing machine from a trauma centre localized in Middle Anatolia Region. 15 patients who hospitalized for hoeing machine were included to study due to lower limp injuries between April 2012 and May 2017. All the medical records were scanned retrospectively to evaluate “the demographic, epidemiologic characteristics of patients, cause of accidents, type of injury, duration of hospital stay and also hospital costs were evaluated retrospectively “. According to database, fifteen patients were hospitalised for lower limp injuries (14 were male, 1 female). The mean age was 45.2 (19-64) years old. The most frequent injury was tibia fracture (64 %). The mean hospital stay time was 14 days (between 1and 53). The mean cost was 11.140,16 (500 and 27.115,08) Turkish Liras. The rate of knee dislocation was 26 %. Most prevalent injury was tibia fracture. Simple precautions can be effective for preventing this kind of injuries. Meticulous examination is important as the rate of knee dislocation is high in these types of traumas. Keywords: Hoeing machine, knee dislocation, agricultural injury, fracture

Introduction Agricultural accidents are related to fatal/non-fatal injuries. International Labor Organisation (ILO) reported that nearly half of work related deaths are associated with agricultural injuries (170.000/335.000 deaths) [1]. Advanced researches indicate that agricultural machinery is responsible for most of these accidents [2]. Tractor and other machinery which powered or operated by tractor power takeoff such as threshing machine, pulverizator, hoeing machine and combine harvester are commonly held responsible for agricultural injuries [3]. Hoeing machine is one of the commonly used devices in farmery in order to weed cleaning and preparing the soil for planting. Hoeing machine is also named as “Pat Pat” because of its sound. This machine is becoming popular, as it is rather cheap and economic. Although the use of this machine seems to be easy, the operator of this machine has to be very careful due to the configuration of this machine. Accidents and lethal consequences arise in the inadequacy of the security measures. *Coresponding Author: Ali Gulec, Selcuk University Faculty of Medicine, Department of Orthopaedics and Traumatology, Konya, Turkey E-mail: dr.aligulec@gmail.com

In English literature, there are limited numbers of orthopaedic papers related to agricultural accidents from Turkey. All of the recent studies were about Black sea region. Selçuk University is one of the main trauma centres of Middle Anatolia Region located in Selçuk University located at the crossroads of main highways and also have a helipad. In this retrospective study we planned to investigate lower limp traumas secondary to agricultural accidents related to hoeing machine of a single center located at Middle Anatolian Region where agriculture is main source of living. Material and Methods This retrospective study was carried out following the approval of local institutional review board. Medical records retrospectively reviewed for patients presenting with lower limb injuries caused by a hoeing machine between April 2012 and May 2017. Patients who were hospitalized in orthopaedics and traumatology department of Selçuk University Hospital. Age, gender, season of accidents, presence of fracture, nerve/vascular damage, additional tissue injury, extent of treatment, number of operations, length of hospital admission, presence of infectious disease state, presence of knee dislocation cost of overall treatment parameters were investigated. 7

doi: 10.5455/medscience.2018.07.8910

Results were stated as mean ± SD. In the data evaluation, the “SPSS” (Statistical Package for Social Sciences) software (Version 16.0; SPSS Inc, Chicago, IL) was used. Regression analysis was used in the evaluation of data with each other and in paired relationships.

Med Science 2019;8(1):7-10

Amputation was performed in one patient with crush syndrome at below the knee level of left lower limb (amputation rate, 6.6 %). Open wounds in different locations of affected lower limbs were present in 12 of 15 patients (open wound rate, 80%) (Figure 1 a, b). Osteomyelitis occurred in one patient and soft tissue infection was diagnosed in another one. Knee dislocation injury seen in 4 patients (26.6%) of which was bilateral in one patient (Figure 2 a, b). Mean number of operations was 3.07 and number of operations performed for two patients with osteomyelitis and soft tissue infection were 12 and 5 in order. Open wound injuries detected in 11 patients; 7 patients were primarily closed while skin graft needed in 3 cases. In one patient urethra and anus were repaired by urologist. Blood transfusion required in 4 cases, and fresh frozen plasma transfusion was done in 3 cases. Mean length of hospital stay was 14 days and average cost of cases was 2950 USD (11,140.16 TL) (Table 1).

Results 15 (1 female, 14 male) patients hospitalized for lower limp injury secondary to hoeing machine accidents. Mean age was 45.2 (1964 years). 12 patients admitted in spring and 3 patients in autumn. One patient died soon after admission secondary to femoral artery and vein rupture in the operating room. One patient had pelvic fracture. Tibial fracture was diagnosed in 9 patients. Femur fracture was seen in 2 patients. Peroneal nerve injury was diagnosed in 2 patients, tibialis posterior artery injury was seen in one patient.

Tablo 1. Demographic data and injury types gender

age

season

knee

additional injury

large bone

medium/ small

infection

operation

hospital

cost

session dislocation 1

male

spring

male

spring

male

spring

fracture

bone fracture

number

time

2553.0

peroneal nerve

left femur

25,228.21

dysfunction

diaphysis

extensive soft tissue

right femur

right patella

soft tissue

27,115.08

distal fibula

14.000

proximal fibula

19,915.77

bilateral tibia

4801.26

fibula

5343.72

distal fibula

osteomyelitis

25.000

10,554.64

3831.81

2800

peroneal nerve dysfunction

diaphysis and right tibia 4

male

spring

injury

diaphysis

soft tissue injury

tibia plato and pilon

male

autumn

bilateral

left lower limb

male

spring

male

autumn

right knee

bilateral lower limb

tibia

skin cuts

diaphysis

tibia

circulatory disorder diaphysis

male

autumn

diaphysis 9

male

spring

left knee

left tibia diaphysis

male

spring

raight lower limb open

right tibia

wounds

diaphysis

left lower limb crash

left tibia

male

spring

injury

diaphysis

male

spring

1500

male

spring

posterior tibial artery

left tibia

1212.0

cut

diaphysis

female

spring

500

male

spring

left knee

acl, pcl, mcl, lcl,

23041

14.46

11,140.16

posterolateral corner average

45.8

doi: 10.5455/medscience.2018.07.8910

Med Science 2019;8(1):7-10

of the patients (76%) were aged forty years and older and most of the patients were male (89.8%). According to our results 93.3 % of the patients were male and the mortality rate was 6.6%. All of our patients admitted to our department in April and October.

Figure 1. Open wound with patient after treatment

The correlation between age and injury rates were studied in previous studies [6]. Virtanen et al. [7] reported a correlation between only 50-54 age period and higher injury rates. Kogler et al. [8] reported that majority of injured farmers were over 40 years old (86%). Also Marsh et al. [9] stated that farmers/workers aged 65 years and older were at increased risk for machine related mortality and injuries. In our study mean age of patients was 45.28 years and although we could not assume a statistical significance because of small number of patients- older ages can be a risk factor for agricultural injuries. Visual impairment, gait and balance disturbances, osteoporosis, slowing of reaction time are all age related physiological changes and can lead accidents in farmers. According to our results hoe machine injuries are rare in female gender (6.6 %). This is similar with previous studies [10,8]. Kogler et al. [8] showed that most of agricultural accidents occurred in summer months which is also the primary harvest season in Turkey. But in our study 12 accidents were occurred in spring and 3 in autumn. In contrast to machines used for harvesting, hoeing machines are used in spring and autumn, which are appropriate seasons for hoeing the soil. So injuries related with hoeing machine occur in these seasons. Machines like hoeing machine or power-driven cultivators can cause serious lower extremity injuries that can result in amputation, severe nerve/vessel damages and death [11]. In our study open wounds, dysfunction of peroneal nerve, arterial injury and femur, tibia, patella or fibula fractures were diagnosed and subsequently treated, only one patient was suffered from crush injury and amputation was performed for this case. Soft tissue infection was another problem for agricultural injuries. In our case series, due to infectious state of the patients, multiple surgical operations were performed. Mean hospital stay is also tends to be longer in patients with infections. In our study mean hospital stay was 14 days, however for the infected cases mean length of hospital stay was 53 days, respectively.

Figure 2. Knee dislocation (2a) and vascular injury (2b)

Discussion Agricultural injuries have significant role on work related mortality and morbidity for all age groups and International Labor Organization (ILO) reported that the highest rate of mortality occurs in developing countries. Agricultural injuries are important cause of serious physical and psychological outcomes and economical burdens [4]. The demographics, mortality rate and admission period were similar with the literature. Von Essen et al. investigated medical records of 294 patients suffered from agricultural machine related injury in North Carolina between 2006-2010 years [5]. Overall mortality rate was 5.1% and most of these cases were emergency (68.4%). Most of the admissions were between April and September which is the period of main farming season in North Carolina. Majority

Knee dislocation is one of the important injuries about lower limp traumas. Knee dislocation can be overlooked during first examination in emergency settings however experienced orthopaedics can easily diagnose the dislocation. Also nerve injury/rupture with or without vascular trauma can accompany osteoarticular lesions. Previously Baque et al. [12] reported posterior dislocation of knee in 10 of 23 injured limbs following accidents related with power-driven cultivators. In our study we diagnosed 4 cases of knee dislocation (one bilateral, others are unilateral). As it is a very serious clinical condition, diagnosing the knee dislocation is really important. An extensive and careful first examination in the emergency department helps to identify the diagnosis and the magnitude of injury [13,14]. Because of possible vascular damage, blood loss, large tissue injury which can cause crush syndrome, a patient with lower limb injury caused by hoeing machine has to be urgently transported to medical center after doing first aid requirements. 9

doi: 10.5455/medscience.2018.07.8910

There are also some limitations of our study. One of them is the small number of the patients included in the study. Only including the lower extremity injuries, which require hospitalization, is another limitation. But up to now, there is not any published study about Middle Anatolia Region where most of the people deal with agriculture.

Med Science 2019;8(1):7-10

among African-American farm workers from Alabama and Mississippi. American J Epidemiology. 2000;152: 640-50. 3.

Unal HG, Yaman K, Gok A. Analysis of Agricultural Accidents in Turkey. J Agr Sci. 2008;14:38-45

Leigh JP, McCurdy SA, Schenker MB. Costs of occupational injuries in agriculture. Public Health Reports. 2002;116;235-48.

Von Essen SG, McCurdy SA. Health and safety risks in production agriculture. West J Med. 1998;169: 214-20.

Meyer RE, Hayes AM. Inpatient hospitalizations related to agricultural machine injuries in North Caroline, 2006-2010. N C Med J. 2011;72:488-91.

Conclusion

Most prevalent injury was tibia fracture. Simple precautions can be effective for preventing this kind of injuries. Meticulous examination is important as the rate of knee dislocation is high in these types of traumas.

Virtanen SV, Notkola V, Luukkonen R, et al. Work injuries among Finnish farmers: A national register linkage study 1996-1997. American J Ind Med. 2003;43:314-25.

Kogler R, Quendler E, Boxberger J. Occupational accidents with mowing machines in Austrian agriculture. Ann Agric Environ Med. 2015;22:137-41.

Marsh SM, Fosbroke DE. Trends of occupational fatalities involving machines, United States, 1992-2010. Am J Ind Med. 2015;58:1160-73.

Severity of lower extremity injuries caused by agricultural machinery is important. These injuries can be decreased with simple preventing precautions. Urgent transportation to a trauma center, careful physical and radiological examination in emergency room carefully, especially for open wounds, nerve/vascular damages are crucial for better clinical outcomes. It is important to remember that the rate of knee dislocation rate is high in such injuries.

Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Before the study, permissions were obtained from local ethical committee. Ali Gulec ORCID: 0000-0001-8265-825X Fatih Durgut ORCID: 0000-0001-5782-4842 Ali Ozdemir ORCID: 0000-0002-8835-9741 Ahmet Yildirim ORCID: 0000-0002-3953-091X Bahattin Kerem Aydin ORCID: 0000-0002-0973-3249

Reference 1.

ILO. 2000. Safety and health in agriculture. International Labour Conference, 88th Session, Geneva, June. Report VI (1), Sixth item on the agenda. Geneva, Switzerland: International Labour Office. p. 206-11. McGwin G, Enochs R, Roseman JM. Increased risk of agricultural injury

10. Momose Y, Suenaga T. Gender differences in the occurrence of nonfatal agricultural injuries among farmers in Fukuoka, Japan. J Rural Med. 2015;10:57-64. 11. Yılmaz E, Belhan O, Karakurt L, et al. Amputasyonların etyoloji, seviye ve yaş grupları açısından değerlendirilmesi. Joint Dis Rel Surg. 2006;2:79-84. 12. Baque P, Trojani C, Batt M, et al. Lower limb trauma caused by power-driven cultivators:report of 23 cases. J Trauma. 1998;45:485-8. 13. Akgun I, Aydingoz O, Ogut T. Complete Traumatic Dislocation of The Knee. Joint Dis Rel Surg. 1996:2;57-60. 14. Sevimli R, M. Korkmaz F, Bilal O. Results of treatment of tibial plafond fractures with articulated external fixation. Scientific Research and Essays. 2014:744-51.

Available online at www.medicinescience.org

ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):11-5

Correlation between homocysteine levels and stroke in patients with acute ischemic stroke Adnan Kirmit1, Aysegul Akagunduz Ege2, Ali Guctekin3, Mustafa Kemal Basarili4, 1Mujgan Ercan Karadag1

Harran University Medical Faculty, Department of Biochemistry, Sanliurfa, Turkey 2 Kulu State Hospital, Konya, Turkey 3 Ankara Numune Training and Research Hospital, Department of Biochemistry, Ankara, Turkey 4 Ministry of Health, Turkish Public Health Institution, Ankara, Turkey 1

Received 06 October2018; Accepted 18 November 2018 Available online 16.11.2018 with doi:10.5455/medscience.2018.07.8932 Copyright ÂŠ 2019 by authors and Medicine Science Publishing Inc. Abstract Ischemic strokes are mostly caused by atherosclerosis, and increased homocysteine levels are considered to play a role in atherosclerosis. The aim of this study was to investigate serum total homocysteine (tHcy) levels in the first 24 h of ischemic stroke patients and to analyze the correlation between tHcy levels and the clinical severity of ischemic stroke. The study included a total of 151 participants including a patient group of 83 patients diagnosed with acute ischemic stroke and a control group of 68 age- and gender-matched subjects with no history of ischemic vascular diseases between June 2006 and December 2007. Demographic characteristics of were recorded for each participant and stroke severity was assessed using the modified Rankin Scale (mRS) in each patient. Serum tHcy, vitamin B12, folic acid, and fibrinogen levels as well as platelet count and lipid profiles were measured for each participant. Serum tHcy levels were significantly higher and the folic acid levels were significantly lower in the patient group compared to the control group (p<0.001, p=0.009, respectively). A negative correlation was found between folic acid and serum tHcy levels and a moderately positive correlation was found between tHcy and age and total cholesterol and LDL cholesterol levels. The covariate analysis of the risk factors adjusted for tHcy indicated that the tHcy levels were significantly higher in the patient group compared to the control group. Additionally, no significant correlation was found between the homocysteine levels and the stroke severity. Serum tHcy level was increased in acute ischemic stroke. Moreover, although the increased tHcy level did not indicate stroke severity, it can be considered as a major risk factor for ischemic stroke. Keywords: Acute ischemic stroke, modified rankin coma scale, homocysteine, vascular risk factors

Introduction Stroke is the clinical manifestation of cerebrovascular diseases, generally described as an acute loss of neurological function because of an abnormal perfusion of brain tissue or bleeding. Strokes are mostly ischemic (87%), resulting from an arterial obstruction associated with a thrombus or embolus. However, hemorrhagic stroke (13%) results from the rupture or break of a blood vessel either within the primary brain tissue or the subarachnoid space [1]. Either ischemic or hemorrhagic, mortality from stroke accounts for 15.6% of the causes of death in the United States [2]. Stroke is the main reason of functional impairment in

patients older than 65 years. Within 6 months after stroke, 26% of the patients become dependent on daily living activities and 46% of them develop cognitive impairment. Stroke changes the lives of not only the patients but also their families and other caregivers. Therefore, it is important to be aware of modifiable and non-modifiable risk factors in the primary and/or secondary prevention of stroke [3]. The modifiable risk factors of ischemic stroke include hypertension, diabetes mellitus (DM), atrial fibrillation, smoking, hyperlipidemia, atherosclerosis, lack of physical activity, and obesity [4]. In addition to these risk factors, serum total homocysteine (tHcy) level has also been shown to be an important risk factor for ischemic stroke [5-10].

*Coresponding Author: Adnan Kirmit, Harran University Medical Faculty, Department of Biochemistry, Sanliurfa, Turkey E-mail: adnankirmit@yahoo.com

Hyperhomocysteinemia is an important risk factor for atherosclerosis. The prevalence of hyperhomocysteinemia is reported to be 20-30% in atherosclerosis and 18-42% in ischemic 11

doi: 10.5455/medscience.2018.07.8932

stroke, with a reported prevalence of 5-7% in the general population [11-13]. Homocysteine is a sulphur containing amino acids and is the precursor of methionine and cysteine. Folate and vitamin B12 are necessary for the conversion of Hcy to methionine, whereas vitamin B6 is necessary for the conversion of Hcy to cysteine [14]. Insufficiency of folate, vitamin B12, and vitamin B6 causes accumulation of Hcy. Hyperhomocysteinemia leads to a number of changes in vessel walls, namely including endothelial dysfunction caused by the induction of TNF-α and nitric oxide synthesis with proinflammatory effects [15]. Some studies have shown a relationship between tHcy and stroke while some others suggest that there is no such relationship or it is a weak relationship even if it exists [11]. Moreover, while some studies propose that tHcy is a predisposing factor for stroke, some others advocate that it is only an outcome of stroke [12]. On the other hand, tHcy has been shown to be elevated within the first hours before and after acute ischemic stroke [8,9]. Furthermore, it has been hypothesized that tHcy elevation is an acute phase-reactant of brain ischemia [16] and this hypothesis is further supported by the fact that no reduction has been achieved in stroke risk in the studies conducted to reduce tHcy levels by using vitamin supplementation [9]. In this study, we aimed to investigate serum tHcy levels in the first 24 h of ischemic stroke patients and to analyze the correlation between tHcy levels and the clinical severity of ischemic stroke. Material and Methods Study population The study included a total of 151 participants including a patient group of 83 patients diagnosed with acute ischemic stroke that were followed-up in the Neurology Clinics at Ankara Numune Education and Research Hospital between June 2006 and December 2007 and a control group of 68 age- and gender-matched subjects with no history of ischemic vascular diseases, no known cerebrovascular risk factors, and no clinical neurological deficits. None of the control subjects had a history of drug use that could affect the tHcy levels. All the participants were informed about the content of the study and gave a written consent before enrollment. The study was approved by Ankara Numune Education and Research Hospital Local Ethics Committee. Patients with subarachnoid hemorrhage, cerebral hemorrhage, intracranial tumors, thyroid and renal dysfunctions, cancer, hepatic failure and patients who had received any drugs within the last seven days before stroke that could affect the tHcy levels (e.g. multivitamins, niacin, methotrexate, tamoxifen, anticonvulsant, bile acid sequestrants, and nitric oxide anesthesia) were excluded from the study. All the participants underwent a detailed physical and neurological examination. On admission, the clinical severity of stroke was assessed in each patient using the modified Rankin Scale (mRS) [17]. Blood Sampling Fasting blood samples of the patients were collected after admission. The samples were placed in 10 mL red-topped serum tubes (Vacutainer, BD, NJ, USA) and then were centrifuged at 4,000 rpm for 8 min. Serum levels of total cholesterol, low-

Med Science 2019;8(1):11-5

density lipoproteins (LDL), high-density lipoproteins (HDL), and triglyceride were analyzed using an enzymatic method on an Aeroset 2000 autoanalyzer (Abbott, Illinois, USA) with compatible same-brand kits. Hemogram parameters were measured routinely using a Cell-DYN 3700 fully automatic hemocytometer (Abbott, Illinois, USA). The tHcy levels were measured using the highperformance liquid chromatography (HPLC) method on a prominence device (Shimadzu, Kyoto, Japan) with compatible RECIPE brand (RECIPE Chemicals, Munich, Germany) homocysteine kit as routinely. The reference range for tHcy was accepted as 5.5-17 μmol/L. Statistical Analysis Statistical analysis was performed using SPSS for Windows version 11.5 (SPSS Inc. Co., Chicago, IL, USA). Normal distribution of continuous variables was tested using the Kolmogorov-Smirnov test. Descriptives were expressed as mean ± standard deviation (SD) for continuous variables with normal distribution and as median (min-max) for those with non-normal distribution. In continuous variables, statistically significant differences between groups were determined using Student’s t-test for parametric variables and the Mann Whitney-U test for non-parametric variables. Correlations between groups were determined using the Pearson’s and Spearman’s correlation coefficients. Categorical variables were expressed as positive/negative and were compared using the Chi-Square test and Fisher’s exact test as needed. For continuous variables, statistically significant differences between the mRS scores and the tHcy levels were examined using One-Way ANOVA for parametric variables and the Kruskal-Wallis test for nonparametric variables. The analysis of covariance (ANCOVA) was used for comparing the tHcy levels between the two groups based on the analysis of the risk factors adjusted for tHcy. A p value of <0.05 was considered significant. Results The 151 participants included a patient group of 83 (39 female and 44 male) patients and a control group of 68 (37 female and 31 male) healthy volunteers. Mean age was 65.77 ± 13.39 (range, 24-87) years in the patient group and 62.12 ± 10.25 (range, 28-82) years in the control group. No significant difference was observed between the two groups with regard to age and gender (p>0.05). A history of hypertension was detected in 47 (56%), DM in 12 (14%), heart disease in 30 (36%), smoking in 27 (32%), and alcohol abuse in 7 (8%) patients (Table 1). Table 1. Demographic characteristics of the groups Patients (n=83)

Controls (n=68)

Age (years)

65.77 ± 13.39

62.11 ± 10.25

0.067

Gender (M/F)

44/39

23/45

0.364

Hypertension [n (%)]

47 (56.6)

23 (33.8)

0.005

DM [n (%)]

12 (14.5)

7 (10.3)

0.443

Heart disease [n (%)]

27 (32%)

Alcohol abuse [n (%)]

7 (8%)

Smoking [n (%)]

27 (32.53)

doi: 10.5455/medscience.2018.07.8932

Serum tHcy levels were significantly higher in the patient group compared to the control group (p<0.001). Folic acid levels were significantly lower in the patient group compared to the control group (p=0.009). No significant difference was found between the two groups with regard to total cholesterol, LDL, HDL, triglyceride,

Med Science 2019;8(1):11-5

vitamin B12, platelet count, hematocrit, and fibrinogen levels No significant difference was found between the two groups with regard to total cholesterol, LDL, HDL, triglyceride, vitamin B12, platelet count, hematocrit, and fibrinogen levels (Table 2). Table 3 presents the gender-based comparison of tHcy levels.

Table 2. Laboratory parameters of the groups Patients (n=83)

Controls (n=68)

tHcy (µmol/L)

18.75 (8.30-55)*

13.85 (7.60-23)*

<0.001***

Total cholesterol (mg/dL)

208.69±51.79**

202.64±44.43**

0.461

LDL (mg/dL)

137.14±41.14**

129.98±38.50**

0.288

Triglyceride (mg/dL)

121 (47-467)*

112(59-399)*

0,965

HDL (mg/dL)

42.77±11.53**

44.75±11.45**

0.305

Platelet count (103/mL)

264 (166-711)*

260,5(156-696)*

0.703

Fibrinogen (mg/dL)

438 (209-916)*

435 (190-850)*

0.652

41.14±6.02**

40.93±6.13**

0.836

241 (70-1053)*

271 (84-1083)*

0.849

4.6 (0.80-12.50)*

6.5 (3.80-12.70)*

0.009

Hematocrit (%) Vitamin B12 (pg/mL) Folic acid (ng/mL)

*Median (min-max) ** Mean±SD*** tHcy (µmol/L) (Unadjusted) Table 3. Comparison of serum tHcy levels between the genders tHcy (µmol/L)

Table 5. ANCOVA analysis

Male (n=67)

Female (n=84)

17.30 (7.60-55)*

14.93 (8.30-53)*

0.019

*Median (min-max)

Serum tHcy levels were moderately positively correlated with age, total cholesterol, and LDL levels and were moderately negatively correlated with vitamin B12 levels. No correlation was found between the tHcy levels and serum levels of fibrinogen, platelet count, hematocrit, HDL, folic acid, and triglyceride (Table 4). On the other hand, the covariate analysis of the risk factors adjusted for tHcy indicated that the tHcy levels were significantly higher in the patient group compared to the control group (Table 5). However, no significant correlation was found between the mRS scores and the tHcy levels in the patient group (Table 6). Table 4. Correlation between tHcy levels and demographic characteristics and laboratory parameters Parameters

Age

0.345

<0.001

Total cholesterol (mg/dL)

0.245

0.028

LDL (mg/dL)

0.243

0.030

Triglyceride (mg/dL)

0.075

0.510

HDL (mg/dL)

0.011

0.926

Platelet count (103/mL)

-0.120

0.297

Fibrinogen (mg/dL)

-0.133

0.261

Hematocrit (%)

0.086

0.455

Vitamin B12 (pg/mL)

-0.300

0.019

Folic acid (ng/mL)

-0.146

0.221

Age (years)

8.18

0.005

Group*

40.44

<0.001

Total cholesterol (mg/dL)

5.21

0.024

Group*

42.07

<0.001

LDL (mg/dL)

5.51

0.020

Group*

41.38

<0.001

Vitamin B12 (pg/mL)

6.08

0.016

Group*

22.27

<0.001

* tHcy (µmol/L) (Adjusted)

Discussion The present study found a significant difference between the patient and control groups with regard to serum tHcy levels [18.75 (8.30-55) μmol/L vs. 13.85 (7.60-23) μmol/L]. Similarly, a previous study reported that the tHcy levels were increased within the first 48 h of acute stroke [18]. Moreover, the Framingham study found a significant correlation between the tHcy levels and stroke incidence [19]. On the other hand, another study advocated that hyperhomocysteinemia is an independent risk factor for stroke and also noted that the stroke patterns in patients with hyperhomocysteinemia make the patients more prone to lesions typical of cerebral microangiopathy and to multiple infarctions compared to patients without hyperhomocysteinemia [20,21].

Table 6. Correlation between the mRS scores and tHcy levels in the patient group mRS Score tHcy

1 (n=5)

2 (n=12)

3(n=17)

4 (n=11)

5 (n=35)

17.40 (14.70-33.50)

19.25 (13.20-37)

17.60 (9-35.80)

18.30 (12.80-38)

20.50 (8.30-55)

0.674*

*Kruskal-Wallis Test

doi: 10.5455/medscience.2018.07.8932

Med Science 2019;8(1):11-5

Previous studies investigating gender-based differences in tHcy levels reported that the tHcy levels were significantly increased in males compared to females and the tHcy levels in females increased and almost reached the levels assessed for males in the postmenopausal period [21,22]. Similarly, we also found that the tHcy levels were higher in males compared to females (Table 3). Previous reports also suggested that the tHcy levels increase in direct proportion to age [21,22]. Similarly, we also detected a positive correlation between age and tHcy levels (Table 4).

severity of stroke, it can be considered as a major risk factor for ischemic stroke.

In a previous study, increased tHcy levels were reported as an independent risk factor for atherosclerosis in the presence of other risk factors such as hypertension, smoking, and DM [10]. However, another study revealed that there was no correlation between tHcy levels and patient characteristics including age, gender, stroke subtype and traditional stroke risk factors in patients with stroke [23]. Similarly, we also found no significant difference in the tHcy levels of patients with and without a history of hypertension, DM, heart disease, smoking, and alcohol abuse and a family history of stroke.

Adnan Kirmit ORCID: 0000-0003-2799-8416 Aysegul Akagunduz Ege ORCID: 0000-0003-1999-8715 Ali Guctekin ORCID: 0000-0003-1947-0742 Mustafa Kemal Basarili ORCID: 0000-0001-7712-2063 Mujgan Ercan Karadag ORCID: 0000-0002-9291-4197

Literature suggests that there is a significant negative correlation between serum folate and tHcy levels in patients with acute ischemic stroke [24,25]. However, there are some other studies suggesting that the tHcy-lowering therapy including vitamin B12, vitamin B6, and folic acid supplementation was not effective on the vascular outcomes of the patients with stroke [26,27]. In our study, we found a negative correlation between the tHcy and vitamin B12 levels and a positive correlation between the tHcy levels and age and total cholesterol and LDL levels. In addition, the covariate analysis of the risk factors adjusted for tHcy indicated that the tHcy levels were significantly higher in the patient group compared to the control group (Table 5). It has been suggested that there is no correlation between the tHcy levels and the neurological examination scores, infarct localization, and other risk factors [28,29]. Moreover, a previous study also noted that there was no significant correlation between the tHcy levels and the mRS scores [21]. Additionally, another study evaluated 113 patients with acute ischemic stroke and reported that no correlation was found between the tHcy levels and the functional outcomes obtained during rehabilitation after acute ischemic stroke [30]. In our study, we found similar results as there was no significant correlation between the tHcy levels and the clinical severity of stroke in the patient group as determined with by the mRS scores. Our study was limited in several ways. First, the prognosis of the patients could have been followed up and their tHcy levels could have been assessed at regular intervals in later periods, which could have provided further information regarding the predictive value of tHcy in the determination of the prognosis of the patients with acute ischemic stroke. Second, regular assessment of tHcy levels during the convalescent period after stroke could have shed light on the controversy of whether elevated tHcy levels are a cause or a result of stroke. Conclusion In conclusion, tHcy level was increased in acute ischemic stroke. Moreover, although the increased tHcy level does not indicate the

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Sidney S, Sorel ME, Quesenberry CP. Comparative Trends in Heart Disease, Stroke, and All-Cause Mortality in the United States and a Large Integrated Healthcare Delivery System. Am J Med. 2018;131:829-36.

Meschia JF, Bushnell C, Boden-Albala B. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:3754-832.

Auriel E, Gur AY, Uralev O. Characteristics of first ever ischemic stroke in the very elderly: profile of vascular risk factors and clinical outcome. Clin Neurol Neurosurg. 2011;113:654-7.

Foody JM, Milberg JA, Robinson K. Homocysteine and lipoprotein (a) interact to increase CAD risk in young men and women. Arterioscler Thromb Vasc Biol. 2000;20:493-9.

Poddar R, Sivasubramanian N, DiBello PM. Homocysteine induces expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human aortic endothelial cells: implications for vascular disease. Circulation. 2001;103:2717-23.

Clarke R, Armitage J, Lewington S. Homocysteine-lowering trials for prevention of vascular disease: protocol for a collaborative meta-analysis. Clin Chem Lab Med. 2007;45:1575-81.

Virtanen JK, Voutilainen S, Happonen P. Serum homocysteine, folate and risk of stroke: Kuopio ischaemic heart disease risk factor (KIHD) study. Eur J Prev Cardiol. 2005;12:369-75.

Lonn E, Yusuf S, Arnold M. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354:1567-77.

10. Newman GC, Bang H, Hussain SI. Association of diabetes, homocysteine, and HDL with cognition and disability after stroke. Neurology. 2007;69:2054–62. 11. Hankey GJ, Eikelboom JW. Homocysteine levels in patients with stroke. CNS drugs. 2001;15:437-43. 12. Perry I, Morris R, Ebrahim S. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. The Lancet. 1995;346:1395-8. 13. Overview of homocysteine https://www.uptodate.com/contents/overview-ofhomocysteine acces date 12.11.2018. 14. Hoffer LJ. Homocysteine remethylation and trans-sulfuration. Metabolism. 2004;53:1480-3. 15. Badner NH, Spence JD. Homocyst (e) ine, nitrous oxide and atherosclerosis. Best Pract Res Clin Anaesthesiol. 2001;15:185-93. 16. Sönmezler A, Ulaş T, Dal MS. Plasma Homocysteine Levels in Patients with

doi: 10.5455/medscience.2018.07.8932 Acute Ischemic Stroke: A Cross-Sectional Study. Turkiye Klinikleri J Med Sci. 2013;33:384-8. 17. Banks JL, Marotta CA. Outcomes validity and reliability of the modified Rankin scale: implications for stroke clinical trials: a literature review and synthesis. Stroke. 2007;38:1091-6. 18. Pezzini A, Del Zotto E, Padovani A. Homocysteine and cerebral ischemia: pathogenic and therapeutical implications. Curr Med Chem. 2007;14:249-63. 19. Bostom AG, Rosenberg IH, Silbershatz H. Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham Study. Ann Intern Med. 1999;131:352-5.

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24. Tanne D, Haim M, Boyko V. Prospective study of Chlamydia pneumoniae IgG and IgA seropositivity and risk of incident ischemic stroke. Cerebrovasc Dis. 2003;16:166-70. 25. Kuo YS, Chang JY, Wang YP. Significantly higher frequencies of hemoglobin, iron, vitamin B12, and folic acid deficiencies and of hyperhomocysteinemia in patients with Behcetâ&#x20AC;&#x2122;s disease. J Formos Med Assoc. 2018;117:932-8. 26. Wang X, Qin X, Demirtas H. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. The Lancet. 2007;369:1876-82. 27. Toole JF. Vitamin intervention for stroke prevention. J Neurol Sci. 2002;203:121-4.

20. Evers S, Koch H-G, Grotemeyer K-H. Features, symptoms, and neurophysiological findings in stroke associated with hyperhomocysteinemia. Arch Neurol. 1997;54:1276-82.

28. Iso H, Moriyama Y, Sato S. Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese. Circulation. 2004;109:2766-72.

21. Howard VJ, Sides EG, Newman GC. Changes in plasma homocyst (e) ine in the acute phase after stroke. Stroke. 2002;33:473-8.

29. Dhamija RK, Gaba P, Arora S. Homocysteine and lipoprotein (a) correlation in ischemic stroke patients. J Neurol Sci. 2009;281:64-8.

22. Hankey GJ, Eikelboom JW. Homocysteine and stroke. Curr Opin Neurol. 2001;14:95-102.

30. Mizrahi EH, Fleissig Y, Arad M. Plasma homocysteine level and functional outcome of patients with ischemic stroke. Arch Phys Med Rehabil. 2005;86:60-3. .

23. Bushnell CD, Goldstein LB. Homocysteine testing in patients with acute ischemic stroke. Neurology. 2002;59:1541-6.

Available online at www.medicinescience.org

ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):16-20

Is there any relationship of postoperative atrial fibrillation with the use of blood products and postoperative hemoglobin levels in patients undergoing coronary artery bypass grafting? Ahmet Yuksel1, Yusuf Velioglu2, Mehmet Ergun Tecimer3, Irem Iris Kan3, Murat Bicer3, Orcun Gurbuz4, Mustafa Tok3, Bulent Ozdemir3, Nofel Ahmet Binicier1, Isik Senkaya Signak3 1 Bursa State Hospital, Department of Cardiovascular Surgery, Bursa, Turkey Abant Izzet Baysal University Faculty of Medicine, Department of Cardiovascular Surgery, Bolu, Turkey, 3 Uludag University Faculty of Medicine, Department of Cardiovascular Surgery Bursa, Turkey

Received 04 June 2018; Accepted 23 July 2018 Available online 01.08.2019 with doi: 10.5455/medscience.2018.07.8861 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The goal of this study was to assess the relationship of postoperative atrial fibrillation (AF) with the use of blood products and postoperative hemoglobin levels following coronary artery bypass grafting (CABG). Eighty patients undergoing isolated CABG from June 2013 to December 2013 in our institution were included in this study, and divided into two groups that contain 40 patients according to their postoperative blood hemoglobin levels in this prospective study. In Group 1 and 2, there were patients that whose postoperative hemoglobin levels were below 10 g/dL and above 10 g/dL, respectively. Groups were compared with each other according to the use of blood products and occurrence of AF, then the relationship between use of blood products and occurrence of AF was analyzed. Moreover, patients that occur postoperative AF and patients that do not occur postoperative AF were compared with each other; thus, risk factor analysis for postoperative AF were performed. Postoperative AF was observed in 12 (30%) patients in Group 1 (mean age: 62.0±9.6 years, 24 male) and 7 (17.5%) in Group 2 (mean age: 60.3±9.0 years, 27 male), but this difference was not found to be statistically significant. When patients that occurred AF and did not occur AF were compared, according to the number of patients that had received blood products, the patients that had occurred AF had received more blood products than the patients whom had not occurred AF although again this difference was not statistically significant. In risk factor analysis; advanced age, low ejection fraction, obesity and the non-use of preoperative beta blocker were found to be risk factors associated with postoperative AF. In accordance with this study, the use of blood products and postoperative hemoglobin levels do not have an important impact on AF that occurs in patients undergoing isolated CABG. However, further studies with larger patient series are needed to elucidate this relationship. Keywords: Atrial fibrillation, blood transfusion, hemoglobin, coronary artery bypass grafting

Introduction Atrial fibrillation (AF) is the most commonly observed dysrhythmia following coronary artery bypass grafting (CABG) surgery. Its incidence following CABG varies between 10% and 40% [1,2]. Although postoperative atrial fibrillation (POAF) is seen as a harmless problem, it is related to increased postoperative morbidity, mortality, and healthcare cost. POAF is accompanied with increased cerebrovascular accident, cardiac insufficiency and the decreased hemodynamic performance of left ventricle [3-5]. The etiology and risk factors of AF are still controversial. Although various risk factors are identified for AF in the literature, advanced age is the only common risk factor reported in all the literature [6,7]. The effects of the use of blood products and postoperative blood hemoglobin levels in the etiology of AF that occurs after *Coresponding Author: Ahmet Yuksel, Bursa State Hospital, Department of Cardiovascular Surgery, Bursa, Turkey, E-mail: ahmetyuksel1982@mynet.com

CABG surgery are debated in recent years and continue to be debated. Although the relationship between the occurrence of AF and especially the use and transfusion of blood products is expressed in almost all studies [8-11], there are only few studies that do not indicate about this relationship [12,13]. The goal of this present study was to evaluate the relationship between the use of blood products and postoperative hemoglobin levels and AF that occurs in patients that were performed CABG for coronary artery disease (CAD). Material and Methods Ethical Declaration The study protocol was approved by the local ethics committee with the decision number of 2013-11/22 at the date of June 18, 2013. The study was conducted in accordance with the principles of the Declaration of Helsinki. All patients were informed about the study, and their informed consent forms were obtained before surgery. 16

doi: 10.5455/medscience.2018.07.8861

Study Population and Design Between June 2013 and December 2013, a total of 80 patients undergoing isolated CABG for CAD in our institution were included in this study. Data of patients were collected, and prospectively analyzed. These patients were divided into two groups of 40 patients according to their postoperative hemoglobin levels. They were grouped as whose postoperative hemoglobin level was below 10 g/dl (Group 1) and whose postoperative hemoglobin level was 10 g/dl and above 10 g/dl (Group 2) during their postoperative follow-up. Exclusion criteria included patients who had a history of arrhythmia, patients who underwent emergency CABG, and patients who had redo cardiac surgery or additional surgery. Patients in both groups were compared with each other according to the use of blood products and the occurrence POAF and then the relationship between the use of blood products and the occurrence of AF was analyzed. By this means, risk factor analysis for POAF was performed and the postoperative follow-up results were compared. For this present study, POAF was defined as AF of any duration in the postoperative period, which requiring medical treatment (beta-blocker, calcium channel blocker, amiodarone, anticoagulants, etc.). Surgical Approach The surgical approach to be applied was planned a day before the surgery; nevertheless, the final decision regarding the surgical technique was made following the evaluation of coronary anatomy and ascending aorta during the surgery. In Group 1, in seventeen patients beating heart coronary bypass surgery technique without cardiopulmonary bypass (CPB), while twenty three patients conventional coronary bypass surgery technique with CPB was performed. In Group 2, in sixteen patients beating heart coronary bypass surgery technique, while twenty four patients conventional coronary bypass surgery was performed. Postoperative Monitoring All patients were transferred to the intensive care unit (ICU) after the operation. Patients were monitored continuously using a cardiac rhythm monitor during ICU follow-up. Daily routine electrocardiography (ECG) recording was taken from all patients during the hospital stay both in ICU and clinic. Additional ECG recording was taken if a patient complained clinical signs of arrhythmia such as palpitation. In ICU and clinical follow-up, the complete blood counts and hemoglobin levels of all patients that were controlled at least once in a day. Patients were transfused when the patients’ hemoglobin levels < 8 g/dl or hematocrit value < 24%. Statistical Analysis All statistical analyses were conducted out using the Statistical Package for Social Sciences (SPSS) program (version 18.0, SPSS, Chicago, Illinois, USA). Whether the data were normally distributed or not was tested by Shapiro-Wilk test. While comparing the two groups; the independent sample t-test was applied for the variables that were distributed normally, and Mann-Whitney U test was applied for the variables that were not distributed normally. The variables that fit to the normal distribution were presented as mean ± standard deviation and for the variables that were not fit were presented as median, minimum and maximum values. For the categorical variables, the n and % values were presented and for the comparison, the test types applied to them were Pearson chi-square test, Freeman-Halton chi-square test and Fisher’s exact test. A p value <0.05 was considered statistically significant.

Medicine Science 2019;8(1):16-20

Results By the evaluation of the two groups which have 40 patients, POAF was observed in 12 (30%) and 7 (17.5%) patients in Group 1 (mean age 62.0±9.6 years, 29 male) and Group 2 (mean age 60.3±9.0 years, 32 male), respectively. However, comparing the two groups, no statistically significant difference was found (p>0.05). In Group 1 to 36 patients (90%), and in Group 2 to 21 patients (52.5%) at least one unit of blood was transfused, and Group 1 was received a total amount of 81 units of blood transfusion, while Group 2 was received 46 units. In Group 1, 13 patients received 1 unit of blood transfusion, 8 patients received 2 units, 10 patients received 3 units, 4 patients received 4 units, and 1 patient received 6 units. In Group 2, 3 patients received 1 unit of blood transfusion, 11 patients received 2 units, and 7 patients received 3 units. Considering each group’s amount of patients that received blood transfusion and the usage of total amount of blood transfusion units, it was appeared that the two groups have a significant statistical difference. Demographic features and comorbidities of patients of each groups are shown in Table 1, and intraoperative data of patients are shown in Table 2. When comparing preoperative and intraoperative data of two groups; there were no statistically significant differences between two groups, and the groups were statistically similar. Postoperative data of patients are shown in Table 3. Among postoperative data of patients, according to lengths of ICU stay, lengths of hospital stay, decline in postoperative average hemoglobin level were statistically significant in terms of the number of patients in which blood product was used and the amount of total used blood product (p<0.05). Table 1. Preoperative demographic features and comorbidities of patients Age, years

Group 1

Group 2

P value

62.0±9.6

60.3±9.0

0.425

Female / Male

11 / 29

8 / 32

0.599

LMCA disease

4 (10%)

3 (7.5%)

1.000

Hypertension

29 (72.5%)

21 (52.5%)

0.106

Hyperlipidemia

16 (40%)

19 (47.5%)

0.652

Diabetes mellitus

21 (52.5%)

15 (37.5%)

0.169

Smoking

20 (50%)

21 (52.5%)

1.000

Alcohol use

3 (7.5%)

1.000

COPD

4 (10%)

7 (17.5%)

0.516

Carotid artery disease

10 (25%)

9 (22.5%)

1.000

Renal dysfunction

5 (12.5%)

4 (10%)

1.000

History of CVE

3 (7.5%)

1.000

History of previous PCI

8 (20%)

7 (17.5%)

1.000

Ejection fraction < 50%

14 (35%)

9 (22.5%)

0.123

11 (27.5%)

8 (20%)

0.599

27.8±3.9

26.8±3.8

0.241

29 (72.5%)

0.474

Obesity Body mass index, kg/m2 Preoperative beta blocker use

25 (62.5%)

Mean hemoglobin levels, g/dl 12.6±1.8 12.8±1.5 0.566 COPD: Chronic obstructive pulmonary disease, CVE: Cerebrovascular event, LMCA: Left main coronary artery, PTCA: Percutaneous coronary intervention

doi: 10.5455/medscience.2018.07.8861 Table 2. Intraoperative data of patients

Table 4. Data of patients in whom POAF occurred and did not occur Group 1

Group 2

P value

LITA use

40 (100%)

39 (97.5%)

1.000

Mean number of distal bypass

2.73±0.89

2.56±0.91

0.814

Aortic cross clamping time, minutes

56.0±11.5

59.5±11.9

0.352

98±24.0

0.838

217.1±46.8

0.896

Total CPB time, minutes

95±21.1

Total operation time, minutes

Medicine Science 2019;8(1):16-20

231.5±50.3

CPB: Cardiopulmonary bypass, LITA: Left internal thoracic artery

Table 3. Postoperative data of patients

POAF(+) [n:19]

POAF(-) [n:61]

P value

66.5±8.4

59.4±8.9

0.003

Female / Male

7 / 12

12 / 49

0.136

LMCA disease

2 (10.5%)

5 (8.2%)

0.668

Hypertension

12 (63.2%)

38 (62.3%)

1.000

Diabetes mellitus

11 (57.9%)

21 (34.4%)

0.120

Chronic obstructive pulmonary disease

5 (26.3%)

6 (9.8%)

0.120

Renal dysfunction

2 (10.5%)

8 (13.1%)

1.000

History of previous PCI

3 (15.8%)

12 (19.7%)

1.000

Ejection fraction <50%

10 (52.6%)

13 (21.3%)

0.021

Obesity

9 (47.4%)

10 (16.4%)

0.011

Body mass index, kg/m2

29.6±4.2

26.8±3.6

0.029

Preoperative beta blocker use

7 (36.8%)

47 (77%)

0.003

Ventilation time, hours

8.1±1.9

7.2±2.8

0.199

8 (42.1%)

18 (29.5%)

0.457

Age, years

Group 1

Group 2

P value

15 (37.5%)

11 (27.5%)

0.474

IABP requirement

1 (2.5%)

1.000

Ventilation time, hours

8.0±2.6

7.2±2.4

0.155

Re-intubation

1 (2.5%)

0 (0%)

1.000

Cerebrovascular event

2 (5%)

0 (0%)

0.494

Wound infection

4 (10%)

2 (5%)

0.675

Inotrope requirement

Pneumonia

1 (2.5%)

1.000

IABP requirement

0 (0%)

1 (1.6%)

1.000

Pneumothorax

0 (0%)

4 (10%)

0.116

Transfused patients

16 (84.2%)

41 (67.2%)

0.255

Sternal dehiscence

2 (5%)

0 (0%)

0.494

Mean postoperative hemoglobin level, g/dl

9.77±1.35

10.48±1.44

0.066

Mediastinitis

0 (0%)

>0.05

Mean length of ICU stay [range], days

2 [1-5]

1 [1-4]

0.008

GIS complications

0 (0%)

1 (2.5%)

1.000

7 [6-21]

5 [1-19]

0.022

Renal dysfunction

5 (12.5%)

1.000

Mean length of hospital stay [range], days

0 (0%)

>0.05

12 (30%)

7 (17.5%)

0.293

Arrhythmias other than AF

11 (27.5%)

8 (20%)

0.599

Length of ICU stay, days

1.80±1.15

1.22±0.77

0.010

Length of hospital stay, days

7.37±4.15

5.80±2.65

0.014

Decline in mean hemoglobin levels, g/dl

5.25±1.68

2.71±1.41

0.041

Transfused patients

36 (90%)

21 (52.5%)

0.001

1 (2.5%)

0 (0%)

1.000

Inotrope requirement

Deep vein thrombosis POAF

Total amount of used blood products, units Mortality

AF: Atrial fibrillation, GIS: Gastrointestinal system, IABP: Intraaortic balloon pump, ICU: Intensive care unit, POAF: Postoperative atrial fibrillation

For the purpose of risk analysis of POAF, patients in which POAF occurred were compared with patients in whom POAF did not occur. Advanced age, low ejection fraction, obesity and the nonuse of preoperative beta blockers were found to be statistically significant factors associated with POAF (p<0.05). In addition, ICU stay and the duration of hospital stay in patients in which POAF occurred were longer than patients in whom POAF did not occur. Data of patients with AF and non-AF postoperatively are shown in Table 4.

IABP: Intraaortic balloon pump, ICU: Intensive care unit, LMCA: Left main coronary artery, POAF: Postoperative atrial fibrillation, PCI: Percutaneous coronary intervention

Discussion Postoperative atrial fibrillation is one of the frequent complications following CABG. AF is a complication that increases mortality and morbidity because of stroke, heart failure, myocardial infarction (MI), thromboembolism, bleeding due to anticoagulation and re-hospitalization [3,14]. These patients require more treatment cost, drug use and nursing service. Therefore, it is important to prevent this cardiac arrythmia and develop optimal strategies for its treatment [15]. In early studies, POAF was defined as a temporary clinical condition, and there were insufficient knowledge about its short and long term effects. However, in more recent studies, effects of POAF on mortality and morbidity were evaluated extensively. It causes prolonged ICU and hospital stay, and leads to the problems for not only patients but also medical staff [14-16]. After cardiac surgery, AF usually occurs at postoperative 2nd and 3rd days. Although POAF is still considered as a ‘’benign phenomenon’’ from many surgeons, it can be also associated with increased cerebrovascular event (CVE), heart failure, and left ventricular hemodynamic performance decrease. After cardiac surgery, 18

doi: 10.5455/medscience.2018.07.8861

patients that have AF have more CVE incidence than patients that do not during hospitalization [4]. AF may also cause hypotension and pulmonary edema. By returning the sinus rhythm, there is a significant recovery on cardiac index. In some studies, even though the level of disease is recovered, patients that have AF have more ICU stay and it is estimated that for each patient that has AF hospital spending is 10.000-11.000 American dollar [17,18]. In this study, we assessed the relationship between the use of blood products and postoperative hemoglobin levels and AF that occurs in patients who underwent CABG. In the literature, the first studies that show the relationship between AF and anemia were applied in 1970s. In a case report, it is shown that AF returns its normal sinus rhythm by blood transfusion to a patient that has AF and a serious anemia and by increasing hemoglobin levels [19]. In most of studies that evaluate the effect of blood hemoglobin levels on AF, it is observed that low hemoglobin levels, anemia, blood loss increase the rate of AF by doing sympathetic system activation. In a study performed by Houge and colleagues [20], it was shown that among risk factors of AF that occurs after cardiac surgery, there was also presence of postoperative anemia that increased the occurrence of reentry that is the mechanism of AF occurrence by the stimulation of sympathetic nervous system. In a study performed by Chelazzi and colleagues [21] that is a review on the occurrence of POAF, it was indicated that anemia, loss of blood and volume could play a role in the occurrence of AF by increasing sympathetic innervation and doing direct cardiac stimulation. However, in limited number of studies such as Auer and colleagues’ study [13], and Ascione and colleagues’ study [22], it was found that there was no significant impact of anemia, blood loss and low hemoglobin levels on the occurrence of AF after cardiac surgery. In this regard, the results of these two studies that evaluate the risk factors of AF that occurs after cardiac surgery show similarities with our study that evaluates the relationship between the occurrence of POAF and anemia and low hemoglobin levels. In almost all studies in the literature, a significant relationship was determined between the occurrence of POAF and the use of blood products and transfusion. Namely, blood transfusion especially transfusion of erythrocyte suspension might strongly be associated with occurrence of POAF after cardiac surgery. In a study performed by Koch and colleagues [8] in which a total of 5841 patients underwent isolated CABG with or without valve replacement, it was found that blood transfusion was associated with the increased POAF risk. In a study performed by Sood and colleagues [10], erythrocyte transfusion in perioperative period was reported to be an important risk factor with a two-fold increase to occurrence of POAF. In a prospective study performed by Choi and colleagues [11] that included 315 off-pump CABG patients, it was similarly reported that erythrocyte transfusion was an important risk factor on the occurrence of POAF. Additionally, in the study performed by Straus and colleagues [23] in which CABG surgery was performed to 140 consecutive patients, and in another study performed by Topal and colleagues [24], it was found that blood product transfusion was the risk factor of POAF. In Gerber’s study [9], in patients in which cardiac surgery was performed, the risk of blood transfusion was analyzed and the occurrence of AF is indicated as transfusion-related cardiac complication. In our study, at least one or more unit blood product was transfused to patients that had low level of postoperative hemoglobin (36 and 21 patients

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were transfused at least one or more unit blood in Group 1 and 2, respectively). In addition, the number of total blood product transfusion that was made to all patients in each group was much more in the group that has patients that have low hemoglobin level (Totally 81 and 46 units of blood product were transfused in Group 1 and 2, respectively). Between two groups, these differences of the number of patients in which blood products were used and total use of blood products were also statistically significant. Although we wanted to avoid the use of blood products as much as possible because of the avoidance of a possible transfusion reaction, it was apparent that this difference was higher in the group that has low hemoglobin level arises from the need to replace low hemoglobin levels. Additionally, when patients in which POAF occurs compared with in which POAF does not occur according to the number of patients in which blood products were used, at least one unit blood product was used in 84% (n:16/19) of patients in which POAF occurs and 67% (n:41/61) of patients in which POAF does not occur, but this difference was not found to be statistically significant. In only a limited number of studies, it was not demonstrated the clear relationship between the use of blood products and the occurrence of POAF. As in Murphy and colleagues’ study [12], the impacts of the use of blood products in cardiac surgery patients were evaluated in terms of mortality, postoperative morbidity and cost, and it was not demonstrated the clear relationship between the use blood products and the occurrence of POAF. In also our study, the patients in whom POAF occurs were compared with the patients in whom POAF does not occur according to the use of blood products. Although the use of blood products was observed higher in the patients in whom POAF occurs, this difference was not found to be statistically significant. In this regard, our study was similar to this study. Several risk factors that are responsible for the occurrence of POAF are defined in the literature. Within these, advanced age is strongest risk factor. Furthermore, some factors such as history of previous AF, low EF, high EuroSCORE score, chronic obstructive pulmonary disease, pulmonary hypertension, left atrial diameter, and prolonged mechanical ventilation time can be associated with the occurrence of POAF [25-27]. In also our study, the patients in which POAF occurs were compared with the patients in whom POAF does not occur and the analysis of risk factors was performed according to the occurrence of POAF. Advanced age, low EF, obesity, and not using preoperative beta blocker were found to be risk factors associated with occurrence of POAF. In addition, the lengths of ICU and hospital stay were longer in patients whom POAF occurs than the patients which POAF does not occur. Main limitations of this present study were the small sample sizes in the groups and to be limited on evaluated data. Another important limitation was comparing the groups in off-pump and on-pump cases without subdividing them. Conclusion In accordance with this study, we deduced that there is no relationship of POAF with the use of blood products and postoperative hemoglobin levels in patients undergoing CABG. When all data are though of as together, more prolonged studies and broader patient participation are necessary to identify the reasons, risk factors, ways of protection and appropriate treatment strategies of POAF. 19

doi: 10.5455/medscience.2018.07.8861

Ahmet Yuksel ORCID:0000-0003-0021-6509 Yusuf Velioglu ORCID:0000-0003-4709-4705 Mehmet Ergun Tecimer ORCID:0000-0001-9617-7561 Irem Iris Kan ORCID:0000-0002-1600-9531 Murat Bicer ORCID:0000-0002-9280-086X Orcun Gurbuz ORCID:0000-0001-8553-7939 Mustafa Tok ORCID:0000-0003-2985-1709 Bulent Ozdemir ORCID:0000-0001-5337-9470 Nofel Ahmet Binicier ORCID:0000-0001-8857-2596 Isik Senkaya Signak ORCID:0000-0003-4030-7827 Competing interests The authors declare that they have no competing interest. Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval The study protocol was approved by the local ethics committee with the decision number of 2013-11/22 at the date of June 18, 2013.

References 1.

Bohatch Júnior MS, Matkovski PD, Di Giovanni FJ, et al. Incidence of postoperative atrial fibrillation in patients undergoing on-pump and off-pump coronary artery bypass grafting. Rev Bras Cir Cardiovasc. 2015;30:316-24.

Polat A, Şahin İ, Yücel C, et al. Coronary vasculature and postoperative atrial fibrillation: a risk factor analysis. Turk Gogus Kalp Dama. 2013;21:567-73.

Mariscalco G, Klersy C, Zanobini M, et al. Atrial fibrillation after isolated coronary surgery affects late survival. Circulation. 2008;118:1612-8.

Saxena A, Dinh DT, Smith JA, et al. Usefulness of postoperative atrial fibrillation as an independent predictor for worse early and late outcomes after isolated coronary artery bypass grafting (multicenter Australian study of 19,497 patients). Am J Cardiol. 2012;109:219-25.

Erdil N, Kaynak M, Dönmez K, et al. Nebivolol in preventing atrial fibrillation following coronary surgery in patients over 60 years of age. Rev Bras Cir Cardiovasc. 2014;29:581-7.

Zaman AG, Archbold RA, Helft G, et al. Atrial fibrillation after coronary artery bypass surgery: a model for preoperative risk stratification. Circulation. 2000;101:1403-8. Mariscalco G, Engström KG, Ferrarese S, et al. Relationship between atrial histopathology and atrial fibrillation after coronary bypass surgery. J Thorac Cardiovasc Surg. 2006;131:1364-72.

Koch CG, Li L, Van Wagoner DR, et al. Red cell transfusion is associated with an increased risk for postoperative atrial fibrillation. Ann Thorac Surg. 2006;82:1747-56.

Gerber DR. Risks of packed red blood cell transfusion in patients undergoing cardiac surgery. J Crit Care. 2012;27:1-9.

10. Sood N, Coleman CI, Kluger J, et al. The association among blood transfusions, white blood cell count, and the frequency of post-cardiothoracic surgery atrial fibrillation: a nested cohort study from the Atrial Fibrillation Suppression Trials I, II, and III. J Cardiothorac Vasc Anesth. 2009;23:22-7. 11. Choi YS, Shim JK, Hong SW, et al. Risk factors of atrial fibrillation following

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off-pump coronary artery bypass graft surgery: predictive value of C-reactive protein and transfusion requirement. Eur J Cardiothorac Surg. 2009;36:838-43. 12. Murphy GJ, Reeves BC, Rogers CA, et al. Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation. 2007;116:2544-52. 13. Auer J, Weber T, Berent R, et al. Risk factors of postoperative atrial fibrillation after cardiac surgery. J Card Surg. 2005;20:425-31. 14. Khan MF, Wendel CS, Movahed MR. Prevention of post-coronary artery bypass grafting (CABG) atrial fibrillation: efficacy of prophylactic betablockers in the modern era: a meta-analysis of latest randomized controlled trials. Ann Noninvasive Electrocardiol. 2013;18:58-68. 15. Dunning J, Treasure T, Versteegh M, et al; EACTS Audit and Guidelines Committee. Guidelines on the prevention and management of de novo atrial fibrillation after cardiac and thoracic surgery. Eur J Cardiothorac Surg. 2006;30:852-872. 16. Filardo G, Hamilton C, Hebeler RF Jr, et al. New-onset postoperative atrial fibrillation after isolated coronary artery bypass graft surgery and long-term survival. Circ Cardiovasc Qual Outcomes. 2009;2:164-9. 17. Onk OA, Erkut B. Is the preoperative administration of amiodarone or metoprolol more effective in reducing atrial fibrillation: After coronary bypass surgery? Medicine (Baltimore). 2015;94:e1576. 18. Frustaci A, Chimenti C, Bellocci F, et al. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation. 1997;96:1180-4. 19. Buxbaum J, Furgerson W. Atrial fibrillation in severe anemia. JAMA. 1970;212:1958-9. 20. Hogue CW Jr, Creswell LL, Gutterman DD, et al. American College of Chest Physicians. Epidemiology, mechanisms, and risks: American College of Chest Physicians guidelines for the prevention and management of postoperative atrial fibrillation after cardiac surgery. Chest. 2005;128:9S-16S. 21. Chelazzi C, Villa G, De Gaudio AR. Postoperative atrial fibrillation. ISRN Cardiol. 2011;2011:203179. 22. Ascione R, Caputo M, Calori G, et al. Predictors of atrial fibrillation after conventional and beating heart coronary surgery: A prospective, randomized study. Circulation. 2000;102:1530-5. 23. Straus S, Kacila M, Omerbasic E, et al. Atrial fibrillation and coronary bypass surgery - what can be risk factors for its’ appearance? Bosn J Basic Med Sci. 2010;10:78-82. 24. Topal AE, Eren MN. Predictors of atrial fibrillation occurrence after coronary artery bypass graft surgery. Gen Thorac Cardiovasc Surg. 2011;59:254-60. 25. Tinica G, Mocanu V, Zugun-Eloae F, et al. Clinical and histological predictive risk factors of atrial fibrillation in patients undergoing open-heart surgery. Exp Ther Med. 2015;10:2299-304. 26. Erdem K, Yazıcı M, Öztürk S, et al. Usefulness of CHA2DS2-VASc scoring system in predicting atrial fibrillation after coronary artery bypass grafting. Turk Gogus Kalp Dama. 2016;24:27-33. 27. Erdil N, Gedik E, Donmez K, et al. Predictors of postoperative atrial fibrillation after on-pump coronary artery bypass grafting: is duration of mechanical ventilation time a risk factor? Ann Thorac Cardiovasc Surg. 2014;20:135-42.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

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Prevalence of frailty syndrome and related factors in older adults living in a nursing home Semsinnur Gocer, Osman Gunay Erciyes University, Faculty of Medicine, Department of Public Health, Kayseri, Turkey Received 07 June 2018; Accepted 24 July2018 Available online 04.10.2018 with doi:10.5455/medscience.2018.07.8904 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract In this study, it was aimed to determine prevalence of frailty syndrome in older adults living in a nursing home in Kayseri and to assess relationship of frailty with sociodemographic characteristics and health-related conditions. This cross-sectional study was conducted on older adults living in a nursing home in Kayseri in 2016. Data were collected by using a sociodemographic questionnaire, Katz Index of Independence of Daily Living Activities, Instrumental Activities of Daily Living Scale, Geriatric Depression Scale and Study of Osteoporotic Fracture Index. It was aimed to include 128 older adults living in the nursing home. A total of 105 people were included. Chi-square test was used for statistical analysis. Of subjects, 56.2% were men; 5.7% were married and 45.7% were literate, 92.4% had health insurance, and 70.5% had regular income. Mean age was 77.5±8.7 years. Prevalence rate of frailty syndrome was 31.4%. Prevalence rate was found to be higher in women and in those aged ≥85 years. It was found that walking difficulty and walking stick use were more prevalent, while general health perception and sleep quality were poorer in older adults with frailty syndrome. Frailty syndrome was detected in approximately one-third of the study group. Prevalence rate of frailty syndrome was found to be higher among women and it was found to be increased by advancing age. The frailty has negative influence on health perception, sleep quality and walking difficulty. It is important to assess older adults for frailty and risk factors and to raise awareness the caregivers on frailty syndrome.. Keywords: Older adult, nursing home, frailty syndrome, daily living activities

Introduction Frailty Syndrome (FS) has various definitions. The most commonly used definition is “increased vulnerability to external stress as a result of loss of physiological reserves and function in neuromuscular, metabolic and immune systems due to aging” [1]. In addition, there are definitions emphasizing altered mobility, decreased strength and presence of nutritional impairments [2,3]. The older adults with FS generally have chronic diseases and functional dependency [1,2]. Losses in muscle strength, sarcopenia, slowing in walk, decreased grid strength and undesired weight loss may be encountered in older adults with FS [4,5]. FS is a clinical condition which isn’t only associated to difficulty in performing daily living activities but also can result in hospitalization and death [6]. It is important to assess frailty in older adults. It is essential to distinguish normal aging process from FS symptoms by monitoring *Coresponding Author: Osman Gunay, Erciyes University, Medicine School, Department of Public Health, Kayseri, Turkey E-mail: gunayos@erciyes.edu.tr

age-related physiological changes [6,7]. Several indices based on screening frailty symptoms such as weight loss, slowed walk, decreased physical activity level, incontinence and exhaustion [2,8,9]. The Cardiovascular Health Study (CHS) index and Study of Osteoporotic Fractures (SOF) index are widely used methods to diagnose FS [8,9]. It is essential to better understand preceding process in order to prevent frailty. It is believed that frailty can be prevented by timely intervention to acute disorders, trauma or stress in this latent period [9,10]. It has been shown that strength exercises, nutritional supplements, weight control, reviewing medications used, early recognition of medical issues, arrangements at home and environment, and assessment of social issues are effective in restoration aging body and maintaining functionality in both latent and apparent processes of frailty [6,10]. In this study, it was aimed to determine FS prevalence in older adults living in a nursing home and to assess the relationship of FS with sociodemographic characteristics and health-related parameters.

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Material and Methods This cross-sectional study was conducted on older adults living in Haci Rukiye Gazioğlu Nursing Home between 21.03.2016 and 29.05.2016. The data related to daily living activities and depressive symptoms in the same group will be published elsewhere [11]. The study was approved by Kayseri Metropolitan Municipality and Ethics Committee on Clinical Research of Erciyes University. We also obtained oral informed consent from the participants. At time of investigation, it was found that 128 of 154 individuals living in the nursing home were ≥65 years old. No sampling was performed as it was aimed to obtain data from all older adults aged ≥65 years living in nursing home. The data were collected by faceto-face interviews. Overall, 23 individuals were excluded from study including eighteen individuals with severe cognitive disorder (Alzheimer’s disease, dementia, psychosis) and communication disability, 2 individuals with incomplete data and 3 individuals lacking at nursing home at time of study were excluded. Final analysis included data from 105 subjects. Data Collection Tools Data were collected by using sociodemographic questionnaire, Geriatric Depression Scale (GDS) [12], Katz Index of Independence of Daily Living Activities (ADL) [13], Instrumental Activities of Daily Living Scale (IADL) [14], and Study of Osteoporotic Fracture Index (SOF) [8]. Sociodemographic Questionnaire The sociodemographic questionnaire was developed by researchers and included 20 items addressing age, gender, education status, occupation, and marital status, number of children, health insurance, economical status and general health status. In addition, height and weight measures were taken by researchers. Geriatric Depression Scale (GDS) Geriatric Depression Scale (GDS) developed by Yesavage et al. [12] and Ertan et al. [15], conducted the validity and reliability study of the Turkish version. It is a scale based on self-report and consists of 30 items and it is requested to answer questions in a yes / no form. Katz Index of Independence of Daily Living Activities (ADL) Katz ADL includes 6 items rating bathing, dressing, toileting, transferring, continence, and feeding. These items are rated as follows: 3 points, able to perform without assistance; 2 points, able to perform with assistance; and 1 point, unable to perform. Total score is between 0 and 18 points. The individual is assessed as ‘dependent’ if total score is 0-6 points, ‘semi-dependent’ if total score is 7-12 points and ‘independent’ if total score is 13-18 points [13]. Instrumental Activities of Daily Living Scale (IADL) The IADL was developed by Lawton and Brody [14]. It includes 8 items rating ability to telephone use, food preparation, shopping, housekeeping, laundry, mode of transportation, responsibility for own medication and ability to handle finances. These items are rated as follows: 3 points, able to perform without assistance; 2

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points, able to perform with assistance; and 1 point, unable to perform. Total score is between 0 and 24 points. The individual is assessed as ‘dependent’ if total score is 0-8 points, ‘semidependent’ if total score is 9-16 points and ‘independent’ if total score is 17-24 points. Study of Osteoporotic Fracture Index (SOF) In elder individual, it assess frailty depending on weight loss ≥5%, inability to do 5 chair stands, and no for question “do you feel yourself full of energy”. The elder individual with at least two of above-mentioned findings are considered as frail [8]. Data Analysis Data obtained from GDS, Katz ADL, IADL and SOF index were analyzed based on their own instructions. The body mass index (BMI) was classified as underweight (<18.50 kg/m2), normal (18.50-24.99), overweight (25.0-29.99) and obese (≥30) [16]. The BMI values were classified in 2 groups as <25 and ≥25, in statistical analysis. Data obtained from this study were analyzed with the SPSS 15.0 package program. Pearson’s chi-square test and Fisher’s exact test were used to assess relationship of frailty with sociodemographic characteristics and health-related parameters. A p value <0.05 was considered as statistically significant in all analyses. Results Of subjects, 56.2% were men; 5.7% were married and 45.7% were literate. Mean age was 77.5±8.7 years. Of subjects, 92.4% had insurance, 70.5% had regular income, 56.2% retired and the proportion of those with 5 or fewer children was 88.6%. As shown in Table 2, 23.8% of subjects reported their general health status as poor. Of subjects included, 22.9% were smokers while 32.4% were ex-smokers. Mean BMI was 21.1±3.4 kg/m2. The BMI was <18.5 kg/m2 in 3.8% and ≥25 kg/m2 in 53.3%. Of subjects included, 61.9% reported difficulty in walking while 39.0% reported stick use and 30.5% reported fall within prior year. At least one chronic disease was reported by 69.5% of subjects included. Table 3 shows effects of sociodemographic factors evaluated and health-related parameters on FS prevalence. The FS prevalence rate was 31.4% in study population. The FS prevalence was found to be significantly higher in age groups of ≥85 years when compared to other age groups (p<0.05). It was also significantly higher among women when compared to men. No significant effect was found for remaining sociodemographic characteristics and health-related parameters. Table 4 presents comparison prevalence of several health issues between older adults with or without FS. The percentages of poor health perception, poor sleep quality, walking difficulty and stick use were 36.4%, 42.4%, 84.8% and 66.7% in older adults with FS, respectively, which were found to be significantly higher than those in older adults without FS (p<0.05). However, it was found that history of fall had no significant influence on dependency as rated by Katz ADL and IADL. 22

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Table1. Sociodemographic characteristics of study population Characteristics Age Groups (year)

Groups

Number

65-74

38.1

75-84

38.1

≥85

23.8

Age (year) (mean ± SD) Gender Job

Education level

Marital status

Number of children Insurance Personal income

Income assessment

Male

56.2

Female

43.8

Retired

56.2

Housewife

43.8

Illiterate

45.7

Literate but no formal education

14.3

Primary school

33.3

College or higher

6.7

Married

5.7

Non-married

6.7

Widow

87.6

≤5

88.6

11.4

Yes

92.4

7.6

Yes

70.5

29.5

Good

21.9

Moderate

31.4

Poor

46.7

Groups

Number

Non-smoker

44.8

Table 2. Some characteristics related to health status in the study population Characteristics Smoking status

Perceived general health status

Walking difficulty Stick use History of fall within prior year Chronic disease Frailty

BMI

BMI (Mean ± SD)

Ex-smoker

32.4

Active smoker

22.9

Good

32.4

Moderate

43.8

Poor

23.8

Yes

61.9

39.0

Yes

39.0

61.0

Yes

30.5

69.5

Yes

69.5

30.5

Yes

31.4

68.6

Lean

3.8

Normal

42.9

Overweight

35.2

Obese

18.1 21.1 ± 3.4

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Table 3. Effects of sociodemographic characteristics and health status on frequency of FS Variables

Age Groups

Gender Marital status

Education level

Income

Smoking

Chronic disease BMI

Groups

65-74

FS Number

15.0

75-84

30.0

≥85

60.0

Male

22.0

Female

43.5

Married

16.7

Single

32.3

No primary school degree

38.4

Primary school or higher

21.4

Good

34.8

Moderate

30.3

Poor

30.6

Non-smoker

36.2

Ex-smoker

32.4

Active smoker

20.8

31.3

Yes

31.5

<25

32.7

30.4

105

31.4

Total

14.517

0.001

5.515

0.019

Fisher’s exact test

0.662

3.248

0.072

0.155

0.926

1.754

0.416

0.001

0.979

0.064

0.800

Table 4. Effect of FS on health status in elder individuals FS Yes (n=33)

No (n=72)

p 0.041

Number

Perceived poor health

36.4

18.0

4.181

Poor sleep quality

42.4

20.8

5.277

0.022

Walking difficulty

84.8

50.0

11.546

<0.001

Stick use

66.7

26.4

15.424

<0.001

History of fall within prior year

33.3

29.2

0.041

0.840

IADL dependent

66.7

48.6

2.973

0.085

ADL semi-dependent

6.1

2.8

0.666

0.373

*: Column percent

Discussion In this study, the FS prevalence rate was found to be 31.4% in elder individuals (Table 3). In a study, FS prevalence rate has been reported to be 7%-32% among community-dwelling older adults [17]. In Cardiovascular Health Study, it was found that; %7 of study group was frail, whereas 47% was in pre-frail stage [18]. In a study from Taiwan, the FS prevalence rate was reported as 11-14.9% in community settings [19]. The FS prevalence rate was found as 30.1% in a study on older adults living in nursing home from Turkey [20]. The FS prevalence rate found in our study was compatible with the literature. In our study, the FS prevalence rate was 15.0% in subjects aged 6574 years, while 60% in those aged ≥85 years, indicating increased

prevalence rate by advancing age (Table 3). In many study, it was reported that the FS prevalence is increased by advancing age [1,6,21]. By advancing age, reduction in physiological reserves, slowness, weakness, decreased physical activity, exhaustion and decreased BMI become more frequent, resulting in an increase in the FS prevalence [4,6,7]. Gender is one of the factors implied in frailty. Female gender is reported as a risk factor for frailty [6,21]. It was reported that frailty is more commonly seen among women in Women Health and Aging study [2] and Cardiovascular Health Study [9]. In our study, the FS prevalence rate was 43.5% among women, indicating a significant difference from men (Table 3). This might be due to higher muscle mass and strength in men than women. 24

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In our study, FS was detected in 38.4% of subjects without formal primary school education whereas 21.4% of those having formal education at varying levels. However, no significant difference was found in FS prevalence according to educational status (Table 3). In a study from Brazil, the factors associated to FS were investigated and authors reported that lower educational level was associated to FS [22]. Again, in a study on subjects aged ≥65 years, Chen et al. suggested a relationship between lower educational status and FS [23]. However, no relationship was found between education level and frailty in the study by Aygör et al. [10]. Higher FS prevalence rate in older adults with lower educational level might be due to greater age and higher prevalence of chronic diseases in this group. In our study, the FS prevalence rate was comparable in subjects with or without chronic diseases (Table 3). In the literature, it has been suggested that chronic diseases is one of the factors associated to FS. In a study by Zaslavsky et al., it was suggested that chronic diseases had influence of likelihood of FS [24]. In addition, it was reported that using 5 or more drugs was associated to FS in a Brazilian study [22]. In our study, the lack of association between presence of a chronic disease and frailty may be due to use of selfreported data regarding chronic diseases and unawareness of older adults about their chronic diseases. In a study on older adults living in a nursing home, it was shown that frailty parameters were less frequent and frailty scores were lower in obese individuals [20]. On contrary, there are studies indicating that FS may be present in obese individuals. It is suggested that this results from loss in lean mass [25-27]. In our study, FS prevalence rate was compared between subjects with BMI<25 and ≥25 due to smaller number of obese individuals. No significant difference was found in FS prevalence between groups (Table 3). Older adults experience challenges to maintain daily living activities independently as a consequence of many negative influences including physical and cognitive as well as economical losses resulting from aging [28-29]. Together with environmental factors, such negative influences cause weakness, decreased mobility and impair balance, resulting increased frailty in elder individual. Thus, the FS affects daily living activities and functional independency of elder individuals and also increases risk for fall [30]. In Women Health and Aging Study and Cardiovascular Health Study, it was found that women with FS experienced more difficulty in performing daily living activities and that they had higher risk for mortality and need for care in a facility [4,9]. It was found that percentage of walking difficulty and stick use were higher in subjects with FS (Table 4). In the literature, it has been reported a relationship between walking difficulty and FS [6, 21]. In older adults with FS, it is anticipated to increase in walking difficulty, falls and stick use due to impaired balance. In our study, the FS was detected in 34.8% of subjects with high income and 30.6% of subjects with poor income; however, no significant association was found between FS and income level (Table 4). Likewise, it was also found that marital status had no significant influence on FS prevalence (Table 4). In the literature, it has been reported that socioeconomic status and living alone are factors affecting likelihood of FS. In a study by Jürschik et al, it was found that FS was more frequent in individuals living alone [31].

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In a study from Brazil, it was reported that living alone and low socioeconomic status were associated to FS [22]. In communitydwelling older adults, economic status and marital status may affect FS prevalence by influencing on factors related to general health status such as nutrition, care and using healthcare services. However, factors such as nutrition and care are independent from economic or marital status in older adults living in the nursing homes. Thus, it isn’t surprising to find that economic and marital status had smaller influence on FS prevalence among older adults living in nursing home. In our study, percentages of subjects reporting poor general health status and poor sleep quality were found significantly higher among those with FS when compared to those without (Table 4). There are studies indicating that the FS is associated to general health perception [10,32]. As most of older adults are unaware of their chronic diseases, subjective health perception may be a better indicator for general health status. The relationship found between FS and general health perception indicates that the FS can be used as an objective indicator for assessment of general health status in older adults. To best of our knowledge, there is no study investigating association between sleep quality and FS. However, it is known that functional loses and psychosocial problems affecting general health status can have influence on likelihood of FS [10,22,25]. It is anticipated that sleep quality may be impaired in elder individuals with FS since above-mentioned factors also lead similar impairment in sleep quality. The FS has negative influences on activities of daily living and functional independency of elder individuals. It was found that prevention of FS improved quality of life in older adults and prolonged the period where older adults live independently [6]. In our study population, it was found that there was history of fall within prior year in 33.3% of subjects with FS whereas 66.7% were dependent in IADL and 6.1% was semi-dependent in Katz ADL. These values were lower in subjects without FS but the differences were not significant (Table 4). This might be due to small numbers of the subjects who are dependent in IADL and semi-dependent in Katz ADL. This study has some limitations. First, it was conducted in a nursing home; thus, sample size was restricted to residents of the nursing home. Secondly, chronic disease and history of fall which may be related to FS, were assessed based on self-reports of the participants. Conclusion Frailty syndrome was detected in approximately one-third of older adults included to the study. Prevalence rate of FS is higher among women and increase by age. FS has negative influence on health perception, sleep quality and walking difficulty. The symptoms of FS should be assessed periodically in older adults and individualized nutritional support and resistance exercises should be provided to maintain functionality and prevent muscle loss. Acknowledgement The authors thank to the Metropolitan Municipality of Kayseri for their permission and to the staff of Hacı Rukiye Gazioglu Nursing Home for their support during

doi: 10.5455/medscience.2018.07.8904 interviews with the participants, and to Erciyes University Scientific Research Projects Unit for the funding. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval The study was approved by Kayseri Metropolitan Municipality and Ethics Committee on Clinical Research of Erciyes University. Semsinnur Gocer ORCID: 0000-0002-2735-0073 Osman Gunay ORCID: 0000-0001-7131-2253

References 1.

Walston J, Hadley EC, Ferrucci L, et al. Research agenda for frailty in older adults. Toward a better understanding of physiology and etiology: Summary from the American Geriatrics Society/ National Institute on Ageing Research Conference on Frailty in Older Adults. J Am Geriat Soc. 2006;54:991-1001.

Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:146-56.

Fiatarone MA, O’neil EF, Ryan ND, et al. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Eng J Med. 1994;330:1769-75.

Fried LP, Ferrucci L, Darer J, et al. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med Sci. 2004;59:255-63.

Rose M, Pan H, Levinson MR, et al. Can frailty predict complicated care needs and length of stay? Intern Med J. 2014;44:800-5.

Kapucu S. Ünver G. Kırılgan yaşlı ve hemşirelik bakımı. Osmangazi Tıp Dergisi. 2017;39;122-9.

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instrumental activities of daily living. Gerontologist 1969;9;179- 86. 15. Ertan T, Eker E, Şar V. Geriatrik depresyon ölçeğinin türk yaşlı nüfusunda geçerlik ve güvenirliği. nöropsikiyatri arşivi. 1997;34:62-71. 16. WHO. Obesity: Preventing and Managing the Global Epidemic: Report of a WHO Consultation on Obesity. Geneva, Switzerland: WHO; WHO Technical report Series 894. 17. Lally F, Crome P. Understanding frailty. Postgrad Med J. 2007;83;16–20. 18. Strandberg TE, Pitkala KH, Tilvis RS. Frailty in older people. European Geriatric Medicine. 2011;2:344–55. 19. Chang C, Chan DC, Kuo KN, et al. Prevalence and correlates of geriatric frailty in a Northern Taiwan community. J Formos Med Assoc. 2011;110:24757. 20. Bahat G, Saka B, Tufan F ve ark. Bakımevinde kalan yatağa bağımlı olmayan yaşlılarda kırılganlık. Geriatri ve Geriatrik Nöropsikiyatri Dergisi. 2009;1(Özel):91-2. 21. Topinková E. Aging, disability and frailty. Ann Nutr Metab. 2008;52;6–11. 22. Pegoran MS, Tavares DMS. Factors associated with the frailty syndrome in elderly individuals living in the urban area. Rev Lat Am Enfermagem. 2014; 22:874-82. 23. Chen CY, Wu SC, Chen LJ, Lue BH. The prevalence of subjective frailty and factors associated with frailty in Taiwan. Archives of Gerontology and Geriatric. 2010;50:43-7. 24. Zaslavsky O, Cochrane BB, Thompson HJ. Frailty: A review of the first decade of research. Biological Research for Nursing. 2012;15:422-32. 25. Rakıcıoğlu N. Yaşlıda Şişmanlık, Ankara: Klasmat Matbaacılık. 2008;8-10.

Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ. 2005;173:489-95. Ensrud KE, Ewing SK, Taylor BC, et al. Comparison of 2 frailty indexes for prediction of falls, disability, fractures, and death in older women. Arch Intern Med. 2008;168:382-9. Bandeen-Roche K, Xue QL, Ferrucci L, et al. Phenotype of frailty: characterization in the women’s health and aging studies. Journal of Gerontology: Med Science. 2006;61;262-6.

10. Aygör H. Edmonton kırılganlık ölçeği’nin türk toplumu için geçerlik ve güvenirliğinin incelenmesi. iç hastalıkları hemşireliği anabilim dalı geriatri hemşireliği yüksek lisans tezi, İzmir, 2013. 11. Gocer S, Gunay O. Kayseri’de bir huzurevinde yaşayan yaşlıların günlük yaşam aktiviteleri ve depresif belirti düzeyleri (Unpublished Study). 12. Yesavage JA, Brink TL, Rose TL et al. Development and validation of geriatric depression screening scale: a preliminary report. J Psychiatric Res. 1983;17:37-49. 13. Katz S, Ford AB, Moskowitz RW, et al. Studies of illness in the aged. The Index of ADL: A standardized measure of biological and psychosocial function. JAMA. 1963;185:914-9. 14. Lawton MP, Brody EM. Assessment of older people: Self-maintaining and

26. Çifçili SS, Dişçigil G. Yaşlılıkta obezite. Türkiye Klinikleri J Fam MedSpecial Topics. 2015;6:85-9. 27. Lim S, Kim JH, Yoon JW, et al. Sarcopenic obesity: prevalence and association with metabolic syndrome in the Korean Longitudinal Study on Health and Aging (KLoSHA). Diabetes Care. 2010;33:1652-4. 28. Taşdelen P, Ateş M. Evde bakım gerektiren hastaların bakım gereksinimleri ile bakım verenlerin yükünün değerlendirilmesi. Hemşirelikte Eğitim ve Araştırma Dergisi. 2012;9:22-9. 29. Yaşar EK. Yaşlıya evde bakım veren aile bireylerinin bakım yükü ve etkileyen faktörler. ege üniversitesi sağlık bilimleri enstitüsü, Yüksek Lisans Tezi, İzmir, 2009. 30. Koyuncu G, Tuna F, Yavuz S. Kırıktan önceki son durak: yaşlıda düşme ve denge kaybının değerlendirilmesi. Turk J Phys Med Rehab. 2017;63:14-22. 31. Jürschik P, Nunin C, Botigue T, Escobar MA, Lavedan A. Prevalence of frailty and factors assosciated with frailty in the elderly population of Lleida, Spain: the FRALLE survey. Archives of Gerontology and Geriatrics. 2012;55:62531. 32. Rockwood, K. What would make a definition of frailty successful? Age and Ageing. 2005;34:432–4..

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

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Relation of homeostasis model of insulin resistance and body mass index with cardiac repolarization inhomogeneity in overweight and obese patients Fatih Kuzu Dumlupinar University, Evliya Celebi Training and Research Hospital, Department of Endocrinology and Metabolism, Kutahya, Turkey Received 25 May 2018; Accepted 25 July 2018 Available online 16.12.2018 with doi:10.5455/medscience.2018.07.8942 Copyright ÂŠ 2019 by authors and Medicine Science Publishing Inc. Abstract In obese individuals, asymptomatic minimal myocardial dysfunction can be encountered even in the absence of structural of functional cardiac alterations. Novel electrocardiographic (ECG) parameters are used to predict arrhythmias related to this situation. We aimed to evaluate body mass index (BMI) and homeostasis model of insulin resistance (HOMA-IR) levels and investigate their relationship with the novel ECG parameters. The study was conducted with 250 individuals in five groups (normoweight, overweight, class I obese, class II obese, and class III obese) each including 50 subjects. The ECGs of the individuals were retrospectively reviewed. Corrected QT (QTc), QTc dispersion (QTcd), Tpeak-Tend (Tp-e) interval, Tp-e dispersion (Tp-ed), and Tp-e/QT and Tp-e/QTc ratios were calculated and their relationship with BMI and HOMA-IR was investigated. ECG parameters indicating ventricular repolarization inhomogeneity were significantly different in overweight individuals compared with the normoweight individuals. Comparing overweight and obese subjects, it was determined that QTc, QTcd and Tp-ed parameters were significantly associated with obesity and showed positive correlations with BMI and HOMA-IR. There was a positive relationship of BMI and HOMA-IR with the novel parameters indicating ventricular repolarization abnormality. Novel and simple ECG parameters including QTc, QTcd, and Tp-ed might be beneficial in monitoring of such patients for critical cardiac events, such as ventricular tachycardia or sudden cardiac death. Keywords: Obesity, electrocardiography, QTc dispersion, Tp-e dispersion

Introduction Obesity can enhance the risk of coronary atherosclerosis by welldefined and generally accepted mechanisms such as dyslipidemia, hypertension and type-2 diabetes mellitus and may also lead to arrhythmias [1-3]. Sudden death has been reported more commonly in obese individuals than in non-obese individuals [4,5]. Electro physiological studies have demonstrated that obese individuals have increased electrical activity, which triggers ventricular arrhythmias in the absence of ventricular dysfunction or clinical heart failure [6,7]. The association of prolonged corrected QT (QTc) interval, QT dispersion (QTd), and QTc dispersion (QTcd) with sudden cardiac death and all-cause mortality has been demonstrated by epidemiological studies [8,9]. Prolonged QTc interval may be helpful in predicting cardiovascular events and risk of mortality. Body mass index (BMI) is the method used most frequently in clinical measurement of obesity and has been found to be directly associated with QTc [9].

*Coresponding Author: Fatih Kuzu, Dumlupinar University, Evliya Celebi Training and Research Hospital, Department of Endocrinology and Metabolism, Kutahya, Turkey E-mail: drfkuzu@hotmail.com

Tpeak-Tend (Tp-e) interval, Tp-e dispersion (Tp-ed), and Tp-e/QT and Tp-e/QTc ratios measured on electrocardiography (ECG) are the novel parameters that have been reported in the literature and recently used to evaluate ventricular arrhythmogenicity in several diseases. Tp-e/QT and Tp-e/QTc ratios in particular are considered more reliable in assessing ventricular repolarization as they are not affected by changes in heart rate [10,11]. To the best of our knowledge, there has been yet no study in the literature demonstrating the relationship between homeostasis model of insulin resistance (HOMA-IR) value, which is a reliable test in assessing insulin resistance, and these novel parameters. The present study aimed to evaluate BMI and HOMA-IR levels and investigate their relationship with the novel ECG parameters. Material and Methods Study population Medical records of the patients followed-up in our endocrinology and metabolism disorders clinic between December 2015 and December 2017 were retrospectively reviewed. Two hundred and 27

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fifty subjects were included in the study. The individuals were classified according to their BMI values as class III obesity (BMI > 40 kg/m2), class II obesity (BMI = 35-39.9 kg/m2), class I obesity (BMI = 30-34.9 kg/m2), overweight (BMI = 25-29.9 kg/ m2), and normoweight (BMI = 18.5-24.9 kg/m2) in line with the recommendations of the World Health Organization. HOMA-IR was used to identify the presence of insulin resistance. HOMA-IR was calculated using the following formula: Fasting blood glucose (mg/dL) x insulin (μIU/mL)/405. HOMA-IR value ≥ 2.7 was considered significant for insulin resistance. Individuals who had no structural abnormality and had normal ejection fraction on the echocardiography were included in the study. On the other hand, patients with coronary artery disease, cerebrovascular event, peripheral vascular disease, valvular heart problems, cardiomyopathy, history of atrial and ventricular arrhythmia, hypertension, thyroid dysfunction, diabetes mellitus, electrolyte disorder, history of chronic diseases, and anemia were excluded from the study. The study protocol was approved by the Institutional Ethics Committee of Dumlupinar University. Electrocardiography Electrocardiography measurements were performed using 12-lead ECG at a speed of 25 mm/s and a voltage of 10 mm/mV while the patient was in supine position. ECG recordings were manually interpreted by three independent cardiologists, who were blind for patients’ clinical information. QT interval was measured from the starting point of QRS complex to the point where the descending limb of T-wave intersected the isoelectric line. QTc was calculated as QT/√RR (Bazzet formula ) [12]. Tp-e interval was measured from the peak point of T-wave to the point where the descending limb of T-wave intersected the isoelectric line. QTcd was calculated as the difference between the longest QTc and the shortest QTc, whereas Tp-e dispersion was calculated as the difference between the maximum and minimum Tp-e intervals. Tp-e/QT and Tp-e/ QTc ratios were calculated using these measurements. Laboratory assessments From the blood samples of the patients drawn after 8-10hour overnight fasting period, levels of blood glucose, insulin, hemoglobin A1c (HbA1c), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, thyroid-stimulating hormone (TSH), and free T4 and complete blood count were recorded. Level of fasting blood glucose was measured using the glucose hexokinase method (Beckman Coulter Ireland Inc.).Insulin serum concentrations were determined by the Beckman Access Ultrasensitive Insulin Assay, which is a simultaneous one-step immunoenzymatic (“sandwich”) assay performed by the automated Access Immunoassay System (Beckman Coulter DXI 600, Fullerton, CA, USA). HbA1c values were measured using high-performance liquid chromatography (Tosoh Bioscience, South San Francisco, CA, USA ). Levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride were determined using an automatic analyzer (Beckman Coulter AU 2700, Brea, CA, USA ). TSH and free T4 were determined by immunoenzymatic method (Beckman Coulter DXI 600 , Fullerton, CA, USA) based on chemiluminescence detection principle.

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Statistical analysis Statistical analysis was performed using the Predictive Analytics Software for Windows version 18.0 (SPSS Inc., Chicago, IL, USA) . The Kolmogorov-Smirnov test was used for normality analysis of the distribution of numerical data. Descriptive data were expressed as mean±standart deviation. For the comparison of two independent groups, the Student’s t-test was used for normally distributed variables and the Mann-Whitney U test was used for non-normally distributed variables. When more than two independent groups were compared, the difference between the groups was analyzed using the one-way ANOVA for each variable. The Tukey’s post hoc test was performed to determine the significance of differences. In addition, the chi-square test was used to compare categorical variables. The Pearson’s correlation test was used for correlation analyses. A p value of less than 0.05 was considered statistically significant. Results The study population comprised 50 class III obese patients (34 females, 16 males, mean age, 39.5±10.8 years), 50 class II obese patients (34 females, 16 males, mean age, 38.7±10.3 years), 50 class I obese patients (32 females, 18 males, mean age, 40.5±10.1 years), and 50 overweight patients (29 females, 21 males, mean age, 39.0±10.9 years) and age- and gender-matched 50 healthy normoweight individuals (29 females, 21 males, mean age, 35.8±10.3 years). There were no significant differences among the study groups in terms of demographic, clinical, and laboratory characteristics including age, systolic blood pressure, diastolic blood pressure, and levels of blood glucose, TSH, and free T4. As was expected, there were significant differences among the groups in terms of BMI, insulin level, HOMA-IR, Hba1c level, and lipid parameters (Table 1). The mean QT, QTc, QTcd, Tp-e, Tp-ed, Tp-e/QT, Tp-e/QTc, and heart rate values in the normoweight and overweight groups are demonstrated in Table 2. All ECG parameters excluding heart rate were significantly different between these groups; the ECG parameters were significantly higher in the overweight group (p=0.002, p<0.001, p<0.001, p<0.001, p<0.001, p<0.001, and p<0.001 , respectively). Intra-group comparison of overweight patients as class I obese, class II obese, and class III obese using ANOVA F-test revealed significant differences in terms of the ECG parameters including QTc, QTcd, and Tp-ed (p=0.01, p=0.04, p=0.049, respectively). Proportional increase in these parameters with weight is presented in Table 3. The whole study population was divided into two groups according to the HOMA-IR level as <2.7 (n=140) and >2.7 (n=110) and these groups were compared. Similar to the groups established based on the BMI values, QTc, QTcd, and Tp-ed were significantly higher in the group with HOMA-IR >2.7 (p<0.001, p<0.001, p<0.001, respectively). The Pearson’s correlation analysis, which was performed to determine the correlation of HOMA-IR and BMI values with the ECG parameters, revealed strongly positive correlations of QTc, QTcd, and Tp-ed parameters with HOMA-IR and BMI values (Table 5). 28

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Table 1. Demographic, clinical and laboratory characteristics of study participants Variables

Normoweight (18.5-24.9 kg/m2)

Overweight (25-29.9 kg/m2)

Class I obesity (30-34.9 kg/m2)

Class II obesity (35-39.9 kg/m2)

Class III obesity (>40 kg/m2)

Female/male (n)

29/21

32/18

34/16

Smoker/nonsmoker (n)

9/41

11/39

8/42

10/40

35.8±10.3

39.0±10.9

40.5±10.1

38.7±10.3

39.5±10.8

0.24

SBP (mm Hg)

118±9.7

116±10.4

121±10.5

120±9.8

121±9.9

0.08

DBP (mm Hg)

68.6±5.5

67.9±7.8

71.0±7.6

71.3±7.4

69.5±7.1

0.74

BMI (kg/m2)

22.0±2.0

27.2±1.2

32.4±1.4

37.5±1.4

45.1±4.5

<0.001

İnsulin (uIU/mL)

6.2±3.5

8.5±4.8

12.8±6.2

13.4±8.7

14.4±7.1

<0.001

Glucose (mg/dl)

92.2±6.4

95.5±7.5

93.2±8.1

95.6±8.5

95.8±9.2

0.08

HOMA-IR

1.4±0.8

2.0±1.2

3.0±1.6

3.1±2.0

3.4±1.7

<0.001

HbA1c (%)

5.2±0.3

5.2±0.4

5.3±0.3

5.5±0.3

<0.001

TSH (uIU/mL)

1.8±0.9

1.9±0.8

2.0±0.9

2.2±0.9

2.3±1.1

0.09

Age (years)

P-value

Free T4 (ng/dl)

0.84±0.10

0.82±0.13

0.81±0.12

0.79±0.09

0.83±0.12

0.25

LDL-C (mg/dl)

103.5±23.1

123.2±29.0

113.8±26.7

119.7±26.1

118.3±29.9

0.009

HDL-C (mg/dl)

52.2±10.7

45.2±11.3

46.8±9.2

46.3±10.0

48.8±10.4

0.02

TC (mg/dl)

174.0±26.5

199.4±32.7

187.0±32.2

198.4±34.9

196.6±32.6

0.001

Triglyceride (mg/dl)

91.4±40.8

143.3±72.2

137.8±73.5

166.0±93.7

144.6±57.0

<0.001

SBP: Systolic blood pressure, DBP: Diastolic blood pressure, BMI: Body mass index, HOMA-IR: Homeostatic Model of Assessment-Insulin Resistance, HbA1c: Hemoglobin A1c, TSH: Thyroid stimulating hormone, LDL-C: Low-density lipoprotein cholesterol, HDL-C: High-density lipoprotein cholesterol, TC: Total cholesterol. Data are shown as means ± s.d. P values were calculated by an ANOVA F-test Table 2. Comparison of the electrocardiographic parameters in the normoweight group and overweight group Groups

QT (ms)

QTc (ms)

QTcd (ms)

Tp-e (ms)

Tp-ed (ms)

Tp-e/QT

Tp-e/QTc

Heart rate (bpm)

Normoweight (18.5-24.9 kg/m )

366.6±24

398.7±19

37.4±11

81.6±12

35.0±9

0.22±0.03

0.20±0.02

72.7±10.3

Overweight (25-29.9 kg/m )

381.4±23

418.6±17

49.3±12

95.4±15

43.6±12

0.24±0.03

0.22±0.03

76.6±11.1

0.002

<0.001

0.07

P-value

Data are shown as means ± s.d. P values were calculated by student t-test. Table 3. Comparison of the electrocardiographic parameters in the overweight group and obese groups Groups (bpm)

QT (ms)

QTc (ms)

QTcd (ms)

Tp-e (ms)

Tp-e disp (ms)

Tp-e/QT

Tp-e/QTc

Heart rate

Overweight (25-29.9 kg/m2)

381.4±23

418.6±17

49.3±12

95.4±15

43.6±12

0.24±0.03

0.22±0.03

76.6±11.1

Class I obesity (30-34.9 kg/m2)

378.8±22

425.3±18

53.3±15

92.4±14

47.2±12

0.24±0.04

0.22±0.03

75.4±9.6

Class II obesity (35-39.9 kg/m )

383.6±23

432.0±21

54.0±15

92.6±13

46.2±13

0.24±0.03

0.21±0.03

76.7±10.7

Class III obesity (>40 kg/m2)

376.4±20

433.1±20

57.7±16

91.8±12

49.6±10

0.24±0.02

0.21±0.02

80.1±10.1

0.38

0.01

0.04

0.53

0.049

0.5

0.06

0.12

P-value

Data are shown as means ± s.d. P values were calculated by an ANOVA F-test Table 4. Comparison of the electrocardiographic parameters in the HOMA-IR < 2.7 group and HOMA-IR > 2.7 group Groups

QT (ms)

QTc (ms)

QTcd (ms)

Tp-e (ms)

Tp-ed (ms)

Tp-e/QT

Tp-e/QTc

Heart rate (bpm)

HOMA-IR < 2.7 (n: 140)

376.9±23

414.2±23

46.3±15

89.4±15

41.8±13

0.23±0.03

0.21±0.03

74.1±10.5

HOMA-IR > 2.7 (n: 110)

378.0±22

430.9±18

55.4±15

92.5±12

47.5±10

0.24±0.02

0.21±0.02

79.1±10.1

0.7

<0.001

0.08

<0.001

0.82

<0.001

P-value

HOMA-IR: Homeostatic Model of Assessment-Insulin Resistance Data are shown as means ± s.d. P values were calculated by student t-test Tablo 5. Pearson correlation analysis between ECG parameters and BMI and HOMA-IR Variables

QTc (ms)

QTcd (ms)

Tp-e (ms)

Tp-e disp (ms)

Tp-e/QT

Tp-e/QTc

BMI (kg/m2)

0.501

<0.001

0.39

<0.001

0.16

0.008

0.35

<0.001

0.13

0.03

0.001

0.98

HOMA-IR

0.37

<0.001

0.28

<0.001

0.11

0.07

0.22

<0.001

0.14

0.02

0.01

0.8

BMI: Body mass index, HOMA-IR: Homeostatic Model of Assessment-Insulin Resistance

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Discussion Potential risk factors of cardiac arrhythmia such as ischemic heart disease, atrial dilatation, systolic and diastolic heart failure, and sleep apnea are significantly more common in obese individuals [13,14]. Moreover, obesity-related minimal asymptomatic myocardial dysfunction may accompany even in the absence of structural or functional cardiac changes [15]. This asymptomatic myocardial dysfunction can increase electrical activity, which triggers ventricular arrhythmias, and can lead to sudden cardiac death [16-18]. Increased QTc and QTcd parameters with increasing BMI have been confirmed in many studies and associated with delayed ventricular repolarization [9,10,19,20]. In line with the literature, , a statistically significant positive correlation of QTc and QTcd parameters with BMI and HOMA-IR was obtained in the present study. Increase in these parameters is a potential marker of ventricular arrhythmias and sudden cardiac death [14,15]. Tp-e, Tp-ed, and ratios of Tp-e/QT and Tp-e/QTc have been defined as the novel electrocardiographic markers of ventricular repolarization abnormality. Electrophysiological studies have demonstrated that prolonged Tp-e interval is correlated with induction or spontaneous development of ventricular tachycardia. The ratios of Tp-e/QT and Tp-e/QTc are also considered as a sensitive index for arrhythmogenesis [12,21-23]. To our knowledge, in the literature, there are two recent studies demonstrating the relation of BMI with these novel parameters in limited number of patients. Braschi et al. [24] compared 60 overweight/obese patients with 60 normoweight individuals in terms of the new ECG parameters and reported no significant relationship between the groups regarding QTd, Tp-e, Tp-ed, and Tp-e/QT ratio. A recent study by Hussain et al. [25] compared Tp-e, Tp-ed, and Tp-e/QT ratio among 34 normoweight, 30 overweight, and 32 obese patients and, likewise, reported no statistically significant relationship. Contrary to these studies, the present study, which was performed in a larger patient group, determined significant differences between normoweight and overweight groups in terms of Tp-e, Tp-ed, Tp-e/QT, and Tp-e/QTc parameters; these parameters were significantly higher in the overweight group. In intra-group comparison of overweight patients as class I obese, class II obese, and class III obese using ANOVA F-test, a significant difference was determined only for Tp-ed parameter in addition to QTc and QTcd parameters. The correlation analysis also revealed a strong correlation between QTc, QTcd, and Tp-ed parameters and BMI. Various theories have been suggested to explain the relation of obesity with delayed ventricular repolarization. The most striking one is the insulin resistance, which is the common comorbidity in obese patients [26,27]. In the study by Laitinen et al. (28), the relationship of insulin resistance and hyperinsulinemia with prolonged QT was demonstrated even in the absence of myocardial infarction or diabetes mellitus [28]. Another study has propounded that insulin leads to prolonged QT by hyperpolarizing the plasma membranes of both stimulatable and non-stimulatable tissues [29]. Hyperinsulinemia may result in hypokalemia, which is an important factor for the development of cardiac arrhythmias, by causing potassium to shift into the cell [26]. As far as we know, there is no study in the literature demonstrating the relationship between HOMA-IR -indicator of insulin resistance- and the novel ECG parameters. In the present study, only Tp-ed, a novel parameter, in addition to QTc and QTcd parameters was significantly higher

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in the group with HOMA-IR >2.7. Similar to the correlation with BMI, there was also a strong correlation between the parameters of QTc, QTcd, and Tp-ed and HOMA-IR. One of the limitations of the present study was the manual measurement of the parameters which might have limited the accuracy of the outcomes. Although manual measurement has been scientifically accepted, digital measurement by converting the paper ECG tracing to digital form using an optical scanner has been reported as an alternative method. Another limitation of the present study was the fact that subclinical ischemic cardiac disease might have been overlooked because performing coronary angiography in all patients was practically not possible. Conclusion There was a positive relationship of BMI and HOMA-IR with the novel parameters indicating ventricular repolarization abnormality. Ventricular repolarization inhomogeneity was observed to be increase in the patients with BMI >25 kg/m2 and HOMA-IR >2.7. Regular monitoring of these patients for critical cardiac events, such as ventricular tachycardia, would be beneficial. Acknowledgement The author thanks Dr. Taner Şen and Dr. Afşin Parspur from the Department of Cardiology and Dr. Rahmi Özdemir from the Department of Pediatric Cardiology for their valuable contributions in the interpretation of the ECG tracing. Competing interests The authors declare that they have no competing interest Financial Disclosure The authors declared that this study has received no financial support Ethical approval Before the study, permissions were obtained from local ethical committee Fatih Kuzu ORCID: 0000-0002-7301-9226

References 1.

Anand RG, Peters RW, Donahue TP. Obesity and dysrhythmias. J Cardiometab Syndr. 2008;3:149-54.

Lavie CJ, Arena R, Alpert MA, et al. Management of cardiovascular diseases in patients with obesity. Nat Rev Cardiol. 2018;15:45-56.

Mozos I. Arrhythmia risk and obesity. J Mol Genet Med. 2014;S1:1747-862.

Eranti A, Aro AL, Kerola T, et al. Body mass index as a predictor of sudden cardiac death and usefulness of the electrocardiogram for risk stratification. Am J Cardiol. 2016;117:388-93.

Agbaedeng T, Mahajan R, Munawar D,et al. Obesity associates with increased risk of sudden cardiac death: a systematic review and meta-analysis. Heart Lung and Circulation. 2017;26:S186.

Pietrasik G, Goldenberg I, McNITT S, et al. Obesity as a risk factor for sustained ventricular tachyarrhythmias in MADIT II patients. J Cardiovasc Electrophysiol. 2007;18:181-4.

Stengl M. Experimental models of spontaneous ventricular arrhythmias and of sudden cardiac death. Physiol Res. 2010;59(Suppl.1): 25-31

Okin PM, Devereux RB, Howard BV, et al. Assessment of QT interval and QT dispersion for prediction of all-cause and cardiovascular mortality in American Indians: the Strong Heart Study. Circulation. 2000;101:61-6.

Guo X, Li Z, Guo L, et al. Effects of metabolically healthy and unhealthy obesity on prolongation of corrected QT interval. Am J Cardiol. 2017;119:1199-204.

10. Suner A, Akgungor M, Kaya H, et al. Novel ventricular repolarization indexes

doi: 10.5455/medscience.2018.07.8942 in prehypertensive and newly diagnosed hypertensive patients: Tp-e interval and Tp-e/QT ratio. Int J Clin Experimental Med. 2016;9;16710-6. 11. Gupta P, Patel C, Patel H, et al. T(p-e)/ QT ratio as an index of arrhythmogenesis. J Electrocardiol. 2008;41:567–74. 12. Goldenberg I, Moss AJ, Zareba W. QT interval: how to measure it and what is” normal”. J Cardiovasc Electrophysiol.2006;17:333-6. 13. Mandviwala T, Khalid U, Deswal A. Obesity and cardiovascular disease: a risk factor or a risk marker?. Current Atherosclerosis Reports. 2016;18:21. 14. Szepietowska B, Polonsky B, Sherazi S, et al. Effect of obesity on the effectiveness of cardiac resynchronization to reduce the risk of first and recurrent ventricular tachyarrhythmia events. Cardiovasc Diabetol. 2016;15:93. 15. Seyfeli E, Duru M, Kuvandık G, et al. Effect of obesity on P-wave dispersion and QT dispersion in women. Int J Obes (Lond). 2006;30: 957-61. 16. Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss:an update of the 1997 American Heart Association scientic statement on obesity and heart disease from the obesity committee of the council on nutrition, physical activity, and metabolism. Circulation. 2006;113:898-918. 17. Lavie CJ, Pandey A, Lau DH, et al. Obesity and atrial fibrillation prevalence, pathogenesis, and prognosis: Effects of weight loss and exercise. J Am Coll Cardiol. 2017;70:2022-35. 18. Messerli FH, Nunez BD, Ventura HO, et al. Overweight and sudden death. İncreased ventricular ectopy in cardiopathy of obesity. Arch Intern Med. 1987;147:1725-8. 19. Omran J, Firwana B, Koerber S, et al. Effect of obesity and weight loss on ventricular repolarization: a systematic review and meta-analysis. Obes Rev. 2016;17:520-30. 20. Pathak RK, Mahajan R, Lau DH, et al. The implications of obesity for cardiac

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arrhythmia mechanisms and management. Canadian J Cardiol. 2015;31:203-10. 21. Castro-Torres Y, Carmona-Puerto R, Katholi RE. Ventricular repolarization markers for predicting malignant arrhytmias in clinical practice. World J Clin Cases. 2015;31:705-20. 22. Demirol M, Karadeniz C, Ozdemir R, et al. Prolonged Tp–e Interval and Tp–e/QT Ratio in Children with Mitral Valve Prolapse. Pediatr Cardiol. 2016;37:1169-74. 23. Ozdemir R, Isguder R, Kucuk M, et al. A valuable tool in predicting poor outcome due to sepsis in pediatric intensive care unit: Tpeak-end/QT ratio. J Tropical Pediatr. 2016;62:377-84. 24. Braschi A, Abrignani MG, Francavilla VC, et al. Novel elektrocardiographic parameters of altered repolarization in uncomplicated overweight and obesity. Obesity. 2011;19:875-81. 25. Hussain G, Farooque I. Effect of obesity on electrocardiographic parameters of ventricular repolarization in healthy adults. J. Evid. Based Med. Healthc. 2017;4(95):5915-20. 26. Drimba L, Döbrönte R, Hegedüs C, et al. The role of acute hyperinsulinemia in the development of cardiac arrhythmias. Naunyn Schmiedebergs Arch Pharmacol. 2013;386:435-44. 27. Van De Borne P, Hausberg M, Hoffman RP, et al. Hyperinsulinemia produces cardiac vagal withdrawal and nonuniform sympathetic activation in normal subjects. Am J Physiol. 1999;276:178–83. 28. Laitinen T, Vauhkonen I, Niskanen L, et al. Prolonged corrected QT interval is associated with acute and chronic hyperinsulinemia in nondiabetic subjects. Diabetes Care. 2003;26:2480–1. 29. Zhang Y, Xiao J, Wang H, et al. Restoring depressed HERG K+ channel function as a mechanism for insulin treatment of abnormal QT prolongation and associated arrhythmias in diabetic rabbits. Am J Physiol Heart Circ Physiol. 2006;291:1446–55

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Medicine Science 2019;8(1):32-6

The effect of measurement uncertainty for HOMA-IR in assessment of insulin resistance Mujgan Ercan1, Aysen Caniklioglu1, Esra Firat Oguz2, Cigdem Yucel2, Mehmet Ozcan3, Fatma Meric Yilmaz4, Sedat Abusoglu5, Canan Topcuoglu2, Yusuf Bayrakceken3 1 Bozok University Faculty of Medicine, Department of Biochemistry, Yozgat, Turkey Ankara Numune Training and Research Hospital, Biochemistry Laboratory, Ankara, Turkey 3 Hacettepe University School of Medicine, Department of Medical Biochemistry Ankara,Turkey 4 Yldirim Beyazit University, Faculty of Medicine, Department of Biochemistry, Ankara, Turkey 5 Selcuk University, Faculty of Medicine, Department of Biochemistry, Konya, Turkey 2

Received 13 June 2018; Accepted 26 July 2018 Available online 18.10.2018 with doi:10.5455/medscience.2018.07.8905 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract In this study, it is aimed to estimate not just the uncertainty measurement for the parameters of glucose and insulin having role when calculating HOMA-IR, but also true positiveness and negativeness in terms of cut-off values. The evaluation of the acceptability of the uncertainty value was also among the goals of the study. The uncertainty measurement for glucose and insulin is calculated as uncertainty measurement of HOMA-IR based on Eurochem/CITAC Guide CG 4. The uncertainty measurement for glucose and insulin was estimated as 3.83% and 4.16%, respectively. The measurement uncertainty for the calculated test HOMA-IR was calculated with cut-off values as 27% (0.27). Based on the cut-off value for HOMA-IR of 2.5%, IR(+) and IR(-) patients were 155 and 265, respectively. If the uncertainty measurement for HOMA-IR was added to its calculation, the cut-off value was detected as 2.23-2.77%. We reported the measurement uncertainty of the calculated test HOMA-IR at 95 % CI as 0.27 between 2.23 - 2.77. Especially for the tests used for screening; determination of cut-off values as a range including measurement uncertainty instead of a single value will be more suitable. No data is found in the literature for the calculated test HOMA-IR up to date. Keywords: HOMA-IR, insulin resistance, cut-off

Introduction Insulin resistance (IR) can be defined as a state in which a given concentration of insulin is associated with a subnormal glucose response in clinical practice. Insulin resistance is known to play a significant pathophysiological role in the development of diabetes, dyslipidemia, hypertension and cardiovascular diseases [1,2]. Prospective studies have shown that it is a strong risk predictor for the development of diabetes or cardiovascular diseases [3-5]. Accurate measurement of IR requires complex techniques that are expensive and time-consuming. Therefore, a number of surrogate indices of IR had been developed [3,6]. The most widely used formula is the homeostatic model of assessment-insulin resistance (HOMA-IR), which uses fasting insulin and glucose levels to calculate IR [7]. HOMA-IR was calculated by using the following *Coresponding Author: Mujgan Ercan, Bozok University Faculty of Medicine, Department of Biochemistry, Yozgat, Turkey E-mail: mujganercan@hotmail.com

formula: HOMA-IR=fasting serum glucose (mg/dL) × fasting serum insulin value (μU/mL)/405. HOMA-IR (the cut-off value for insulin resistance) ≥ 2.5 was identified as an indicator of insulin resistance [8]. In the clinical laboratory, all measurements are affected by some type of errors with different significancy. The potential sources of errors are classified basically as preanalytical, analytical and postanalytical [9]. The quantitative expression of the error is a value termed the uncertainty of measurement (UM) [10,11]. The practical benefit of UM is to check if the patient’s values correlate with quality goals or to compare the measured value of the same patient with the previous results or clinical decision value [12,13]. Clinicians mostly compare test results with reference values or previous values of the same patient. Laboratory results must be reliable and accurate for this reason, however, laboratory results include different type of errors in practice [9]. UM is important for accurately interpreting results, especially those that are close to the limit and are crucial for making a clinical decision [14]. Currently, few clinical laboratories present UM values in their reports. In 32

doi: 10.5455/medscience.2018.07.8905

the literature, measurement of uncertainty studies are limited in number. There are even fewer studies regarding hormone tests. Providing the clinician with the measurement uncertainty of the analysis will be of great importance in the treatment of the disease and patient’s follow-up care. When calculating UM, it is important to calculate the standard uncertainty value including all uncertainty factors. Total uncertainty value is calculated by combining all standard uncertainty values, while the expanded uncertainty value is estimated by multiplying total uncertainty by a coverage factor (k=1.96). UM is the value that is added to the laboratory results as ± value representing the dispersion of the test result [9]. In this study, it is aimed to estimate not just the measurement of uncertainty for the parameters of glucose and insulin when calculating HOMA-IR, but also true positiveness and negativeness in terms of cut-off values. The evaluation of the acceptability of the uncertainty value was also among the goals of the study. Material and Methods The HOMA-IR results of 420 subjects admitted to Endocrinology Clinic in Bozok University, Faculty of Medicine were evaluated retrospectively for three months period between September and November 2017. Blood samples were collected into yellow capped gel containing tubes (5 mL BD Vacutainer SST II advance, Becton, Dickinson and Company Franklin Lakes, NJ, USA). Measurement of glucose and insulin were carried out with Abbott Architect ci8200 autoanalyser. Glucose levels were measured using hexokinase method, while insulin levels were estimated by chemiluminescence immunoassay technique. HOMA-IR≥2.5 was used as the cut-off value by our endocrinologists. Patients with fasting blood glucose ≥126 mg/dL were not included in the study. The UM for glucose and insulin were calculated by using internal and external quality (one world accuracy) control data. In this study, we used the Eurochem/CITAC Guide CG 4 to calculate the UM of HOMA-IR. uCVglucose=√(((x1) +(x2) )/2) 2

uCVinsulin =√(((y1)2+(y2)2)/2) x1 and y1: uncertainty of internal quality control x2 and y2: uncertainty of external quality control For routine use, homeostatic model of assessment-insulin resistance (HOMA-IR) is derived as follows: HOMA-IR=fasting serum glucose (mg/dL)×fasting serum insulin (μU/mL)/405.

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If the calculation is done by multiplication or division, the squares of the CVs are summed and the square roots are taken (15). uCVglucose = √(((x1)2+(x2)2)/2) uCVinsulin =√(((y1)2+(y2)2)/2) uCV HOMA-IR=√ (uCVglucose)2+ (uCVinsulin)2 SD HOMA-IR= uCV HOMA-IR x HOMA-IR (The cut-off value for HOMA-IR=2.5 ) The expanded uncertainty of HOMA-IR; U HOMA-IR= SD HOMA-IR x1.96 (k) Measurand (analyte)=value +/-U U is the expanded uncertainty of HOMA-IR The study was approved by the Ethical Committee of Bozok University, Faculty of Medicine (Ref number.2017/58). Results Mean age of 420 subjects (M=74, F=346) included in the study was 37±10 years. In accordance to the routinely used cut-off value (≥2.5) in our hospital, 265 participants were IR negative and 155 were IR positive. UM of the internal quality control for insulin and glucose tests in our laboratory were calculated as 5.8%, 4.28%, respectively, while external quality control measurements for these tests were estimated as 1.03% and 3.32%, respectively (Table 2 and 3). The measurement uncertainty for the calculated test HOMAIR was calculated with cut-off values as 0.14 ((5.66x2.5)/100). Expanded HOMA-IR value was calculated as (0.14x1.96) x0.27 (Table 3). Our test result according to expanded measurement uncertainty of HOMA-IR is 2.5±0.27. In 95% of confidence interval, our real value is between 2.23-2.77. At this maximum error rate, the limit values were determined as 2.5 for 0 error rate, 2.23 for -0.27 error rate and 2.77 for +0.27 error rate (Table 4). Retrospective evaluation of HOMA-IR values of 420 subjects (according to cut-off value) revealed 265 results as negative, while 155 results as positive when the cut-off is defined as 2.5. When the maximum low error rate (-0.27) was accepted, 193 subjects were positive, 227 subjects were negative. When the maximum high error rate (+0.27) was accepted, 121 subjects were positive, while 299 were negative (Table 5).

Table 1. %CV values of internal quality control Glucose (n=128) Level1 control (mg/dL)

Glucose (n=128) Level2 control (mg/dL)

Glucose (n=128) Level3 control (mg/dL)

Insulin (n=91) Level1 control (µIU/mL)

Insulin (n=91) Level2 control (µIU/mL)

Insulin (n=91) Level3 control (µIU/mL)

Mean

45.36

123.67

285.74

15.06

46.93

113.39

1.88

6.45

9.29

0.95

3.16

4.48

%CV

4.15

5.22

3.25

6.32

6.74

3.95

4.28

5.8

SD: Standard deviation; %CV: (SD/Mean)*100; Rw: Laboratory reproducibility Rw=√(L1 control material %CV)²+(L2 control material %CV)²+( L2 control material %CV)2/3

doi: 10.5455/medscience.2018.07.8905

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Table 2. External quality control within and between groups bias values and Standard uncertainty for glucose Glucose bias within group (deviation%)

Glucose biasEQA2 within group

Glucose bias between groups (deviation%)

Glucose biasEQA2 between groups

-3.6

12.96

-6.2

38.44

-9.5

90.25

-7.3

53.29

-3.4

11.56

-5.7

32.49

Uncertainty value %

4.68

EQA Samples 1

RMS bias

0.11

3.32

RMS bias: √[(glucose bias within group) + (glucose bias between groups)2]/2 2

Table 3. External quality control within and between groups bias values and Standard uncertainty for insulin Insulin bias within group (deviation%)

Insulin biasEQA2 within group

Insulin bias between groups (deviation%)

Insulin biasEQA2 between groups

-0.93

0.8649

4.55

20.7025

-2.44

5.9536

7.45

55.5025

2.01

4.0401

11.56

133.6336

Uncertainty value %

0.34

EQA Samples

RMS bias

1.42

1.03

RMS bias: √[(insulin bias within group) + (glucose bias between groups)2]/2 2

Table 4. Calculation of uncertainty value Calculations UCV(glukoz)

Uncertainty value %

√(Rw(glucose)2+RMS(glucose)2)/2 √(((4.28)2+(3.32)2))/2

UCV(insulin)

3.83

√(Rw(insulin)2+RMS(insulin)2)/2 √(((5.8)2+(1.03)2)/2

UCV(HOMA-IR)

4.16

√( UCV(glucose)2+ UCV(insulin)2 √(((3.83)2+(4.16)2))/2

SD(HOMA-IR)

5.66

UCV(HOMA-IR)x 2.5/100 (5.66x2.5)/100

U(HOMA-IR)

SD(HOMA-IR)x k

Expanded uncertainty (confidence interval 95%)

0.14x1.96

0.14 0.27

Table 5. Error rates for 0.27 uncertainty, cut-off values and values of true positive and true negative Mistake rate

Cut off

IR+

IR-

2.5

155

265

-0.27

2.23

186

234

+0.27

2.77

126

294

Discussion Uncertainty of Measurement (UM) parameter, associated with the result of measurement, that characterizes the dispersion of the values that could reasonably be attributed to the measured (the quantity intended to be measured) [16]. UM provides quantitative estimates of the level of confidence that a laboratory has in its analytical precision of test results. Therefore, it represents the expected variability in a laboratory result if the test is repeated a second time. Both imprecision and bias are taken into account. Hence, it is a measure of precision to which biological variation and a confidence level (coverage probability based on normal distribution) have been applied. UM is reported in standard

deviation (SD) units or relative SD expressed as the coefficient of variation (%CV) [15,16]. Errors near values of clinical decision limits have gain much importance lately. These errors are mainly caused by measurement uncertainty [17]. These errors may cause increase in medical expenses, malpractices and sometimes even life threatening situations for patients [18]. For these reasons, reporting of patient results with UMs is much important in tests with critical values which help clinical diagnosis. However, consensus have not been reached up to date on this subject. The determination of UM for calculated tests according to clinical decision concentration or cut-off value will be helpful. In the present study, we reported the measurement uncertainty of the calculated test HOMA-IR at 95% CI as 0.27 between 2.23-2.77 which takes attention to consideration 34

doi: 10.5455/medscience.2018.07.8905

of UM results in determination of cut-off values. Especially for the tests used for screening, determination of cut-off values as a range including measurement uncertainty instead of a single value will be more suitable. Internal and external quality control data for glucose and insulin were used in this study for determination of uncertainty. Internal quality control data reflects the precision of the method used, while external quality control data gives an objective evaluation of laboratory performance [19,20]. Any research related to the calculated test as HOMA-IR have not been conducted in the literature yet. The aim of this study is to detect the lower limit for a reporting range of HOMA-IR formula in order to determine UM for clinical decision limits and cut-off values to lower the rate of false negatives. In our study, low limit of the cut-off value with UM was calculated as 2.23 and 7% (25 cases) false negative ratio was detected, which may underestimate true diagnosis. The primary goal of medical laboratories is to produce and report high quality, accurate reproducible results. Each laboratory should evaluate their analysis routines, compare their performance characteristics with other laboratories and periodically update their performance characteristics as it will be affected by time, new chemicals and equipment’s [21,22]. The standardization problems in insulin test is currently persistent. That’s why UM (from systematic and random errors) of each measured parameter should be calculated to detect 95% CI and acceptability in terms of Westgard database should be questioned. In our study, the measurement uncertainty of glucose in HOMAIR calculation is 3.83% and expanded uncertainty is 7.66%. Our data seems to exceed total acceptable error limits (TEa%) give in Westgard biological database criteria (6.96%) [23], however it is in concordance with CLIA 88 (10%) and Fraser (7.9%) criteria [24]. Ozlem et al. detected measurement uncertainty of glucose as 7.26% in their study. UM value detected in our data is 7.66% which was higher than those in the study conducted by Ozlem et al. [25]. In a similar study was found measurement uncertainty of glucose as 7.38% [26]. UM for insulin was found as 4.16% and expanded uncertainty was found as 8.32% in our study. These values are within the TEa (32%) of Westgard [23]. There are limited number of studies for UMs of calculated tests. In addition, to our knowledge any studies have not been carried out for UMs of both insulin and HOMA-IR. Conclusion As a result, when evaluating insulin resistance calculation, consideration of glucose and insulin measurement uncertainties may be helpful in clinical decision for not only the management of treatment, but also overcoming misdiagnosis. Notification of the clinicians for UM is of great importance. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves.

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Cigdem Yucel ORCID: 0000-0003-2647-440X Mehmet Ozcan ORCID: 0000-0002-1222-2802 Fatma Meric Yilmaz ORCID: 0000-0002-8252-5975 Sedat Abusoglu ORCID: 0000-0002-2984-0527 Canan Topcuoglu ORCID: 0000-0003-1479-1600 Yusuf Bayrakceken ORCID: 0000-0002-5652-8168

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Magri CJ, Fava S, Galea J. Prediction of insulin resistance in type 2 diabetes mellitus using routinely available clinical parameters. Diabetes Metab Syndr. 2016;10 Suppl 1):96-101.

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Aregbesola A, Virtanen JK, Voutilainen S, et al. Serum ferritin and glucose homeostasis: change in the association by glycemic state. Diabetes Metab Res Rev. 2015;31:507-14.

Matthews DR, Hosker JP, Rudenski AS,et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412-9.

Ellison S, Williams A. EURACHEM/CITAC Guide CG 4: Quantifying uncertainty in analytical measurement. 2012. pp. 4–6.

10. Matar G, Poggi B, Meley R, et al. Uncertainty in measurement for 43 biochemistry, immunoassay, and hemostasis routine analytes evaluated by a method using only external quality assessment data. Clin Chem Lab Med. 2015;53:1725-36. 11. Kin Tekce B, Tekce H, Aktas G, et al. The role of the uncertainty of measurement of serum creatinine concentrations in the diagnosis of acute kidney injury. Ren Fail. 2016;38:305-10. 12. Beck SC, Lock RJ. Uncertainty of measurement: an immunology laboratory perspective. Ann Clin Biochem. 2015;52(Pt 1):7-17. 13. Theodorsson E. Uncertainty in measurement and total error: tools for coping with diagnostic uncertainty. Clin Lab Med. 2017;37:15-34. 14. White GH, Farrance I, AACB Uncertainty of Measurement Working Group. Uncertainty of measurement in quantitative medical testing: a laboratory implementation guide. Clin Biochem Rev. 2004;25:1–24 15. Moses G, Crawford L. Traceability and measurement of uncertainty for medical laboratories. QMP-LS.OLA.2011. Canada (http://www.qmpls.org). 16. Farrance I, Frenkel R. Uncertainty of Measurement: A Review of the Rules for Calculating Uncertainty Components through Functional Relationships. Clin Biochem Rev. 2012;33:49-75. 17. Plebani M. Errors in clinical laboratories or errors in laboratory medicine? Clin Chem Lab Med. 2006;44:750–9

Ethical approval Before the study, permissions were obtained from local ethical committee.

18. European Co-operation for Accreditation of Laboratories, EAL-G23, Edition 1, August. 1996

Mujgan Ercan ORCID: 0000-0002-9291-4197 Aysen Caniklioglu ORCID: 0000-0001-8128-6044 Esra Firat Oguz ORCID: 0000-0002-8147-5379

19. 1Feinberg M, Boulanger B, Dewe W, et al. New advances in method validation and measurement uncertainty aimed at improving the quality of chemical data. Anal Bioanal Chem. 2004;380:502-14.

doi: 10.5455/medscience.2018.07.8905 20. Adams TM. A2LA Guide for the Estimation of Measurement Uncertainty In Testing July 2002. 21. ISO 15189:2014.Medical laboratories requirements for quality and competence. 2nd ed. International organization for standards, Geneva,Switzerland, 2014 22. Kuwa K. Internal Quality Control and External Quality Assessment on POCT. Rinsho Byori. 2015;63:224-31. 23. Ricos C, Alvarez V, Cava F, et al. Current databases on biologic variation:

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pros, cons and progress. Scand J Clin Lab Invest. 1999;59:491-500. 24. Fraser CG. Biological variation: from principle to practicies. 140 AACC Press,Washington. 2001 25. Öztürk O, Serdar M, Öztürk M, et al. Calculation of uncertainty for glucose: may it affect the diagnosis of gestational diabetes? Turk J Biochem. 2012;37;68–72 26. Chen H, Zhang L, Bi X, et al. Two evaluation budgets for the measurement uncertainty of glucose in clinical chemistry. Korean J Lab Med. 2011;31:167-171.

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Medicine Science International Medical Journal

Medicine Science 2019;8(1):37-41

Traumatic cataract study: Surgical outcomes of blunt versus penetrating ocular injuries Cetin Akpolat, Ferhat Evliyaoglu, Muhammed Mustafa Kurt, Aylin Karadas, Mehmet Necdet Cinhuseyinoglu, Mustafa Nuri Elcioglu Okmeydani Training and Research Hospital, Clinic of Ophthalmology, Istanbul, Turkey Received 10 July 2018; Accepted 25 July2018 Available online 13.11.2018 with doi:10.5455/medscience.2018.07.8914 Copyright ÂŠ 2019 by authors and Medicine Science Publishing Inc. Abstract The aim of the present study is to evaluate the results of traumatic cataract surgery with regard to the type of trauma, mainly in the assessment of visual acuity. Fortyfour patients who had been diagnosed with traumatic cataracts were included in this retrospectively designed study. The patients were divided into blunt and penetrating groups according to the type of trauma. Pre- and postoperative ocular findings of the cases were evaluated. Visual acuity, intraocular pressure, intra- and postoperative complications, associated injuries, and surgical approaches were analyzed. Thirty-three of the cases were male (75%) and 11 (25%) were female. There were 23 patients (52.27%) in the blunt group and 21 (47.72%) in the penetrating group. The pre-operative mean vision of the subjects included in the blunt and penetrating groups was 0.82 and 0.96 logMAR, respectively. Ten (22.72%) eyes were hypotonic (<8mmHg), most of which were found in the penetrating group. The mean postoperative vision was 0.22 and 0.39 logMAR in the blunt and penetrating groups, respectively. Posterior capsule perforation was observed in five cases (11.36%) as an outcome of trauma and in two cases (4.54%) as a surgical complication. Anterior vitrectomy was performed in 15 cases and a capsular tension ring was implanted in five cases. In 34 cases (77.27%), an intraocular lens was implanted, and 10 cases (22.72%) were left as aphakic. The follow-up period of the cases was 12 months. The most important factors affecting the final vision of patients undergoing traumatic cataract surgery are preoperative visual acuity and the severity of the trauma. The time of surgery should be individualized according to the severity of the case. Surgical success is related to the type of trauma and the experience of the surgeon. Keywords: Traumatic cataract, blunt injury, penetrating injury, phacoemulsification

Introduction Ocular trauma is a leading cause of visual loss and blindness [1]. The type of ocular trauma may be penetrating or non-penetrating. The formation of traumatic cataracts is associated with an open globe injury or contusion to the eye [2]. Infrared energy, electric shock, and ionizing radiation may also cause traumatic cataracts [2,3]. Traumatic cataracts are a common complication of ocular trauma [4]. Traumatic cataracts generally give rise to several accompanying findings depending on the type and severity of the trauma [5,6]. Associated injuries to other ocular structures create a significant medical and surgical challenge to ophthalmologists [7]. Consequently, a detailed history, careful ophthalmic examination, and defined case management should be utilized, which facilitate the process and provide the best possible visual outcome. *Coresponding Author: Cetin Akpolat, Okmeydani Training and Research Hospital, Clinic of Ophthalmology, Istanbul, Turkey E-mail: akpolatcetin@yahoo.com

Management of traumatic cataracts remains a challenge. Obtaining accurate keratometry and axial-length measurements, timing the surgery, and implanting the intraocular lens (IOL) are prominent challenges in the management of traumatic cataracts [8]. The preferred approach to a patient with a penetrating eye injury is first to fix the corneal or scleral laceration (if one exists) and then perform the removal of the cataract [9,10]. The secondary extraction of the cataract may be performed with better visibility during surgery and with less chance of postoperative complications [11]. In this retrospective study, we will report the results of traumatic cataract surgery, including the surgical approach, type of trauma, and postoperative complications. Material and Methods Study Design and Patients The study was designed in retrospective fashion and the data were obtained via chart review of medical records. The study adhered to the principles of the Declaration of Helsinki, and the Institutional 37

doi: 10.5455/medscience.2018.07.8914

Review Board (IRB) approved the study protocol. Informed written consent was obtained from all of the patients prior to surgery. The study included 44 eyes of 44 adult patients who were diagnosed with traumatic cataract at the Department of Ophthalmology. Adult patients diagnosed with traumatic cataract due to blunt or penetrating injury were included in the study. The patients were divided into two groups based on the type of trauma: closedglobe injuries served as Group 1 (Blunt Group), and open-globe injuries as Group 2 (Penetrating Group). Patients with a history of previous uncontrolled glaucoma or active ocular inflammation were excluded from the study. The primary data analyzed for the purpose of the study included best-corrected visual acuity (BCVA) as measured by a logarithm of the minimum angle of resolution (logMAR) units, intraocular pressure (IOP) as measured by Goldmann applanation tonometry (IOP<8mmHg was assigned as ocular hypotonia), and intra- and postoperative complications and associated injuries. In addition to BCVA and IOP, detailed ophthalmic examinations including anterior-segment evaluation by slit-lamp biomicroscopy, funduscopy with +90D lens, and B-scan (in cases of hazy media) were performed prior to surgery and following the surgery at days one and seven and at months one, three, six, and 12. The outcome of surgery was assessed primarily by comparing the final (12th month) and baseline BCVA. Surgical Technique All surgeries were performed by the same surgeon. The anatomical integrity of the globe was first restored in patients with penetrating injury. The phacoemulsification technique with the Alcon Infiniti Vision System was performed for cataract extraction in cases without lenticular subluxation or zonulolysis and cases with mild lenticular subluxation or partial zonulolysis. In cases with marked lenticular subluxation and/or with zonular dialysis of more than half, intra-capsule cataract extraction (ICCE) was performed. Anterior vitrectomy was performed in patients who had ICCE and preoperative or intraoperative posterior capsule rupture. In addition to primary posterior chamber intraocular lens (PCIOL) implantation, secondary PCIOL was performed in some patients. The acrylic foldable three-piece PCIOL (Alcon AcrySof MA60BM, USA) was implanted in all patients with or without capsular support according to the formula of Sanders-RetzlaffKraff (SRK-T). In those cases in which IOL power calculation was not possible using the biometry of the affected eye, it was performed using the biometry of the fellow eye. A capsular PCIOL was implanted in cases with adequate capsular-bag support. The PCIOL was implanted into the sulcus in patients with inadequate capsular-bag support. Scleral-fixated IOL (SFIOL) was performed in patients with inadequate capsular support. All patients were treated with the appropriate topical regimen, and postoperative complications were managed accordingly as soon as they were diagnosed. Statistics Continuous data were presented as mean ± standard deviation, and categorical measurements were noted as numbers (%). Normal distribution (checked by the Kolmogorov-Smirnov test) and random sample selection were the given assumptions during data analysis. All statistical analyses were performed via Statistical

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Package for the Social Sciences (SPSS) version 19.0 (IBM Co., Armonk, NY, USA) using the (two-tailed and dependent) Student’s t-test and the independent samples t-test to determine the significance of intra- and intergroup study parameters. A p value of less than 0.05 was considered to indicate statistical significance. Results Demography and Surgical Intervention A total of 44 patients were included in the study. The mean age of the patients was 34.26 ± 4.27 (21–62) years. The blunt and penetrating groups were composed of 23 (52.27%) and 21 (47.72%) patients, respectively. With regard to mode of injury, both blunt and penetrating trauma were observed more frequently among males, with a higher proportion in the penetrating group. The patients were followed up for 12 months. All patients visited our hospital within 24 hours following injury and received the proper emergent surgical or medical treatment according to the severity of the case. (Table 1) The most common causative agents were stones and thorns for the blunt and penetrating groups, respectively. Total cataract was the most common type (86.11%) among the type of cataracts (rosette, absorbed lens matter, calcified, and posterior subcapsular). The time lapses between visiting our hospital and surgery ranged from zero to one month. Cataract extraction combined with primary PCIOL implantation was more prevalent in Group 1 (Blunt Group). Cataract extraction followed by secondary PCIOL implantation was considerably more common in Group 2. More than 75% of the patients underwent implantation of the PCIOL into the capsular bag or sulcus, and the remaining patients underwent surgery for implantation of SFIOL. The time duration between cataract surgery and secondary PCIOL was two to four months. Primary wound repair (four patients with corneal laceration in the penetrating group), foreign-body removal (one patient in the penetrating group), pupilloplasty (one patient in the penetrating group), and vitreoretinal surgery (one patient in the blunt and one patient in the penetrating group) were also performed in addition to cataract extraction. (Table 1) Table 1. Age and intraocular lens placement in blunt and penetrating groups Blunt Total (N)

Penetrating

35.42±6.88

32.26±4.14

PCIOL-bag

PCIOL-sulcus

SFIOL

Age (mean, y)

PCIOL: Posterior chamber intraocular lens, SFIOL: Scleral-fixated intraocular lens

Associated Injuries and Complications Several associated ocular injuries were observed among the patients with traumatic cataracts. The involvement of the anterior segment was more prevalent than that of the posterior segment. Traumatic mydriasis, secondary glaucoma, lens dislocation, and anterior-chamber hyphema (ACH) were commonly seen in eyes with closed-globe injuries. Corneal laceration, lens dislocation, anterior capsule violation, uveal prolapses, and iris synechia were 38

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the most common associated anterior-segment ocular injuries in eyes with open-globe injuries. Vitreous hemorrhage and retinal detachment (RD) were the associated posterior-segment findings with blunt-type trauma. Posterior capsular rupture caused by trauma was detected during the surgery in five cases, and two cases had posterior capsular rupture intra-operatively as a surgical complication. Anterior vitrectomy was performed and a PCIOL was implanted into the sulcus in five cases, and two cases received SFIOLs two to four months after the first surgery. Besides these, eight patients with lens dislocation underwent an anterior vitrectomy, and an SFIOL was implanted in those patients two to four months after the cataract extraction. Five patients were fitted with an implanted capsular-tension ring combined with PCIOL implantation into the capsular bag due to partial zonulysis. The complications noted during the study period included a transient increase in IOP, cystic macular edema (CME) corneal decompensation, posterior capsule opacification (PCO), retinal detachment, and endophthalmitis. Visual Acuity and IOP

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In Group 1, one eye had perception of light, eight eyes had visual acuity <0.1, 12 had visual acuity 0.1 - 0.5, and two had visual acuity >0.5 upon admission. In Group 2, two cases had perception of light, 11 eyes had visual acuity <0.1, seven had visual acuity 0.1 - 0.5, and one had visual acuity >0.5 upon admission. In both groups, a significant (p <0.05) improvement was observed in the mean of the final BCVA at the 12th month compared to the baseline. In Group 1, 17 cases saw visual improvement, and four cases had no visual changes, whereas two cases experienced a decrease in visual acuity. Among Group 2, 14 cases had visual improvement, four cases had no visual changes, and three cases experienced a decrease in visual acuity. (Table 2) There was no statistical change (p=0.368) between the means of the baseline and final IOP values in the blunt group, while a significant increase (p <0.05) was observed in Group 2. Three (13.04%) and seven (33.33%) eyes were evaluated as hypotonic (<8mm) preoperatively in Groups 1 and 2, respectively. Three (13.63%) patients developed secondary glaucoma (controlled via medical therapy) in Group 1, while no patients had glaucoma in Group 2 during the study period. (Table 2)

Table 2. Alteration of BCVA and IOP in blunt and penetrating groups Parameters

Blunt

Penetrating

Admission

0.82±0.34

0.96±0.48

0.384

12th month

0.22±0.16

0.39±0.20

0.026*

0.001*

0.002*

BCVA(logMAR)

P IOP(mmHg) Admission

15.82±2.46

11.22±2.86

0.088

12th month

14.10±3.08

14.55±2.50

0.468

0.368

0.038*

*: Statistically significant, BCVA: Best corrected visual acuity, IOP: Intraocular pressure

Discussion This retrospective study was designed to report the outcomes of traumatic cataract surgeries in adult patients based on the type of trauma. Best corrected visual acuity, IOP, demographic properties, associated ocular injuries, emergent intervention, implanted IOL, intra- and postoperative complications, and other surgical procedures were the main data assessed in the study. Traumatic cataract remains an important cause of visual impairment in spite of new diagnostic and therapeutic developments [12,13]. In addition to surgical complications, associated ocular injuries such as corneal laceration and retinal detachment may cause poor prognoses [14–16]. It is much more difficult to treat traumatic cataract as compared to atraumatic cataract, as there is a higher risk of intra- and postoperative complications due to lens subluxation, zonulysis, and other associated ocular injuries [17,18]. More attention must be paid to postoperative inflammation due to accompanying injuries and because the cataract surgery is a second intraocular intervention following the primary repair in cases with a penetrating eye injury [18]. The success of visual rehabilitation in traumatic

cataract cases without adequate capsular support depends upon the choice of the surgical procedure, the experience of the surgeon, and the preferred type of IOL [19]. Capsular bag or sulcus-implanted PCIOL, iris-fixated IOL (IFIOL), anterior-chamber IOL (ACIOL), and SFIOL are the surgical treatment options for traumatic cataract cases [8]. The use of IOL provides minimal aniseikonia and a predictable refractive outcome. Posterior chamber IOL placement into the capsular bag and sulcus has several advantages, as its physiological placement of the IOL is nearest to the original lens position. Anterior chamber IOL implantation is often limited due to complications such as irreversible corneal endothelial loss, corneal decompensation, iris atrophy, iris sphincter erosion, pupil ectopia, and glaucoma [20]. Although SFIOL implantation requires experience and may be a challenging and time-consuming technique, it has many advantages in comparison with ACIOL, such as providing a good physiological placement of the IOL, having a mechanical barrier between the vitreous cavity and the anterior chamber, and having no contact with the corneal endothelium or trabecular meshwork. On the other hand, IOL subluxation, dislocation, endophthalmitis, and RD are important complications of SFIOL and should be considered before implantation [21,22]. In this study, we observed 39

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RD in one case with SFIOL, but there was no other complication related to SFIOL. Iris-fixated IOLs provide an improved design and a greater distance from the endothelium, are easy to implant, and represent a promising technique, but they may result in iris chafing, uveitis, and pupillary constriction [23,24]. Furthermore, iris fixation is not applicable in cases of significant iris trauma, so SFIOL is the treatment of choice in that situation. Several studies have reported that nearly half of traumatic cataract cases experienced penetrating injuries, and a male majority has been observed among the victims, possibly because of the involvement of males in sports and outdoor activities; this was supported in our findings [25–27]. Sharma et al. [28] studied traumatic-cataract patients with respect to age and found that 50% of patients with traumatic cataracts were less than fifteen years old. However, we did not study subjects in the pediatric age range. Sharma et al. [28] reported that traumatic-cataract patients might have good visual outcomes with proper management, which supports our outcomes. Like Sharma et al. [28], we found that the most common causative agents were stones and thorns for Groups 1 and 2, respectively. However, it is probable that the diverse causative agents reported in the literature depend on region or country, as the most common causes of traumatic cataract may vary according to the region of the study. We noted that corneal laceration was the most common accompanying ocular damage in Group 2, which was strongly supported by other studies [29,30]. Studies show that most patients have cataract surgery within one month in blunt-type traumas, whereas this duration may exceed two months in open-eye injuries, which was also supported in our study [31,32]. Because the final visual assessment is the most important prognostic factor for the success of surgery, most studies focus on the evaluation of visual acuity. We observed a significant visual improvement postoperatively in both groups, supporting many studies [33–35] on this topic. It was statistically comparable to evaluate the intergroup mean of BCVA values at baseline and final visit, as the difference between the numbers of patients was statistically insignificant (n=23 and 21, p=0.542). Baseline BCVA values of the groups were similar (p=0.384). Both groups had a significant visual improvement, with Group 1 showing a statistically better visual improvement than Group 2 (p=0.026). We speculate that this may be related to the fact that, of the associated ocular injuries, corneal laceration was the more common in Group 2. Despite the intergroup similarity of mean IOP measurements at baseline and final visit, we infer that the significant increase of IOP in Group 2 was due to a high proportion of preoperative hypotonic patients compared to Group 1 (2.83:1). We timed the surgery according to the case, so we did not study this statistically. Tabatabaei et al [36]. conducted a study to determine the proper time for traumatic cataract surgery after open-globe injuries. They observed no difference between an early and a late procedure with regard to post-surgical BCVA and prominent intraoperative and postoperative complications. Better visibility due to amelioration of corneal damage and edema, more accurate IOL calculation, and less postoperative inflammation are the benefits of late or secondary intervention [37]. However, it is reasonable to perform the surgical procedure sooner in some special situations, such as the rupture of the anterior capsule and the presence of lens material in the anterior chamber, which may

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cause an increase in IOP, prolonged inflammation and anterior/ posterior synechiae, and a need for visual rehabilitation and amblyopic therapy in the pediatric/young population [38]. Posterior capsule opacification and CME were the late complications seen in both groups. We observed that a transient IOP increase and PCO did not affect visual acuity after treatments by anti-glaucomatous regimen and Nd: YAG laser, respectively, six months after surgery. Although we experienced some intraoperative difficulties, such as corneal edema and capsular tear, as well as postoperative complications, such as RD and endophthalmitis, we did not find a significant difference in the rates of complications between the two groups. To our best knowledge, a few studies have reported the outcomes of traumatic cataract surgery performed by the phacoemulsification technique. Kalyanpad and Shinde [39] found in their study that phacoemulsification with PCIOL is also an important modality of treatment in traumatic cataract.. Conclusion In conclusion, the present study revealed that phacoemulsification and ICCE are successful techniques for treating traumatic cataracts, improving the final visual acuity in blunt- and penetrating-type traumas. Success is also associated with the type and severity of trauma and the experience of the surgeon. Moreover, BCVA improvement may be greater in Group 1 than in Group 2. Its retrospective nature, sample size, study period, and absence of age analysis are the limitations of the study. New studies could be conducted in consideration of these limitations. Competing interests The authors declare that they have no competing interest. Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Before the study, permissions were obtained from local ethical committee. Cetin Akpolat ORCID: 0000-0002-7443-6902 Ferhat Evliyaoglu ORCID: 0000-0003-3260-686X Muhammed Mustafa Kurt ORCID: 0000-0002-4667-3046 Aylin Karadas ORCID: 0000-0001-9343-1421 Mehmet Necdet Cinhuseyinoglu ORCID: 0000-0002-6074-9107 Mustafa Nuri Elcioglu ORCID: 0000-0002-8238-9106

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Brar GS, Ram J, Pandav SS, et al. Postoperative complications and visual results in uniocular pediatric traumatic cataract. Ophthalmic Surg Lasers. 2001;32:233-8.

25. Smith D, Wrenn K, Stack LB. The epidemiology and diagnosis of penetrating eye injuries. Acad Emerg Med. 2002;9:209-13.

10. Verma N, Ram J, Sukhija J, et al. Outcome of in-the-bag implanted squareedge polymethyl methacrylate intraocular lenses with and without primary posterior capsulotomy in pediatric traumatic cataract. Indian J Ophthalmol. 2011;59:347-51. 11. Mester V, Kuhn F. Ocular trauma: principles and practice. New York (NY): Thieme; 2002. Lens In: Kuhn F, Pieramici DJ. Editors; pp. 180-204. 12. Shah M, Shah S, Khandekar R. Ocular injuries and visual status before and after their management in the tribal areas of Western India-A historical cohort study. Grafes Arch Clin Exp Ophthalmol. 2008;246:191-7. 13. Wos M, Mirkiewicz-Sieradzka B. Traumatic cataract--treatment results. Klin Oczna. 2004;106:31-4. 14. Lacmanovic Loncar V, Petric I. Surgical treatment, clinical outcomes, and complications of traumatic cataract: Retrospective study. Croat Med J. 2004;45:310-3. 15. Sternberg P, Jr de Juan E, Jr Michels RG, et al. Multivariate analysis of prognostic factors in penetrating ocular injuries. Am J Ophthalmol. 1984;98:467-72. 16. Greven CM, Collins AS, Slusher MM, et al. Visual results, prognostic indicators, and posterior segment findings following surgery for cataract/ lens subluxation-dislocation secondary to ocular contusion injuries. Retina. 2002;22:575-80. 17. Zaman M, Sofia I, Muhammad DK. Frequency and visual outcome of traumatic cataract. J Postgrad Med Inst. 2006;20:330-34. 18. Gayton JL, Sanders V, Van Der Karr M. Pupillary capture of the optic in secondary piggyback implantation. J Cataract Refract Surg. 2001;27:1514-5. 19. Dakshayani R, Rakesh. Analysis of visual prognosis after surgery in traumatic cataract. J Evid Based Med Healthc. 2014;1:1029-46. 20. Morrison D, Sternberg P, Donahue S. Anterior chamber intraocular lens (ACIOL) placement after pars plana lensectomy in pediatric Marfan syndrome. J AAPOS. 2005;9:240-2. 21. Schmidt JC, Nietgen GW, Freisberg L, et al. Modified transscleral suture for sulcus fixation of posterior chamber lenses. J Cataract Refract Surg. 2002;28:15-7. 22. Solomon K, Gussler JR, Gussler C, et al. Incidence and management of complications of transsclerally sutured posterior chamber lenses. J Cataract Refract Surg. 1993;19:488-93.

26. Ashwini K, Robin R, Kimbley G. Surgical intervention for traumatic cataracts in children: epidemiology, complications and outcomes. J AAPOS. 2009;13:170-9. 27. Srivastava U, Lalramhluri R, Rawat P, et al. Clinical evaluation of post traumatic cataract in tertiary care hospital. International Journal of Scientific & Research Publications. 2014;4:1-6. 28. Sharma AK, Aslami AN, Srivastava JP, et al. Visual outcome of traumatic cataract at a tertiary eye care centre in north india: A prospective study. J Clin Diagn Res. 2016;10:NC05-8. 29. Munndada R, Shinde S, Pathan MS, et al. Badaam observational study of ocular damage and visual loss associated with traumatic cataract patients at tertiary care hospital in aurangabad maharashtra. Internation Med J. 2014;1:35-6. 30. Reddy AK, Ray R, Yen KG. Surgical intervention for traumatic cataracts in children: Epidemiology, complications, and outcomes. J AAPOS. 2009;13:170-4. 31. Memon MN, Narsani AK, Nizamani NB. Visual outcome of unilateral traumatic cataract. J Coll Physicians Surg Pak. 2012;22:497-500. 32. Jagannath C, Penchalaiah T, Swetha M, et al. Visual outcome of traumatic cataract in a tertiary care hospital, Tirupati. Internation Arch Integrat Med. 2015;2:111-5. 33. Yen KG, Reddy AK, Weikert MP, et al. Iris-fixated posterior chamber intraocular lenses in children. Am J Ophthalmol. 2009;147:121-6. 34. Shah MA, Shah SM, Shah SB, et al. Morphology of traumatic cataract: does it play a role in final visual outcome? BMJ Open. 2011:29:1. 35. Kuhn F. Traumatic cataract: what, when, how. Graefes Arch Clin Exp Ophthalmol. 2010;248:1221-3. 36. Tabatabaei SA, Rajabi MB, Tabatabaei SM,et al. Early versus late traumatic cataract surgery and intraocular lens implantation. Eye (Lond). 2017:31;1199-204. 37. Memon MN, Narsani AK, Nizamani NB. Visual outcome of unilateral traumatic cataract. J Coll Physicians Surg Pak. 2012; 22:497-500. 38. Rubsamen PE, Cousins SW, Winward KE, et al. Diagnostic ultrasound and pars plana vitrectomy in penetrating ocular trauma. Ophthalmology 1994;101:809-14. 39. Poonam N. Kalyanpad, Chhaya A. Shinde. Traumatic cataract: different modalities of treatments and its outcome. Med Pulse-Internation Med J. 2014;1:217-21.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):42-7

Reliability of multi-vessel off-pump coronary artery by-pass surgery in patients who have low risk profile Hakan Fotbolcu1, Erhan Kaya2 2

1 Pendik Regional Hospital, Department of Cardiology, Istanbul, Turkey Pendik Regional Hospital, Department of Cardiovascular Surgery, Istanbul, Turkey

Received 04 July 2018; Accepted 26 July 2018 Available online 19.09.2018 with doi:10.5455/medscience.2018.07.8864 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract We investigated the reliability of multi-vessel off-pump coronary artery by-pass surgery in patients who have low risk profile. This study included 53 patients who undergone off-pump coronary artery by-pass surgery. Patients have been allocated two groups in terms of graft count. 1 and 2 vessel patients were defined as Group A and 3,4,5 vessel patients as Group B. Baseline and serial post-operative CK-MB values were obtained. Ejection fraction (LVEF), mitral-myocardial systolic velocities (lateral S’ and septal S’), mean E’, left ventricle filling pressure index (E/E’ ratio) and tricuspid-S’ were calculated at pre and postoperative period. Intensive care unit stay time was moderately correlated with pre mean E’ (r = -0.32, p=0.020) and pre E/E’ ratio (r = 0.34, p=0.013). ∆ CK-MB values were similar between two groups (p=0.263). There are no differences between groups in terms of ∆ LVEF, ∆ mean E’, ∆ lateral S’ and ∆ tricuspid S’. ∆ E/ E’ ratio was mildly in favour of group A patients (-2.31 ± 2.70 vs. -0.29 ± 2.89, p=0.007). Furthermore, ∆ septal S’ was slightly in favour of group A patients (0.71 ± 2.39 cm/s vs. -0.66 ± 1.73 cm/s, p=0.017). Multi-vessel off-pump coronary artery by-pass surgery seems as safe as 1 and 2 vessels despite small differences in terms of cardiac function alterations in patients who have low risk profile. Keywords: Multi-vessel off-pump coronary artery surgery, reliability, low risk profile

Introduction

Material and Methods

Off-pump coronary artery bypass (OPCAB) graft surgery has been assessed as a safe alternative to conventional coronary artery bypass graft surgery with cardiopulmonary bypass (ONCAB) for myocardial revascularization since it may be associated with decreased postoperative morbidity [1,2]. Perioperative myocardial ischemia is an important complication, increasing mortality and morbidity after cardiac surgery [3]. Clinical trials revealed that the release of troponin I following OPCAB is lower than after ONCAB [4]. A major pitfall to OPCAB was difficulty of performing coronary anastomoses with the needed precision, particularly on the lateral and posterior surfaces of the heart. Recent improvement in the technology has allowed multiple-vessel grafting in all coronary areas using OPCAB possible with a graft patency comparable to ONCAB [2].

Fifty-three patients who have undergone off-pump coronary artery by-pass surgery were included in this study. Patients were divided into two groups in terms of used graft count at the operation. 1 and 2 vessels were defined group A and 3,4 and 5 vessels were defined group B. The following patients were excluded from this study: severe morbid obesity [body mass index (BMI) > 35], moderate or severe heart valve insufficiency and/or stenosis, congenital heart disease, atrial fibrillation, left bundle branch block, established myocardial infarction within last one week, left ventricular ejection fraction (LVEF) < 40 %, symptomatic heart failure, poor echocardiographic image quality, stroke, chronic obstructive pulmonary disease, chronic renal failure or musculoskeletal disorder.

The aim of our study was to investigate reliability of multi-vessel off-pump coronary artery by-pass surgery in patients who have low risk profile using close cardiac enzyme monitoring and prepostoperative detailed echocardiographic parameters in terms of cardiac function alterations. *Coresponding Author: Hakan Fotbolcu, Pendik Bölge Hastanesi, Department of Cardiology, Istanbul, Turkey E-mail: hakan_fotbolcu@yahoo.com

All study patients underwent a thorough clinical, anthropometric, and laboratory investigation. Participants were classified as hypertensive if resting systolic blood pressure was ≥140mmHg and/or diastolic blood pressure was ≥90 mmHg or if they took antihypertensive medications. Diabetes was diagnosed according to World Health Organization criteria [5]. Smoking history was defined as any current or past form of tobacco use. Height and weight of all subjects were measured and the body mass index (BMI) was calculated as weight (kg) divided by height² (m). Blood samples were obtained one day ago from the operation. All patients 42

doi: 10.5455/medscience.2018.07.8864

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had serial measurement of CK-MB values at the following times: preoperatively at 6, 12, 18, 24, 48h after the end of the operation. The postoperative highest value of CK-MB was defined peak CKMB. ∆ CK-MB was calculated as peak CK-MB minus baseline CK-MB.

systolic function was evaluated with lateral S’ and the septal S’. Right ventricular systolic function was assessed with tricuspid S’ since these parameters are relatively less effected from the preload condition. The values of ∆ were calculated as post-operative value minus pre-operative value for all echocardiographic parameters.

Operative technique: The heart was approached via standard median sternotomy. Normothermia was ensured during the operations by warming the operative theatre and using a heating mattress. A single no:1 silk suture, which had been passed previously through a gauze swab, was placed in the posterior pericardium at the midline between the inferior vena cava and the left inferior pulmonary vein. This retraction stitch enabled vertical displacement of the cardiac apex. Intravenous heparin (80 IU/kg) was administered prior to beginning the distal anastomoses with a target activated clotting time between 250-300 s. The distal anastomosis of left internal mammary artery (LIMA) on left anterior descending (LAD) was performed first. Proximal anastomoses of venous or free arterial grafts were made before performing distal anastomoses. A tissue stabilizer (ACROBAT-i Stabilizer System - Maquet) was used in all patients. Distal anastomoses were performed by the aid of a CO2-water blower (Clearview Medtronic, Inc., Minneapolis, MN). Anastomosis time was defined as sum of each distal anastomosis time. Operation time was defined from skin to skin time. Patients who were taken intensive care unit (ICU) at postoperative period were discharged to service in case of extubation and hemodynamic stabilization.

Statistical Analysis The distributions of continuous variables were evaluated using Shapiro-Wilk test. The results with distribution were expressed as mean ± standard deviation. Categorical variables were expressed as percentages. Statistical analyses were performed using SPSS for Windows version 23.0. For continuous variables, the differences between two groups were compared using Mann Whitney U-test for non-parametric data. Pre-post comparisons were done with Wilcoxon test for paired samples. Categorical parameters were analyzed using χ2 test. Correlation was assessed using Spearman’s correlation coefficient. p< 0.05 was considered as statistically significant for all tests.

Echocardiographic measurements: Each patient underwent standard transthoracic two- dimensional echocardiography one day ago from the operation. Post-operative echocardiographic parameters were taken between 48h and 72h after operation. Patients who developed atrial fibrillation were treated with amiodarone infusion. Post-operative echocardiographic parameters were taken after sinus rhythm was restored for these patients. All echocardiographic measurements were performed by one operator, who was blinded for the clinical and laboratory results of the study group. GE Vivid S5 cardiovascular ultrasound machine (GE, Vingmed, Horten, Norway) with a 2,5 MHz phasedarray transducer was used for each study subject. End-diastolic volume (EDV), end-systolic volume (ESV) and ejection fraction (EF) was calculated using the biplane Simpson’s method. From the apical four-chamber view, pulse-wave Doppler recordings of the mitral inflow were obtained with the sample volume placed at the tips of the mitral valve leaflets. Peak velocities of early (E) was measured by pulse-wave Doppler. All Doppler signals were recorded with a chart recorder set at 100 mm/sec. The averages of 3 cycles were used. The TDI program was set to pulse-wave Doppler mode. Filters were set to exclude high frequency signals. Gains were minimized to allow a clear tissue signal with minimal background noise. The TDI of the diastolic and systolic velocities was obtained from the apical 4-chamber view. A 1.5-mm sample volume was placed at the lateral corner of mitral, septal corner of mitral and lateral corner of tricuspid annulus. Analysis was performed for early (E’) and myocardial systolic velocity (S’). Mean E’ was calculated as septal E’ plus lateral E’ divided by 2 for diastolic performance of left ventricle. In addition, E/E’ (mean E’) was calculated as an indicator of left ventricle filling pressure. Left ventricular

Results Fifty-three patients (mean age 61.00 ± 8.78 years) were included in this study. Thirty-eight patients (71.7%) have hypertension diagnosis and twenty patients (37.7%) have diabetes mellitus diagnosis. Twenty-nine patients (54.7%) were smoker. Atrial fibrillation has occurred in ten patients (18.9%) at postoperative period. According to graft count, six patients (11.3%) have 1, fifteen patients (28.3%) have 2, twenty-three patients (43.4%) have 3, four patients (7.5%) have 4 and five patients (9.4%) have 5. LIMA-LAD anastomosis was used for all patients. Saphenous vein grafts were usually used for non-LAD anastomosis. Arterial grafts were used only five patients (9.4%) for non-LAD anastomosis. For all group, mean ICU stay time was assessed 1362.64 ± 429.61 minutes, mean operation time was calculated 116.17 ± 28.05 minutes and mean anastomosis time was measured 49.06 ± 25.42 minutes. Mean CK-MB value of all group has significantly increased at postoperative period (1.42 ± 0.79 ng/dl vs. 39.36 ± 56.31 ng/dl, p<0.001). Pre-op and post-op echocardiographic parameters of all patients are presented in Table-1. LVEF has decreased mildly but statistically significant at postoperative era (p=0.001). Mean E’ has increased (p=0.046) and E/ E’ ratio has decreased (p=0.009) at postoperative period. For tissue Doppler velocities, only tricuspid S’ value has changed in favour of decreasing (p<0.001). The Spearman’s correlation analysis that was including graft count, age, BMI, hypertension, diabetes mellitus, smoking, atrial fibrillation, LDL-cholesterol, creatinine, potassium, hematocrit, ∆CK-MB, anastomosis time, operation time, ICU stay time and echocardiographic parameters was performed on the all patients. There is a mild correlation between graft count and ∆ E/E’ ratio (r = 0.27, p=0.050). Furthermore, there are negative correlations between graft count and ∆ Septal S’ (r = -0.33, p=0.015) and ∆ Tricuspid S’ (r = -0.31, p=0.022). As expected, there are strong correlations between graft count and anastomosis time (r = 0.90, p<0.001) and operation time (r = 0.77, p<0.001). We have detected a significant correlation between atrial fibrillation incidence and pre E/ E’ ratio (r = 0.33, p=0.017). ICU stay time was moderately correlated with pre mean E’ (r = -0.32, p=0.020) and pre E/E’ ratio (r = 0.34, p=0.013) (Figure-1). Operation time was correlated with

doi: 10.5455/medscience.2018.07.8864

∆ CK-MB (r = 0.28, p=0.043) and ∆ E/ E’ ratio (r = 0.31, p=0.024). ∆ CK-MB was correlated with ∆ EF (r = -0.41, p=0.002) and ∆ E/ E’ ratio (r = 0.39, p=0.003). Table 1. Change of echocardiographic parameters in all patients. Echocardiographic parameters

Pre-Op (n=53)

Post-Op (n=53)

EDV (mL)

108.79 ± 32.01

93.04 ± 24.96

<0.001

ESV (mL)

43.32 ± 18.84

40.51 ± 15.24

0.097

LVEF (%)

61.17 ± 6.58

57.08 ± 7.57

0.001

Mean E' (cm/s)

6.81 ± 1.78

7.34 ± 1.79

0.046

E/ E' ratio

10.59 ± 2.86

9.50 ± 3.39

0.009

Lateral S' (cm/s)

7.58 ± 2.17

7.25 ± 2.06

0.338

Septal S' (cm/s)

7.36 ± 1.66

7.25 ± 1.90

0.621

Tricuspid S' (cm/s)

13.19 ± 3.04

9.30 ± 2.04

<0.001

EDV; left ventricular end-diastolic volume, ESV; left ventricular end-systolic volume, LVEF; left ventricular ejection fraction, Mean E’; mean of mitral annular peak diastolic E’ velocities, Lateral S’; mitral lateral annulus peak myocardial systolic velocity, Septal S’; mitral septal annulus peak myocardial systolic velocity, Tricuspid S’; tricuspid lateral annulus peak myocardial systolic velocity Table 2. Baseline clinical, biochemical and operation parameters of subgroup patients Variables

Group A (n=21)

Group B (n=32)

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(p=0.263) (Figure-2). Change of echocardiographic parameters in Group A patients are presented Table-3. Value of LVEF was decreased mildly in postoperative period (60.86 ± 6.69 vs. 56.57 ± 8.63, p=0.025). E/ E’ ratio has improved slightly (10.90 ± 2.67 vs. 8.59 ± 2.77, p=0.002). Only tricuspid S’ value of tissue Doppler velocities has changed in favour of mildly decreasing (11.90 ± 2.91 cm/s vs. 8.90 ± 2.30 cm/s, p=0.001). Change of echocardiographic parameters in Group B patients are presented Table-4. LVEF was decreased mildly in postoperative period (61.38 ± 6.61 vs. 57.41 ± 6.92, p=0.015). Values of septal S’ and tricuspid S’ have decreased slightly [(7.78 ± 1.75 cm/s vs. 7.13± 1.86 cm/s, p=0.042) and (14.03 ± 2.87 cm/s vs. 9.56 ± 1.85 cm/s, p<0.001)]. Comparison of changes on echocardiographic parameters in subgroup patients are presented Table-5. There is no difference between subgroups in term of values of ∆ LVEF (p=0.848). ∆ E/ E’ ratio was mildly in favour of group A patients (-2.31 ± 2.70 vs. -0.29 ± 2.89, p=0.007). Furthermore, ∆ septal S’ was slightly in favour of group A patients (0.71 ± 2.39 cm/s vs. -0.66 ± 1.73 cm/s, p=0.017). Table 3. Change of echocardiographic parameters in Group A patients Echocardiographic parameters

Pre-Op (n=21)

Post-Op (n=21)

EDV (mL)

105.33 ± 38.83

90.00 ± 30.59

0.002

ESV (mL)

42.67 ± 23.44

39.52 ± 17.45

0.243

LVEF (%)

60.86 ± 6.69

56.57 ± 8.63

0.025

Mean E' (cm/s)

6.35 ± 1.23

7.11 ± 1.78

0.106

10.90 ± 2.67

8.59 ± 2.77

0.002

Age, (year)

62.24 ± 8.97

60.19 ±8.70

0.413

E/ E' ratio

Male, n (%)

17 (81)

28 (87.5)

0.698

Lateral S' (cm/s)

7.24 ± 2.46

7.62 ± 2.26

0.452

Diabetes mellitus, n (%)

8 (38.1)

12 (37.5)

0.965

Septal S' (cm/s)

6.71 ± 1.31

7.43 ± 1.99

0.221

Hypertension, n (%)

15 (71.4)

23 (71.9)

0.972

Tricuspid S' (cm/s)

11.90 ± 2.91

8.90 ± 2.30

0.001

Smoking, n (%)

8 (38.1)

21 (65.6)

0.049

AF incidence, n (%)

3 (14.3)

7 (21.9)

0.722

1.71 ± 0.46

3.44 ± 0.76

<0.001

BMI (kg/m²)

28.25 ± 3.32

29.12 ± 4.77

0.630

Hematocrit (%)

40.31 ± 3.92

40.53 ± 3.74

0.928

Serum creatinine (mg/dl)

0.82 ± 0.11

0.86 ± 0.21

0.696

Potassium (mEq/l)

4.48 ± 0.36

4.26 ± 0.26

0.008

LDL-Cholesterol (mg/dl)

111.94 ± 32.39

123.78 ± 31.58

0.220

Baseline CK-MB (ng/dl)

1.45 ± 0.82

1.40 ± 0.78

0.834

Peak CK-MB (ng/dl)

27.06 ± 30.47

47.43 ± 67.45

0.203

Anastomosis time (minute)

26.10 ± 13.36

64.13 ± 19.42

<0.001

Operation time (minute)

93.29 ± 24.19

131.19 ± 18.84

ICU stay time (minute)

1339.05 ± 120.82

1378.13 ± 547.31

Graft Count, n

EDV; left ventricular end-diastolic volume, ESV; left ventricular end-systolic volume, LVEF; left ventricular ejection fraction, Mean E’; mean of mitral annular peak diastolic E’ velocities, Lateral S’; mitral lateral annulus peak myocardial systolic velocity, Septal S’; mitral septal annulus peak myocardial systolic velocity, Tricuspid S’; tricuspid lateral annulus peak myocardial systolic velocity Table 4. Change of echocardiographic parameters in Group B patientss Pre-Op (n=32)

Post-Op (n=32)

EDV (mL)

111.06 ± 27.06

95.03 ± 20.77

<0.001

ESV (mL)

43.75 ± 15.50

41.16 ± 13.86

0.213

<0.001

LVEF (%)

61.38 ± 6.61

57.41 ± 6.92

0.015

0.220

Mean E' (cm/s)

7.11 ± 2.04

7.50 ± 1.81

0.274

E/ E' ratio

10.40 ± 2.99

10.10 ± 3.67

0.601

Lateral S' (cm/s)

7.81 ± 1.98

7.00 ± 1.92

0.061

Septal S' (cm/s)

7.78 ± 1.75

7.13± 1.86

0.042

Tricuspid S' (cm/s)

14.03 ± 2.87

9.56 ± 1.85

<0.001

BMI; Body Mass Index, CK; Creatine Kinase, ICU; Intensive care unit

Baseline clinical, biochemical and operation parameters of subgroup patients are presented Table-2. Mean graft count of group A and group B was different (1.71 ± 0.46 vs. 3.44 ± 0.76, p<0.001). Group B patients had lower potassium level compared to group A patients despite similar serum creatinine levels. Higher smoking rates were observed in group B. As expected, anastomosis time (p<0.001) and operation time (p<0.001) was longer in Group B patients. Group B patients have higher ∆ CK-MB values than group A but this difference did not reach statistical meaning

Echocardiographic parameters

doi: 10.5455/medscience.2018.07.8864 Table 5. Comparison of changes on echocardiographic parameters in subgroup patients Echocardiographic parameters

Pre-Op (n=21)

Post-Op (n=32)

∆ LVEF (%)

-4.29 ± 7.04

-3.97 ± 8.13

0.848

∆ Mean E' (cm/s)

0.76 ± 1.95

0.39 ± 1.82

0.380

∆ E/ E' ratio

-2.31 ± 2.70

-0.29 ± 2.89

0.007

∆ Lateral S' (cm/s)

0.38 ± 2.50

-0.81 ± 2.33

0.089

∆ Septal S' (cm/s)

0.71 ± 2.39

-0.66 ± 1.73

0.017

∆ Tricuspid S' (cm/s)

-3.00 ± 2.95

-4.06 ± 3.27

0.161

LVEF; left ventricular ejection fraction, Mean E’; mean of mitral annular peak diastolic E’ velocities, Lateral S’; mitral lateral annulus peak myocardial systolic velocity, Septal S’; mitral septal annulus peak myocardial systolic velocity, Tricuspid S’; tricuspid lateral annulus peak myocardial systolic velocity

Figure 1. Correlation between ICU stay time and pre E/E’ ratio (filling pressure index)

Figure 2. Comparison of ∆ CK-MB values in subgroup patients Discussion Given that for all population we found that, there is not significant alteration on early postoperative left ventricular systolic functions since lateral S’ and septal S’ values do not change although

Med Science 2019;8(1):42-7

LVEF value mildly decrease. Furthermore, we found that, early revascularization has improved early left ventricular diastolic function and filling pressure by taking these results into account for improvement of mean E’ and E/ E’ ratio values at postoperatively. Since cardiopulmonary bypass is avoided, OPCAB has superiority in myocardial protection compared with ONCAB [6]. It has been reported that OPCAB is associated with better myocardial energy preservation, less oxidative stress, and minimal myocardial damage [7]. There are several randomized and prospective studies as well as low level of evidence studies supporting the clinical advantages of OPCAB in reducing myocardial infarction rate compared with that of ONCAB [8]. Besides, in some studies, there was no striking difference in the incidence of postoperative myocardial infarction between ONCAB and OPCAB [9]. However, the release of myocardial enzyme including troponin I has been declared to be reduced after OPCAB compared to ONCAB [4]. The elimination of traditional myocardial protection strategies such as cardioplegia and the hypothermia and accumulated myocardial dysfunction associated with hemodynamic instability or coronary flow interruption during coronary anastomosis raises the need for myocardial protection to preserve myocardial function during OPCAB [10]. Therefore, protecting the myocardium from ischemia is still one of the main problems cardiovascular surgeons have faced. The main question in our mind was whether or not myocardial dysfunction increase as number of graft count step up. It seems that increased graft count number does not affect myocardial functions harmfully by taking these results into account for no differences ∆ CK-MB, ∆ Mean E’, ∆ Lateral S’, ∆ Tricuspid S’ and ∆ LVEF values between subgroups despite ∆ E/ E’ ratio and ∆ septal S’ values in slightly favour of group A patients. We have reached another important data in terms of right ventricular systolic function. The values of tricuspid S’ have decreased mildly postoperative period for all patients. There is no difference between subgroups in terms of ∆ Tricuspid S’ despite mild negative correlation between graft count and ∆ Tricuspid S’. Right ventricular dysfunction after cardiac surgery is a well-known phenomenon that can be seen immediately after cardiac surgery. Both contraction and filling of the right ventricular are impaired after coronary by-pass graft surgery, however, the mechanism of this phenomenon is not yet understood exactly. It may be result from intraoperative ischemia, intraoperative myocardial damage and the use of cardiopulmonary pump [11,12]. Several clinical trials have shown that intraoperative right ventricle dysfunction can last up to 6 months after the surgery [13]. Some other studies have reported that the echocardiographic right ventricular dysfunction can last up to even 1 year after CABG [14,15] although some studies have detected a minor clinical value for such disorders [14]. Recently, Khani M et al have shown reversible right ventricular systolic function which is improved after three months from operation in patients who have undergone OPCAB [16]. In addition to literature, our findings have shown that increased graft count may affect slightly negative right ventricular systolic function despite no difference between subgroups. We have found important finding about correlation between atrial fibrillation incidence and pre E/ E’ ratio. A meta-analysis demonstrates important evidence that OPCAB reduces the occurrence of atrial fibrillation with a 20% RR reduction compared 45

doi: 10.5455/medscience.2018.07.8864

to ONCAB [17]. Advanced age, arterial hypertension, obesity, male sex, abrupt withdrawal of beta blockers, and diabetes mellitus were also detected to be predisposing factors of postoperative supraventricular arrhythmias [18]. Depressed left ventricular systolic function has also been underlined as an important factor for the AF after conventional CABG surgery [19]. It has been shown that aging and hypertension results in major cardiovascular changes, including decreased elasticity and compliance of the aorta and great arteries [20]. These alterations produce a higher systolic pressure, increased resistance to left ventricular ejection fraction, and subsequent mild LVH and fibrosis. It has been demonstrated that left ventricular early diastolic filling progressively slows after the age of 20 years, so by 80 years the rate is reduced on an average up to 50% [21]. Increased fibrosis of left ventricular myocardium is a mechanism for the reduced filling rate arising in the early diastolic phase. More ventricular filling occurs in late diastole as the result of a more vigorous atrial contraction. The augmented atrial contraction is accompanied with atrial hypertrophy at an earlier stage and atrial enlargement at a later one, creating in this way a susceptible substrate for the genesis of reentry arrhythmias. All of these physiopathological changes may be represented by E/ E’ ratio which has been shown to be the most accurate and relatively preload-independent noninvasive predictor of LV filling pressure. This ratio has demonstrated excellent reproducibility, with an E/ E’ ratio >15 found to be the best Doppler predictor of increased mean LV diastolic pressure and pulmonary artery wedge pressure [22]. Recently, some studies have found that increased LV filling pressure, assessed by E/ E’ ratio, is an independent predictor of 30-day and 1-year MACE in patients who undergo elective offpump coronary artery bypass graft surgery [23,24]. Furthermore, we have found that ICU stay time was moderately correlated with pre mean E’ and pre E/E’ ratio. These findings have underlined importance of that the diastolic function and LV filling pressure values of patients at preoperative period may affect postoperative hemodynamic stabilization at intensive care unit. Since there is no correlation graft count and atrial fibrillation incidence and no difference of atrial fibrillation incidence between subgroups, graft count number does not seem to affect development of atrial fibrillation. Given that these valuable data, E/E’ ratio is important predictor for patients who undergone OPCAB even in situation of preserved ejection fraction and low risk profile. Conclusion In conclusion, multi-vessel off-pump coronary artery by-pass surgery seems as safe as 1 and 2 vessels despite small differences in terms of cardiac function alterations in patients who have low risk profile. Limitation of the study Patients may have been allocated to specific groups for each graft count if study population number had been sufficient. Then, more specific data may have been obtained in relation to graft count and change of cardiac functions. Another limitation of this study is that we could not obtained post-operative late period echocardiographic parameters. We may have shown whether or not these changes of cardiac function are permanent if we had got these data. Competing interests The authors declare that they have no competing interest

Med Science 2019;8(1):42-7

Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Before the study, permissions were obtained from local ethical committee. Hakan Fotbolcu ORCID: 0000-0003-4047-5230} Erhan Kaya ORCID: 0000-0002-3072-7070

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Calafiore AM, Di Mauro M, Contini M, et al. Myocardial revascularization with and without cardiopulmonary bypass in multivessel disease: Impact of the strategy on early outcome. Ann Thorac Surg. 2001; 72:456-62.

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Alwan K, Falcoz PE, Alwan J, et al. Beating versus arrested heart coronary revascularization: evaluation by cardiac troponin I release. Ann Thorac Surg. 2004;77:2051-5.

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Ascione R, Lloyd CT, Gomes WJ, et al. Beating versus arrested heart revascularization: Evaluation of myocardial function in a prospective randomized study. Eur J Cardiothorac Surg. 1999;15:685-90.

Gerritsen WB, van Boven WJ, Driessen AH, et al. Off-pump versus on-pump coronary artery bypass grafting: Oxidative stress and renal function. Eur J Cardiothorac Surg. 2001;20:923-9.

Puskas JD, Williams WH, Duke PG, et al. Off-pump coronary artery bypass grafting provides complete revascularization with reduced myocardial injury, transfusion requirements, and length of stay: A prospective randomized comparison of two hundred unselected patients undergoing off-pump versus conventional coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2003;125:797-808.

Cartier R, Brann S, Dagenais F, et al. Systematic off-pump coronary artery revascularization in multivessel disease: Experience of three hundred cases. J Thorac Cardiovasc Surg. 2000;119:221-9.

10. Guyton RA, Thourani VH, Puskas JD, et al. Perfusion-assisted direct coronary artery bypass: Selective graft perfusion in off-pump cases. Ann Thorac Surg. 2000;69:171-5. 11. Ascione R, Caputo M, Angelini GD. Off-pump coronary artery bypass grafting: not a flash in the pan. Ann Thorac Surg. 2003;75:306-13. 12. Rose EA. Off-pump coronary-artery bypass surgery. N Engl J Med. 2003;348:379-80. 13. Pegg TJ, Selvanayagam JB, Karamitsos TD, et al. Effects of off-pump versus on-pump coronary artery bypass grafting on early and late right ventricular function. Circulation. 2008; 117:2202-10. 14. Hedman A, Alam M, Zuber E, et al. Decreased right ventricular function after coronary artery bypass grafting and its relation to exercise capacity: a tricuspid annular motion-based study. J Am Soc Echocardiogr. 2004;17:12631. 15. Roshanali F, Yousefnia MA, Mandegar MH, et al. Decreased right ventricular function after coronary artery bypass grafting. Tex Heart Inst J. 2008; 35:250-5. 16. Khani M, Hosseintash M, Foroughi M, et al. Assessment of the effect of offpump coronary artery bypass (OPCAB) surgery on right ventricle function using strain and strain rate imaging. Cardiovasc Diagn Ther. 2016;6:138-43.

doi: 10.5455/medscience.2018.07.8864 17. Møller CH, Penninga L, Wetterslev J, et al. Clinical outcomes in randomized trials of off- vs. on-pump coronary artery bypass surgery: systematic review with meta-analyses and trial sequential analyses. Eur Heart J. 2008; 29:2601-16. 18. Mathew JP, Parks R, Savino JS, et al. Atrial fibrillation following coronary artery bypass surgery: predictors, outcomes and resource utilization: multicenter study of perioperative ischemia research group. JAMA. 1996;276:300–6. 19. Hakala T, Pitka¨nen O, Hippelainen M. Feasibility of predicting the risk of atrial fibrillation after coronary artery bypass surgery with logistic regression model. Scand J Surg. 2002;91:339–44. 20. 2Gardin JM, Arnold AM, Bild DE, et al. Left ventricular diastolic filling in the elderly: the cardiovascular health study. Am J Cardiol. 1998;82:345–51.

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21. Schulman S, Lakatta EG, Fleg JL, et al. Age-related decline in left ventricular filling at rest and exercise. Am J Physiol. 1992;263:1932–8. 22. Ommen SR, Nishimura RA, Appleton CP, et al. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Dopplercatheterization study. Circulation. 2000;102:1788 –94. 23. Lee EH, Yun SC, Chin JH, et al. Prognostic implications of preoperative E/e’ ratio in patients with off-pump coronary artery surgery. Anesthesiology. 2012;116:362-71. 24. Jun NH, Shim JK, Kim JC, et al. Prognostic value of a tissue Doppler-derived index of left ventricular filling pressure on composite morbidity after offpumpcoronary artery bypass surgery. Br J Anaesth. 2011;107:519-24.

Available online at www.medicinescience.org

ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):48-52

Is cerebral edema effective in idiopathic intracranial hypertension pathogenesis?: Diffusion weighted MR imaging study Kerim Aslan Ondokuz Mayis University Faculty of Medicine, Department of Radiology, Samsun, Turkey Received 13 June 2018; Accepted 29 July 2018 Available online 25.10.2019 with doi:10.5455/medscience.2018.07.8906 Copyright ÂŠ 2019 by authors and Medicine Science Publishing Inc. Abstract The aim of this study is to research whether cerebral edema is effective in the pathogenesis of patients with idiopathic intracranial hypertension (IIH) by using diffusion weighted imaging (DWI) and apparent diffusion coefficient (ADC) measurements. Thirty-six IHH patients who received DWI and 36 age- and sex-matched healthy control group were assessed retrospectively. ADCmin, ADCmean, and ADCmax values were measured from different regions of the brain for both IHH patients and the control group. The Studentâ&#x20AC;&#x2122;s t-test was used to compare the ADCmin, ADCmax, ADCmean values acquired from distinct parts of the brain parenchyma of IIH patients with the values of control group. No significant difference was found between ADCmin, ADCmax, and ADCmean values of IIH and control group in bilateral frontal, parietal temporal and occipital lobe cortical and subcortical white matter, caudate nucleus head, putamen, thalamus, corpus callosum splenium and genu (P>0.05). This study showed that cerebral edema cannot be a significant mechanism in the pathogenesis of IIH. Keywords: Diffusion-weighted imaging, apparent diffusion coefficient, idiopathic intracranial hypertension, cerebral edema

Introduction Idiopathic intracranial hypertension (IIH) is a neurological disease characterized by increased intracranial pressure (ICP) in which cerebrospinal fluid (CSF) component is normal and the etiology of which is not known [1-3]. The most common symptom in IHH is headache, permanent or temporary sight disturbance, back and neck pain, and pulsatile tinnitus. Comorbid findings are papilledema and increased CSF pressure [4-6]. Although the definitive pathophysiology of IIH is still unknown, cerebral edema, increased cerebral blood flow, increase in CSF production, CSF outflow obstruction and increase in venous sinus pressure are among potential pathogenic mechanisms [6,7]. Although Sahs et al. [8] found histological proof about cerebral edema in post-mortem in patients with IIH, Wall et al. [9] could not find histological proof of cerebral edema. In patients with IIH, the presence of cerebral edema and its role in increased intracranial *Coresponding Author: Kerim Aslan, Department of Radiology, Ondokuz Mayis University Faculty of Medicine, Samsun, Turkey E-mail: mdkerim@hotmail.com

pressure can be evaluated non-invasively with diffusion weighted imaging (DWI) techniques which characterize the diffusion features of water molecules in the brain. Apparent diffusion coefficient (ADC), which is obtained from DWI, measures the isotropic total size of water diffusion in tissue and gives quantitative information about free water fraction which includes extracellular and intracellular water in the tissue [10]. A few previous DWI studies showed that IIH patients have a convective transepandimal water flow which causes cerebral edema [11-13]. However, some diffusion studies reported that cerebral edema is not a factor in IIH pathogenesis [14-16]. It is not yet clear whether cerebral edema is effective in IIH pathogenesis due to the inconsistency of studies conducted on the subject so far. Recent studies conducted with DWI reported that minimum ADC (ADCmin) values are superior to mean ADC (ADCmean) and maximum ADC (ADCmax) values in differentiating high-grade glioma from solitary metastases [17,18] and low-grade meningioma from high-grade meningioma [19,20]. To the best of our knowledge, there are no studies in literature which have reported the use of MR diffusion metrics including ADCmin, ADCmax, and ADCmean parameters to research whether cerebral edema is effective in the pathogenesis of IIH. 48

doi: 10.5455/medscience.2018.07.8904

The aim of this study is to research whether cerebral edema has a role in the pathogenesis of IIH patients by using DWI and ADCmin, ADCmean, and ADCmax measurements. Material and Methods Patients This study was approved by the local ethics committee of our institution. Electronic medical records (March 2015 - February 2018) were used for this retrospective study. Patients were first identified in the electronic medical records database by searching for the keywords “idiopathic intracranial hypertension”. Seventyfour patients were determined retrospectively. Only the patients who had a definitive diagnosis of IIH fulfilling the revised Dandy criteria [21] and those with minimum age of 18 were included in the study (n=55). Of these, 13 patients were excluded due to the following exclusion criteria: cerebral vascular disease (n=2), pregnancy (n=1), history of head trauma (n=1), neurological or psychiatric disease (n=2), other severe medical disease (n=3), alcohol or drug dependency (n=1), incidentally found arachnoid cyst (n=1) and cerebral atrophy (n=2). In addition, 4 patients were excluded since they did not have DWI and 2 patients were excluded since their DWI had obvious artefacts. Finally, 36 patients (5 men, 31 women; mean age [±SD], 35.1±5.3 years) were included in the study. All of these patients had one or more MR findings [optic nerve sheath distension (21/36), intraocular protrusion of prelaminar optic nerve (7/36), tortuosity of optic nerve (12/36), and partially empty sella (15/36)] supporting IIH diagnosis (Figure 1). In all IIH patients, CSF opening pressures were measured by LP. The mean CSF opening pressure was 34.9±5.7 cm H2O.

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matter, caudate nucleus head, putamen, thalamus, corpus callosum splenium and genu) similar to Giedon et al. [13] and Bastin et al.’s [14] studied (Figure 2). ROI area was between 17 and 86 mm2 (mean 37 ± 4 mm2).

Figure 1. Qualitative MRI signs in a 35-year-old female patient with idiopathic intracranial hypertension. A, Axial T2-weighted image shows bilateral distension of the perioptic subarachnoid space (thin green arrows), bilateral intraocular protrusion of prelaminar optic nerve (arrowheads), and bilateral tortuosity of optic nerve (thin green arrows). B, Coronal fat-suppressed T2-weighted image shows bilateral distension of the perioptic subarachnoid space (thin green arrows). C, Sagittal T2-weighted image shows partially empty sella (thin green arrow). D, Sagittal T2-weighted image shows bilateral tortuosity of optic nerve (green arrow).

The control group consisted of 36 age- and sex-matched patients without brain metastases who were being investigated for staging of primary malignancies of other systems in a similar database (May 2015–June 2017) (5 men, 31 women; mean age [±SD], 38.4±6.1 years). There were no significant differences in age or sex distribution between patients with IHH and controls (p=0.34; p=1.000, respectively). These patients not suffered from neurological disorders. Brain MRIs of these patients were reported to be normal in neuroradiology department. In addition, electronic medical records of all control patients were reviewed and the patients who had the specified IIH diagnosis were excluded from the control group. MR Imaging DWI was performed with a single-shot spin-echo EPI (repetition time/ echo time: 3376/74 ms, section thickness: 5 mm, field of view: 230, matrix: 128x128, number of excitations: 2, intersection gap: 1 mm, b values: 0 and 1000 s/mm2, scanning time: 1 min 02 s). ADC maps were automatically generated. Image Analysis DWI datasets were transferred to the workstation. A neuroradiologist who was unaware to the clinical symptoms of the IIH patients and control groups reviewed the DWI independently and randomly. Since cortex and white matter distinction was not made clearly over ADC maps for both IIH patients and the control group, T2 weighted sequence was used as reference imaging. Quantitative ADCmin, ADCmean, and ADCmax values were measured with regions of interest (ROIs) from brain regions (bilateral frontal, parietal, temporal, and occipital lobe cortical and subcortical white

Figure 2. ROI measurement areas of a 21-year-old female IIH patient hand-drawn circular regions of interest (ROIs) through T2 weighted sequence were placed automatically on same localization and same size ADC maps. In T2-weighted (A) and ADC maps (B), there are hand-drawn circular ROIs in bilateral putamen, caudate nucleus head, thalamus, corpus callosum splenium and genu, frontal cortical and subcortical white matter. In T2-weighted (C) and ADC maps (D), there are ROIs in bilateral temporal and occipital cortical and subcortical white matter. In T2-weighted (E) and ADC maps (F), there are ROIs in bilateral parietal cortical and subcortical white matter.

Statistical Analysis Statistical analyses were performed using the Statistical Package for the Social Sciences (IBM SPSS Statistics version 21; IBM, Armonk, NY, USA). The Student’s t-test was used to compare 49

doi: 10.5455/medscience.2018.07.8904

the ADCmin, ADCmax, ADCmean values acquired from distinct parts of the brain parenchyma of IIH patients with the values of control group. P values less than 0.05 were considered statistically significant. Results Table 1 shows the demographic and clinical characteristics of IIH patients and the control group. There were no significant differences in age or sex distribution between patients with IHH and controls (p=0.34; p=1.000, respectively). The mean CSF opening pressure was 34.9±5.7 cm H2O. Parenchymal abnormality was not found in conventional MRI and DWI sequences off all IIH patients and the control group. Table 2 summarizes the quantitative values containing mean and

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related statistical analysis of ADCmin, ADCmax and ADC mean values, in different brain regions for IIH and control group. There was no statistically significant difference between ADCmin, ADCmax, and ADCmean values of IHH and control group in bilateral frontal, parietal, temporal, and occipital lobe cortical and subcortical white matter, caudate nucleus head, putamen, thalamus, corpus callosum splenium and genu (P>0.05). Table 1. Demographic and clinical characteristics of the participants

Age (years)

IHH

Control group

(Mean±SD)

p value

35.1 ± 5.3

38.4 ± 6.1

0.342

Gender, Females/Males

31/5 (86%/14%)

1.00

CSF pressure (cmH2O)

34.9 ± 5.7

Idiopathic intracranial hypertension (IIH). NA not applicable

Table 2. Mean ADCmin, ADCmax, and ADCmean values for IIH patients and control group* ADCmin

ADCmax

ADCmean

Region

IHH

Control

IHH

Control

IHH

Control

Frontal CX R

0.622

0.643

0.52

0.951

0.927

0.56

0.788

0.772

0.58

Frontal CX L

0.634

0.609

0.44

0.932

0.914

0.48

0.803

0.781

0.42

Frontal SWM R

0.575

0.590

0.26

0.860

0.897

0.16

0.709

0.724

0.52

Frontal SWM L

0.562

0.587

0.11

0.901

0.883

0.34

0.695

0.718

0.40

Parietal CX R

0.604

0.623

0.47

0.997

0.952

0.07

0.801

0.789

0.55

Parietal CX L

0.629

0.656

0.08

0.976

0.944

0.28

0.808

0.795

0.58

Parietal SWM R

0.554

0.579

0.10

0.823

0.848

0.22

0.686

0.709

0.26

Parietal SWM L

0.542

0.568

0.07

0.849

0.832

0.44

0.672

0.694

0.22

Temporal CX R

0.638

0.663

0.14

1.021

0.967

0.10

0.816

0.761

0.07

Temporal CX L

0.621

0.659

0.08

0.943

0.965

0.31

0.787

0.803

0.38

Temporal SWM R

0.539

0.557

0.31

0.833

0.851

0.41

0.721

0.699

0.34

Temporal SWM L

0.567

0.596

0.07

0.873

0.859

0.55

0.716

0.702

0.41

Occipital CX R

0.617

0.641

0.10

0.933

0.951

0.42

0.782

0.811

0.12

Occipital CX L

0.597

0.628

0.09

0.955

0.932

0.36

0.791

0.801

0.44

Occipital SWM R

0.514

0.529

0.20

0.825

0.842

0.44

0.702

0.684

0.42

Occipital SWM L

0.525

0.546

0.26

0.858

0.827

0.16

0.679

0.711

0.11

CC splenium

0.503

0.531

0.20

0.802

0.841

0.26

0.682

0.696

0.38

CC genu

0.478

0.497

0.11

0.785

0.809

0.35

0.639

0.620

0.31

Thalamus R

0.578

0.545

0.18

0.912

0.878

0.31

0.742

0.751

0.44

Thalamus L

0.592

0.561

0.22

0.911

0.873

0.20

0.758

0.776

0.24

Head of caudate R

0.580

0.552

0.07

0.876

0.900

0.31

0.743

0.770

0.07

Head of caudate L

0.557

0.541

0.35

0.860

0.895

0.20

0.750

0.779

0.10

Putamen R

0.565

0.587

0.22

0.843

0.875

0.26

0.705

0.722

0.45

Putamen L

0.582

0.556

0.20

0.824

0.850

0.31

0.715

0.741

0.31

*Except for the p-values, minimum, maximum, and mean apparent diffusion coefficient (ADCmin, ADCmax, and ADCmean) (s/mm²), idiopathic intracranial hypertension (IIH), right cortex (CX R), left cortex (CX L), right subcortical white matter (SWM R), left subcortical white matter (SWM L), corpus callosum (CC).

doi: 10.5455/medscience.2018.07.8906

Discussion IIH is a cerebral intracranial pressure increase with normal CSF compound which is not dependent on a secondary reason (the reason of which is not found). In IIH, neuroimaging findings are optic nerve sheath distension, intraocular protrusion of prelaminar optic nerve, tortuosity of optic nerve, and partially empty sella [22,23]. Despite the increasing number of researches, the pathophysiology underlying IIH has not been completely clarified. Among these, cerebral edema is remarkable. In the current study, I researched whether cerebral edema can play a role in the pathogenesis of patients with IIH with quantitative ADC measurements by using DWI. No statistically significant difference was found in ADCmin, ADCmax, and ADCmean values of different regions of the brain between healthy control group and IIH (P > 0.05). These results can bring to mind that cerebral edema does not play a role in IIH pathogenesis. DWI measures the random translational motion of water molecules in biological tissues of ADC isotropic quantitatively and reflects some pathological states in the brain [24, 25]. This way, ADC gives clues about the cellularity of the tissue, interstitial distance, myelinization degree and the microstructural organization of white matter tracts. Increase in water diffusion in interstitial distance in white matter tracts results in ADC increase [26]. Water diffusion is anisotropic in cerebral white matter. For this reason, water diffusion is restricted perpendicularly, while it is not restricted in parallel direction in white matter tracts. Water diffusion in gray matter is not restricted [27]. Some of the DWI studies in IIH patients reported ADC increase in some regions of the brain, which indicates cerebral edema [11-13]. In their two studies, Sorensen et al. [11,12] compared IIH patients with the control group and reported periventricular increased water diffusion in some patients while they reported increased water diffusion in the whole brain in other patients. Thus, they reported that IIH patients have a convective transependimal water flow and intracellular brain water accumulation which causes cerebral edema. Partly supporting this hypothesis, Gideon et al. [13] showed increase in ACD values associated with increased water diffusion in subcortical white matter in IIH patients when they were compared with the control group. However, they did not find significant ADC increase in other regions of the brain in IIH patients. As a result, unlike my study, these studies reported significant increase in some regions of the brain in IIH patients when compared with the control group. Some of the DWI studies which examined whether cerebral edema was a factor in the pathogenesis of IIH patients could not find diffusion abnormalities signaling brain edema in the patients [1416]. Bastin et al. [14] demonstrated that no significant difference between IIH patients and the control group in the average diffusivity of water in any region of the brain and they reported that diffuse brain edema was not a feature of IIH. Similarly, Bicakci et al. [16] did not find any diffusion anomaly in IIH patients with DWI. However, they did not conduct quantitative assessment in their study. Similarly, in the current study no significant difference was found between ADC values of IHH patients and control group in different regions of the brain including bilateral frontal, parietal temporal and occipital lobe cortical and subcortical white matter, caudate nucleus head, putamen, thalamus, corpus callosum splenium and genu (P > 0.05). Owler et al. [15] showed that when

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compared with the control group, diffusion parameters in putamen and head of the caudate nucleus increased in IIH patients; however, no significant differences were found in thalamus, cerebral white matter or cortical regions. They reported that cerebral edema was not a factor in the pathogenesis of IIH. Schmidt et al. [28] did not find significant differences in fractional anisotropy (FA) and mean diffusivity (MD) values between IIH patients and the control group by using diffusion tensor imaging. Although FA and MD have very high sensitivity in microstructural changes, they are not very specific. Recently directional diffusivity metrics radial and axial diffusivity (RD and AD) have been used to better characterize WM microstructure and to maximize specificity [29]. Tract-based spatial statistics (TBSS) is the voxel wise statistical analytical method developed to assess DTI metrics (FA, MD, RD, AD). TBSS can assess automatic, operator-independent whole-brain WM integrity [30]. Future studies can assess with TBSS whether cerebral edema is effective in the pathogenesis of IIH patients. To the best of our knowledge, this is the first study reporting ADCmin values in researching cerebral edema in IIH pathogenesis. In my study, no difference was found between ADCmin, ADCmax and ADCmean values in different regions of the brain in IIH patients (P > 0.05). Although there were no statistically significant differences in ADCmin, ADCmean and ADCmax values between IIH patients and the control group, ADCmin values were found to be superior to ADCmean and ADCmax values. In the current study, the results brought to mind that cerebral edema cannot have a role in IIH pathogenesis. There were some limitations in the study. First of all, since it was a retrospective study, BMI index was not known for the patient and the control group. In order to confirm the results of our study, prospective studies which measure BMI index for the patient and the control group are needed. Secondly, lumbar puncture was not performed on the healthy control group. In addition, the whole healthy control group did not show any signs of intracranial pressure increase (headache, impaired sight) and since they did not have OCT screening, papilledema symptom is not probable. Lastly, some of the IIH patients did not have (n=15) MR venography. However, despite being highly unlikely, I may therefore have missed small venous pathologies. Conclusion In this study, no significant difference was found between the ADCmin, ADCmax and ADCmean values obtained from the certain diverse regions of the brains of IHH patients compared to the normal healthy control group. The results of this study suggested that cerebral edema cannot be an important mechanism in IIH pathogenesis. In the next step, whole brain DTI studies are required which are conducted with diffusion parameters including axial and radial diffusivity which are more specific when compared with microstructural tissue changes. Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval This work has been approved by the Institutional Review Board. Kerim Aslan ORCID: 0000-0001-6322-7163

doi: 10.5455/medscience.2018.07.8906

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1Wall M. Update on Idiopathic Intracranial hypertension. Neurol Clin. 2017;35:45-57.

Dhungana S, Sharrack B, Woodroofe N. Idiopathic intracranial hypertension. Acta Neurol Scand. 2010;121:71–82.

McCluskey G, Mulholland DA, McCarron P, et al. Idiopathic Intracranial Hypertension in the Northwest of Northern Ireland: Epidemiology and Clinical Management. Neuroepidemiology. 2015;45:34-9.

Ball AK, Clarke CE. Idiopathic intracranial hypertension. Lancet Neurol. 2006;5:433-42.

Wall M, George D. Idiopathic intracranial hypertension: a prospective study of 50 patients. Brain. 1991;114:155-80.

Markey KA, Mollan SP, Jensen RH, et al. Understanding idiopathic intracranial hypertension: mechanisms, management, and future directions. Lancet Neurol. 2016;15:78-91. Skau M, Brennum J, Gjerris F, et al. What is new about idiopathic intracranial hypertension? An updated review of mechanism and treatment. Cephalalgia. 2006;26:384-99. Joynt RJ, Sahs AL. Brain swelling of unknown cause. Neurology. 1956;6:8013. Wall M, Dollar JD, Sadun AA, et al. Idiopathic intracranial hypertension. Lack of histologic evidence for cerebral edema. Arch Neurol. 1995;52:141-5.

10. Le Bihan D, Breton E, Lallemand D, et al. Separation of diffusion and perfusion in intravoxel incoherent motion MR imaging. Radiology. 1988;168:497–505 11. Sorensen PS, Thomsen C, Gjerris F, et al. Increased brain water content in pseudotumour cerebri measured by magnetic resonance imaging of brain water self-diffusion. Neurol Res. 1989;11:160–4. 12. Sorensen PS, Thomsen C, Gjerris F, et al. Brain water accumulation in pseudotumour cerebri demonstrated by MR-imaging of brain water selfdiffusion. Acta Neurochir Suppl (Wien). 1990;51:363–5. 13. Gideon P, Sorensen PS, Thomsen C, et al. Increased brain water self-diffusion in patients with idiopathic intracranial hypertension. Am J Neuroradiol. 1995;16:381–7.

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16. Bicakci K, Bicakci S, Aksungur E. Perfusion and diffusion magnetic resonance imaging in idiopathic intracranial hypertension. Acta Neurol Scand. 2006;114:193-7. 17. Han C, Huang S, Guo J, et al. Use of a high b-value for diffusion weighted imaging of peritumoral regions to differentiate high-grade gliomas and solitary metastases. J Magn Reson Imaging. 2015;42:80-6. 18. Lee EJ, terBrugge K, Mikulis D, et al. Diagnostic value of peritumoral minimum apparent diffusion coefficient for differentiation of glioblastoma multiforme from solitary metastatic lesions. AJR Am J Roentgenol 2011;196:71–6. 19. Watanabe Y, Yamasaki F, Kajiwara Y, et al. Preoperative histological grading of meningioma’s using apparent diffusion coefficient at 3T MRI. Eur J Radiol. 2013;82:658-63. 20. Aslan K, Gunbey HP, Tomak L, et al. The diagnostic value of using combined MR diffusion tensor imaging parameters to differentiate between low- and high-grade meningioma. Br J Radiol. Published Online: 31.05.2018 21. Wall M, Corbett JJ. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology 2014;83;198-9. 22. Raoof N, Sharrack B, Pepper IM, et al. The incidence and prevalence of idiopathic intracranial hypertension in Sheffield, UK. Eur J Neurol. 2011;18:1266–8. 23. Friedmann DI, Liu GT, Digre KB. Revised criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2013;81:1159–65. 24. Kanaan RA, Shergill SS, Barker GJ, et al. Tract-specific anisotropy measurements in diffusion tensor imaging. Psychiatr Res. 2006;146:73–82. 25. Mukherjee P. Diffusion tensor imaging and fiber tractography in acute stroke. Neuroimaging Clin North Am. 2005;15:655–65. 26. Salvay DM, Padhye LV, Huecker JB, et al. Correlation Between Papilledema Grade and Diffusion-Weighted Magnetic Resonance Imaging in Idiopathic Intracranial Hypertension. J Neuroophthalmol. 2014;34:331-5. 27. Hajnal JV, Doran M, Hall AS, et al. MR imaging of anisotropically restricted diffusion of water in the nervous system: technical, anatomic and pathologic considerations. J Comput Assist Tomogr. 1991;15:1–18. 28. Schmidt C, Wiener E, Lüdemann L, et al. Does IIH Alter Brain Microstructures? - A DTI-Based Approach. Headache. 2017;57:746-55.

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Available online at www.medicinescience.org

ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):53-7

Analysis of the dermatoglyphics of patients with obstructive sleep apnea Mustafa Canbolat1, Hilal Ermis2, Furkan Cevirgen1, Deniz Senol1, Turgay Karatas3, Evren Kose1, Davut Ozbag1 1 Inonu University, Faculty of Medicine, Department of Anatomy, Malatya, Turkey Inonu University, Faculty of Medicine, Department of Chest Diseases, Malatya, Turkey 3 Malatya Training and Research Hospital, Department of General Surgery, Malatya, Turkey 2

Received 15 May 2018; Accepted 30 July 2018 Available online 23.11.2018 with doi:10.5455/medscience.2018.07.8934 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Dermatoglyphics outside the normal distribution may be signal of hereditary anomaly in prenatal period. Obstructive sleep apnea syndrome (OSAS) is defined as the suspension of breathing for 10 seconds or more. Genetic predisposition can be suggesated in the OSAS. The aim of this study is to assess through dermatoglyphics whether genetic factors are effective in OSAS because skin glyphs and pharyngeal are originate from ectoderm. Our study was conducted with 134 volunteers, 68 (21 females, 47 males) individuals with OSAS and 66 (21 females, 48 males) healthy individuals. The photographs of the palms and fingertips of the right and left hands of the participants were taken with high definition cameras. These images were enlarged with computer and their dermatoglyphics were assessed. Fingertip loop types, total number of fingertip lines, total a-b line numbers and atd angles were assessed in healthy individuals and patients with OSAS. We found a statistically significant difference between the right and left hand atd values of healthy individuals and individuals with OSA. atd values can be used as an early indicator of OSAS. Keywords: Dermatoglyphics, Obstructive sleep apnea, Genetic

Introduction Dermatoglyphics, formed from a combination of Latin derma (skin) and glyph (cavity), are special patterns formed by the epidermal ridges on finger tips, the palms and soles [1]. Dermatoglyphics appear between the prenatal 10th and 18th weeks and their formation is completed on the 19th week [2]. Dermatoglyphics do not change according to age or environmental effects and patterns differ from person to person [1,3,4]. Dermatoglyphics outside the normal distribution signal a hereditary anomaly in prenatal period [5]. The genes effective in the formation of dermatoglyphics are polygenic [4]. Since the anomalies about the number rand structure of chromosomes cause changes in dermatoglyphics, these epidermal patterns on fingers, palms and soles can be used as auxiliaries in the diagnosis of diseases [6,7]. Apnea, which mens “apnoia” in Greek is defined as the suspension of breathing for 10 seconds or more [8]. Recurrent suspension of breathing during sleep due to apnea results in decreases in oxygen saturation, interrupted sleep, being sleepy and tired during the day [9]. Sleep apnea is a serious disease which

*Coresponding Author: Mustafa Canbolat, Inonu University, Faculty of Medicine, Department of Anatomy, Malatya, Turkey E-mail: mustafa.canbolat@inonu.edu.tr

influences a great number of body systems and creates a risk factor for diseases such as hypertension, ischemic heart disease, diabetes, obesity and cerebrovascular diseases [10,11]. This disease, which greatly affects a person’s quality of life, was defined in 1970s for the first time and it was accepted as a social health problem in 1990s. Accidents such as Chernobyl and Exxon Valdez have been found to result from disease related cognitive disorders and day time somnolence [12]. There are three types of apnea as obstructive, central and mixed. Obstructive sleep apnea syndrome (OSAS) is the obstruction of mouth and nose respiration despite an effort for respiration, central apnea is the absence of both respiratory effort and airflow, and mixed type apnea starts with central apnea and continues despite an effort for respiration [12]. Although there have been developments about the disease, there are still difficulties in the diagnosis and treatment [13). Early diagnosis of this disease is important for the prevention of life threatening situations such as hypertension, cardiovascular diseases, cerebrovascular disease and traffic accidents [14). In this disease, the physiopathology of which includes a great number of factors, the primary reason of the disease is the constriction or obstruction of the pharyngeal airway. Under normal conditions, pharyngeal airway does not constrict with pressure from the outside due to its anatomical position. However, with the co-occurrence of some factors, although there 53

doi: 10.5455/medscience.2018.07.8934

is no pressure coming from the outside, airway can be obstructed during sleep [15]. In apnea, there is a disproportion between soft tissue and bone skeleton boundary. Thus, the canal constricts when the soft tissues in the airway cover too much of a place and/or due to the narrowness of the bone skeleton [16]. In apnea patients, deviations from healthy population such as small pharynx diameter [17], smaller and anteriorly located mandibula and maxilla [18, 19], inferiorly located hyoid bone [20], lateral pharyngeal wall thickness, increase in the tongue and total soft tissue volume [21] show that genetic predisposition can be discussed in the disease. Deviations from the normal in the anatomical structure of the pharyngeal area are one of the main situations which are thought to have an influence on sleep apnea syndrome. Ectoderm neural crest cells form the structure of the middle of the face and the skeletal structure of pharyngeal arcus and all other tissues in this area, including cartilage, bone, tooth, tendon, skin, meninx, sensory neurons and gland stroma. Similarly, our skins and extensions are also ectodermic [22]. Thus, a change that can occur embryologically will result in these two structures being influenced together. Our purpose in this study is to assess through dermatoglyphics whether genetic factors are effective in obstructive sleep apnea syndrome.

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We considered the largest of these as fingertip ridge number. We considered the number of ridges on a finger on which there were arch type fingertip loop types as zero. By adding up the fingertip ridge numbers of 10 fingers of an individual, we found the total fingertip ridge number of that individual (Figure 1).

Figure 1. Dermal ridges between triradius, fingertip loop type centre

We found a-b ridge number by counting the dermal ridges intersecting the straight line combining the triradius of index finger (a) and the lower part of the middle finger (b). We found the a-b ridge number separately for each hand. The total number of both gave us the total a-b ridge number (Figure 2).

Material and Methods 2017/30 protocol numbered ethical board approval was taken from İnonu Inonu University, Faculty of Medicine. Clinical Researches Ethical Board for our study. All our volunteers read and signed the informed consent form. Our healthy volunteers were chosen among individuals who did not have obstructive apnea syndrome, those who did not have anyone diagnosed with obstructive apnea syndrome in the family, and those who did not have any diseases or suspicions of any diseases which had genetic transition such as diabetes mellitus, cardiovascular disease, hypertension, systemic disease, birth anomaly, based on the self-reports of this group. We were also careful that these individuals did not have any deformities that could prevent us from seeing the dermatoglyphics on their palms or finger tips. Our patient group consisted of individuals who were referred to Inonu University Faculty of Medicine, Sleep Polyclinic and who were diagnosed with “Obstructive Sleep Apnea Syndrome” with an apnea-hypopnea index (AHI) of 15 and over as a result of polysomnographic examinations.

Figure 2. Dermal ridges between triradius a and triradius b

We found the atd angle by calculating the angle between the ridges from the triradius on the sole of the index finger (a) to the axial triradius on the sole of the palm (t) to the triradius on the lower part of the little finger (Figure 3).

All finger tips and palms on the right and left hands of both the healthy group and the patient group were photographed with high definition camera (NIKON D3200). These images were transferred to computer. The measurements were made on these images by using Digimizer Version 4.6.1 program. Our data were analyzed and classified according to Cummins and Midlo’s method [23]. Fingertip ridge number was obtained by counting the fingertip dermal ridges intersecting the straight ridge combining fingertip loop type centre and triradius. In fingertip patterns in the form of loops or double loops, we obtained more than one fingertip ridge.

Figure 3. Evaluation of atd angle

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Statistical Analysis IBM SPSS Statistics 22.0 program was used for statistical analyses. Normality distribution of the data was tested with Shapiro-Wilk test. Since the data were not normally distributed, median, minimum (min) and maximum (max) values were used as descriptive. Mann-Whitney U test was used for statistical analyses. p<0.05 value was considered as statistically significant.

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loop types of an individual with OSA and healthy volunteers in terms of other fingertip loop types (Table 3). Table 1.Distribution of individuals with OSA and healthy individuals by gender Groups

Results

Our study was conducted with 134 volunteers, 68 (21 females, 47 males) individuals with OSA and 66 (21 females, 48 males) healthy individuals (Table 1).

Female

Male

Total

OSA

30.9

69.1

50.7

Healthy

31.9

68.1

49.3

OSA: Obstructive sleep apnea

We found that the average age of males with OSAS was 50 (2779), while the average age of females with OSAS was 60 (44-75). We found that the average age of healthy males was 31 (19-54), while the average age of healthy females was 23 (19-59) (Table 2).

Table 2. Age distribution of individuals with OSA and healthy individuals

In our study, arch, which is a fingertip loop type, was found more in both females and males with OSAS than healthy individuals. However, this difference was not statistically significant. No statistically significant difference was found between the fingertip

Groups

Female

Male

Med (Min-Max)

OSA

60 (44-74)

50 (27-79)

Healthy

23 (19-59)

31 (19-54)

OSA: Obstructive sleep apnea

Table 3. The distribution percentage of fingertip loop types of individuals with OSA and healthy individuals Female

Fingertip loop type

Male

OSA (%)

Healthy (%)

OSA (%)

Healthy (%)

Whorl

29.5

35.8

.253

47.5

43.5

.324

Ulnar loop

55.2

57.6

.647

44.7

50.3

.733

Radial loop

1.4

.083

1.4

3.1

.891

Arch

13.9

5.2

.351

6.4

3.1

.366

OSA: Obstructive sleep apnea

We found a statistically significant difference between the right and left atd values of males with OSAS and healthy males. We also found a statistically significant difference between the right and left atd values of females with OSAS and healthy females. Independent

of gender, we found a statistically significant difference between the right and left atd values of all healthy individuals and all individuals with OSAS. In our study, we could not find any differences between groups in terms of ab ridge numbers (Table 4, 5).

Table 4. Comparison of atd angle and ab ridge count of individuals with OSA and healthy individuals by gender

ab ridge count

atd angle

Parameter

Groups

Male n

Med (Min-Max)

right

OSA

42.89˚ (31.66-51.42)

hand

Healthy

41.18˚ (31.38-50.76)

left

OSA

43.02˚ (34.82-52.85)

hand

Healthy

41˚ (33.27-46.67)

right

OSA

41 (32-60)

hand

Healthy

42 (32-56)

left

OSA

43 (36-54)

hand

Healthy

42 (33-55)

Female p .007

.008

.318

.433

Med (Min-Max)

43.97˚ (36.38-47.34)

41.67˚ (33.77-44.72)

45.15˚ (36.22-47.04)

40.14˚ (34.95-45.32)

42 (34-52)

41 (35-50)

44 (36-48) 44 (34-52)

p .015

.000

.860

.184

OSA: Obstructive sleep apnea

doi: 10.5455/medscience.2018.07.8934

Med Science 2019;8(1):53-7

Table 5. Comparison of atd angle and ab ridge count of individuals with OSA and healthy individuals independent from gender Parameter

Groups

Med (Min-Max)

atd angle

All OSA

43.54 (31.66 - 51.42)

.000

(right hand)

All healthy

41.19 (31.38 – 50.76)

atd angle

All OSA

41.15 (34.82 – 52.85)

(left hand)

All healthy

40.92 (33.27 – 46.67)

ab ridge count

All OSA

41 (32 – 60)

(right hand)

All healthy

42 (32 – 56)

ab ridge count

All OSA

43 (36 – 54)

(left hand)

All healthy

43 (33 – 55)

.000 .437 .855

OSA: Obstructive sleep apnea

No differences were found between groups in terms of total

fingertip ridge number and total ab ridge number (Table 6).

Table 6. Comparison of total fingertip ridge number and total ab ridge number of individuals with OSA and healthy individuals Parameter

Groups

Male n

Med (Min-Max)

Total fingertip

OSA

167 (73-237)

ridge number

Healthy

173 (65-286)

Total ab ridge

OSA

83 (71-114)

Healthy

83 (66-111)

number

Female p .451 .888

Med (Min-Max)

150 (9-246)

156 (28-223)

84 (70-100)

86(69-100)

p .443 .435

OSA: Obstructive sleep apnea

Discussion Our study was built on the hypothesis that the skin glyphs originating from ectoderm and pharyngeal area would be influenced together in case of a genetic influence. In our study, significant difference was found between the atd angles of individuals with OSA and healthy individuals. This difference was found in both right and left hand. In addition, atd angle was found to be different between the patients and the healthy group both when the genders were assessed in their own right and when the assessments were made independent of genders. No statistically significant differences were found between groups in terms of fingertip loop types, ab ridge numbers, total finger ratio ridge numbers and total ab ridge numbers. Due to the variations in OSAS phenotype, it is difficult to research the candidate genes responsible for genetics. Previous regression analyses have also supported that explaining the familial aggregation in OSA is a complex situation consisting of many factors interacting in a complex way and including environmental elements [24]. The results of our study bring to mind that in such a situation, if OSA is found in the family, dermatoglyphics can be useful as a predictive method of the disease in other individuals.

especially in females. Arch rate was found to be higher in healthy males (3.1%). In our study, ulnar loop had the highest percentage. In studies conducted with Hodgkin patients, total fingertip ridge number was found as 126.95±34.68 in healthy males, while it was found as 108.53±42.79 in healthy females. In our study, total ridge numbers of males were found to be higher than those of females. atd angle was found as 51.97±10.21˚ in the right hand and as 48.64±10.88˚ in the left hand of healthy males, while it was found as 52.50±11.69˚ in the right hand and it was found as 51.97±10.21˚ in the left hand. Since our data were not normally distributed, we used median values and no statistically significant differences were found between healthy males and healthy females. Total ab ridge number was found as 76.07±11.89 in healthy males and as 74.07±7.28 in healthy females in studies conducted with Hodgkin patients. We found similar results in our study.

There are studies investigating the associations between diseases thought to be influenced by genetic factors and dermatoglyphics. In a great number of diseases such as leukemia [25], schizophrenia [26] and breast cancer [27], in which genetic factors are thought to have an influence, dermatoglyphics has been studied between genders [28] and ethnic groups [29].

In a study conducted with migraine patients [31], while the arch type was found in the right hands of the control group females with a rate of 9% and in the left hands with a rate of 11%, it was found as 8% in the right hands of men and as 6% in the left hands of men. Arch rate is very high when compared with our results. In this study conducted with migraine patients, atd angles were found to be statistically significant between the patient and the control group. Nervous system is also ectodermic in terms of embryological development. Thus, like in our study, genetic influence causes deviations from the normal in ectodermic structures. ab ridge number and total fingertip ridge numbers are parallel to the results of our study in healthy control group.

In a study conducted on Hodgkin patients [30], fingertip loop type percentages in healthy males were found as arch (1.2%), loop (37,4%), ulnar loop (55.9%) and radial loop (5.5%); while in healthy females they were found as arch (6.8%), loop (32.9%), ulnar loop (56.1%) and radial loop (4.2%). According to the results of our study, radial loop rate was found very high in both genders-

In a study conducted with colon ca patients [32], ulnar loop was found as the most frequent loop type like in our study. Arch rate was found as 3.6% in healthy males and as 2.8% in healthy females. While the arch rate was similar to the results of our study in males, the rate was less than 5.2% in females. When ab ridge number, total fingertip ridge number and atd angles were analyzed, 56

doi: 10.5455/medscience.2018.07.8934

the results were found to be similar to our results. In previous studies which stated that obstructive sleep apnea syndrome had a genetic component, it was shown that factors associated with OSA such as familial predisposition to obesity, craniofacial problems including short maxilla and mandibula, respiratory control and response during sleep shared a common genetic root [33]. Our study is the first one with dermatoglyphics to support that patients with obstructive apnea syndrome have genetic component. Needless to say, the results obtained from dermatoglyphics are not diagnostic. However, since there are deviations from the normal, it will encourage about further research. For example, in a study conducted on breast cancer [34], a decrease was found in total fingertip ridge numbers. In another study conducted on cancer patients [35], increases were shown in loops in patients and in another study [36], increases were found in ulnar loops in cancer patients. In conclusions, atd values can be used as an early indicator of OSAS. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval 2017/30 protocol numbered ethical board approval was taken from İnonu Inonu University, Faculty of Medicine. Clinical Researches Ethical Board for our study. Mustafa Canbolat ORCID: 0000-0001-6986-8578 Hilal Ermis ORCID: 0000-0002-1764-9098 Furkan Cevirgen ORCID: 0000-0003-0181-4463 Deniz Senol ORCID: 0000-0001-6226-9222 Turgay Karatas ORCID: 0000-0002-1480-606 Evren Kose ORCID: 0000-0002-0246-2589 Davut Ozbag ORCID: 0000-0001-7721-9471

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12. Thorpy MJ. Classification of Sleep Disorders, Neurotherapeutics. 2012;9:687701. 13. Yurtlu Ş, Sarıman N, Levent E, et al. Short-term positive airway pressure therapy response in obstructive sleep apnea patients: impact of treatment on the quality of life. Tuberk Toraks. 2012;60:327-35. 14. Benbir G, Karadeniz D. Uyku ile ilişkili solunum bozuklukları: Obstrüktif uyku apne sendromu. Türkiye Klinikleri. 2010b;3:27-40. 15. Arens R, Marcus CL. Pathophysiology of upper airway obstruction: a developmental perspective. Sleep. 2004;2:997-1019. 16. Ryan CM, Bradley TD. Pathogenesis of obstructive sleep apnea. J Appl Physiol. 2005;99:2440-50. 17. Schwab RJ, Gupta KB, Gefter WB, et al. Upper airway and soft tissue anatomy in normal subjects and patients with sleep-disordered breathing. Significance of the lateral pharyngeal walls. Am J Respir Crit Care Med. 1995;152:1673-89. 18. Riley R, Guilleminault C, Herran J, t al. Cephalometric analyses and flow volume loops in obstructive sleep apnea patients. Sleep 1998;6:303-11. 19. Watanabe T, Isono S, Tanaka A, et al. Contribution of body habitus and craniofacial characteristics to segmental closing pressures of the passive pharynx in patients with sleep-disordered breathing. Am J Respir Crit Care Med. 2002;165:260-5. 20. Riha RL, Brander P, Vennelle M, t al. A cephalometric comparison of patients with sleep apnea/hypopnea syndrome and their siblings. Sleep. 2005;28:315-20. 21. Schwab RJ, Gefter WB, Hoffman EA, t al. Dynamic upper airway imaging during awake respiration in normal subjects and patients with sleepdisordered breathing. Am Rev Respir Dis. 1993;148:1385-400. 22. Sadlet TW. Medical Embryology. Çeviri: Başaklar AC. Medikal Embriyoloji, 7. Baskı. Ankara: Palme Yayıncılık, 1996;298-303. 23. Cummins H, Midlo C. Finger prints palms and soles. Blakiston: Philadelphia (reprinted, Dover, New York). 1961. 24. Holberg CJ, Natrajan S, Cline MG, et al. Familial Aggregation and Segregation Analysis of Snoring and Symptoms of Obstructive SleepApnea. Sleep Breath. 2000;4:21-30 25. Menser MA, Purvis-Smith SG. Dermatoglyphics in leukemia. Lancet. 1972;1:956-7.

Başaran, N. Tıbbi Genetik, 7. baskı. İstanbul: Güneş & Nobel Tıp Kitapevi; 1999. p. 19-76.

26. Yousefi-Nooraie R, Mortaz-Hedjri S. Dermatoglyphic asymmetry and hair whorl patterns in schizophrenic and bipolar patients. Psychiatry Res. 2008;157:247-50.

Atasu M, Say B. Klinisyenlere Dermatoglifik Bilgiler. Ankara: Hacettepe Üniversitesi Yayınları; 1970. p. 1-74.

27. Natekar PE, Desouza F. Pandey AK. Axial Triradii in Carcinoma Breast. Anthropologist. 2006;8:193-5.

Schaumann B, Alter M, Atasu M (Çeviren ). Tıpsal Kusurlarda Deri Oymacıkları. SpringerVerlag; 1990. p. 145.

Nora JJ, Fraser FC, Bear J, Greenberg CR, Patterson D, Warburton D. Medical Genetics, Principles and Practice, 4th Ed. Philadelphia: Lea & Febiger; 1993. p. 113.

28. Gutiérrez ER, Alonso C, Romero E, et al. Variability of fingerprint ridge density in a sample of Spanish Caucasians and its application to sex determination. Forensic Sci Int. 2008;180:17-22.

Fraser FC, Nora JJ. Genetics of Man, 2nd ed. Philedelphia: Lea & Febiger; 1986. p. 98.

Emery AEH, Mueller RF. Elements of Medical Genetics, 8th Ed. London: Churchill Livingstone, 1992. p. 125.

Cannor JM, Ferguson-Smith MA. Essential Medical Genetics, 4th Ed. Blackwell Scientific Publications; 1993. p. 115.

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29. Karmakar B, Yakovenko K, Kobyliansky E. Quantitative digital and palmar dermatoglyphics: sexual dimorphism in the chuvashian population of Russia. Homo. 2008;59:317-28. 30. Polat MH. Hodgkin Hastalığında Dermatoglifik Özellikler. Van Tıp Dergisi. 1998;5:206-9. 31. Sancıoğulları V, Çevik S, Erdal M, et al. Dermatoglyphic features in migraine. Cumhuriyet Med J. 2015;37:113-20. 32. Polat MH, Caner M. Dermatoglyphic Signs in Patients With Colon Cancer. Ege Tıp Dergisi. 2000;39:39-44. 33. Gaudette E, Kimoff RJ. Pathophysiology of OSA. Eur Respir Mon. 2010; 50:3150. 34. DeAndres Basauri L, Barneo L, Carulla J. Genetic factors in breast cancer. Oncology. 1975;32:27-33.

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35. Lynch HT, Kaplan AR, Moorhouse A, et al. Dermatoglyphic peculiarities in members of a high cancer risk kindred. Pog Exp Tumor Res. 1974;19:325-32.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):58-62

Determination of fibromyalgia syndrome in patients with non-cardiac chest pain in accordance with 1990 and 2010 diagnostic criteria Arif Gulkesen Firat University, Faculty of Medicine, Department of Physical Medicine and Rehabilitation, Elazig, Turkey Received 20 June 2018; Accepted 31 July 2018 Available online 26.09.2018 with doi: 10.5455/medscience.2018.07.8884 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract To determine the frequency of Fibromyalgia syndrome (FMS) in accordance with the American College of Rheumatology (ACR) 1990 and ACR 2010 FMS classification criteria, also to assess the pain intensity, functional and emotional status of patients whoare admitted to the cardiology clinic with a complaint of chest pain without a cardiologic pathology. 107 female patients with chest pain, who admitted to cardiology polyclinic after discarding cardiac chest pain, directed to Physical Medicine and Rehabilitation polyclinic, were included to the study. All patients were assessed in terms of age, height, weight, body mass index (BMI), chronic pain duration, Visual Analog Scale (VAS), Fibromyalgia Impact Questionnaire (FIQ), Widespread Pain Index (WPI), Symptom Severity Scale (SS) and Back Anxiety Depression Scale (BADS). The ACR was assessed according to the 1990 and 2010 FMS classification criteria. It was found that 3(2.8%) of these patients met only the 1990 criteria, 3(2.8%) only met the 2010 criteria and 16(15%) met both the 1990 and 2010 criteria, but 85(79.4) did not meet any of the criteria. The number of tender points, WPI, SS and FIQ values of the clinical and functional evaluation parameters of FMS were higher in the FMS group and this result was statistically significant (p<0.001). The frequency of FMS in patients with non-cardiac chest pain (NCCP) is similar to the frequency of FMS in general population. In patients with NCCP, FMS is a diagnosis that should be taken into account. Keywords: Non-cardiac chest pain, fibromyalgia syndrome

Introduction Chronic widespread pain syndromes have been known for several centuries. However, recently, FMS has been described as a separate disorder. Over time, the relationship between visceral pain and fibrosis has begun to be understood. Fibromyalgia syndrome (FMS) is a clinical tablature without specific laboratory findings in which painful tender points (TP) are detected by palpation of the physical examination with diffuse pain and stiffness in the musculoskeletal system [1,2]. Although etiology and pathophysiology are not fully understood, neuroendocrine dysfunctions, central pain mechanisms and central sensitivity are the most important factors [3-5]. Raynaud’s phenomenon, sickle symptoms, reticular skin color change, restless legs syndrome, hypermobility syndrome, skin sensitivity, dysmenorrhea, subjective swelling in hands, headache, dizziness, headache, irritable bowel and bladder syndrome, abdominal and chest pain, jaw pain, Raynaud’s Coresponding Author: Arif Gulkesen, Fırat University, Faculty of Medicine, Department of Physical Medicine and Rehabilitation, Elazığ, Turkey, E-mail: agulkesen@hotmail.com

phenomenology, paresthesia, and are accompanied by symptoms

mitral valve prolapse and complaints [6,7].

Chest pain can be caused by many causes. Chest wall and neck musculoskeletal structures are the most common causes of chest pain. The pain resulting from these structures can often be confused with angina pectoris, pleurisy and other visceral diseases [8]. FMS syndrome often causes chest pain. Touching, moving and breathing on the chest wall in FMS patients can increase chest pain. Patients with FMS are frequently seen as chronic fatigue, intestinal dysfunction, or mood disorders [9]. Although there are problems with non-cardiac chest pain (NCCP), which usually involve the musculoskeletal system, there are few studies showing the prevalence of FMS in NCCP. Many FMS patients do not fully meet the standard diagnostic criteria. Since health workers often diagnose FMS by excluding other diagnoses, as there is no definite, definitive diagnostic criterion, FMS should not be considered an exclusion diagnosis (10). Since symptoms are widespread and ambiguous, it is difficult to diagnose FMS and often the diagnosis can be skipped. However, pain, fatigue and sleep disturbance are 58

doi: 10.5455/medscience.2018.07.8884

the three main symptoms seen in almost all patients [11,12]. The aim of this study is to determine the frequency of FMS according to the American College of Rheumatology (ACR) 1990 and ACR 2010 FMS classification criteria in patients with a chest pain complaint without a cardiological pathology and to evaluate of pain severity, functional and emotional status, and the relationship between non-cardiac chest pain and disease parameters of FMS. Material and Methods Patients 107 female patients were included in the study.The patients applied to the Cardiology polyclinic with chest pain and referred to the Physical Medicine and Rehabilitation outpatient clinic after cardiac chest pain was excluded. A local ethics committee approved the study and a written informed consent was obtained from all patients. Patients who were younger than 18 years and older than 65 years, patients with systemic inflammatory rheumatic disease, patients who could not be contacted in terms of sociocultural status, patients with acute or known clinical disorder (malignancy, fracture etc.) at work time and pregnant patients were not included. None of the patients had antidepressant medication, muscle relaxants or analgesic use, and only those who stopped taking medication at least 3 weeks prior to work were included in the study. Clinical evaluations All patients were filled in a structured form that covers age, height, weight, body mass index (BMI), duration of chronic pain, widespread pain, and accompanying symptoms. All patients’ chest painswere assessed on a 100 mm Visuel Analogue Scale (VAS), which was looked by the patient and the physician. The disease severity was determined by the Turkish version of the Fibromyalgia Effect Questionnaire (FIQ) in both groups of patients. All patients received the Widespread Pain Index (WPI) and Symptom Severity (SS) scale, which were used in the 2010 FMS classification criteria. Back Anxiety and Depression Scale (BADS) was used to assess emotional status in all patients with chronic chest pain. All NCCP patients studied were evaluated by a specialist physician according to ACR 1990 and 2010 FMS classification criteria for FMS presence. Patients with a widespread pain that lasted for at least 3 months according to the criteria developed by ACR in 1990, and at least 11 of the 18 digital palpation-tender points were evaluated as FMS . In the same way, all patients with a WPI≥7 and an SS scale score≥5 or a WPI 3-6 and an SS scale score≥9 according to the criteria developed by ACR in 2010 and whose symptoms persisted at similar level for at least 3 months, patients without impairment were evaluated as FMS [13].Patients with chest pain who met both or only met one of the ACR 1990 and 2010 classification criteria constituted the FMS group, while those with chest pain who did not meet both of these criteria constituted the non-FMS group. Besides, whole blood count, erythrocyte sedimentation rate, serum CRP, RF values and routine biochemical values of all patients were evaluated.

Med Science 2019;8(1):58-62

The results were evaluated using SPSS (IBM, SPSS Statistics for Windows, Version 20.0, Armonk, NY: IBM Corp.). The results were evaluated using parametric and nonparametric statistical methods for data with normal and non-normal distribution. Comparisons between groups were made using independent group t tests for parametric values and Mann-Whitney U tests for nonparametric values. Categorical data were analyzed by Chi - square test. Correlations between the parameters were assessed using Spearman and Pearson correlation analysis. Data descriptive statistical methods were taken p<0.05 for statistical significance. The results are given as mean±standard deviation. Results The mean age of all NCCP patients was 41.93±10.45 and the mean duration of chest pain was 3.40±3.90 months. The mean VAS scores of 107 patients’ chest pain evaluated by the patient and the doctor were 45.50±26.10 and 32.70±24.50, respectively. All patients had moderate pain. The mean number of tender points in all patients was 5.80±4.52.85(79.4%) patients were premenopausal and the remaining 22 patients were in peri and postmenopausal period (Table 1). Of the total 107 patients who were evaluated according to the 1990 and 2010 FMS classification criteria of ACR, 3(2.8%) only met the 1990 criteria, 3(2.8%) only the 2010 criteria and 16(15% but 85(79.4) did not meet any of the criteria (Table 1). Table 1. Demographic and clinical parameters of all chest pain patients All Patients with Chest Pain (n:107) Age (years)

41.93±10.45 (20–65)

Height (cm)

162.20±5.54 (150–173)

Weight (kg)

69.87±11.65 (47–96)

BMI (kg/cm2)

26.58±4.44 (17.27–40.17)

Pain duration (month)

3.40±3.90 (1–20)

Patient’s pain assessment (0-100 mm VAS)

45.5±26.1 (1–100)

Physician’s pain assessment (0-100 mm VAS)

32.7±24.5 (0–80)

Tender point count (0-18)

5.80±4.52 (0-18)

FIQ (0-100)

40.38±19.22 (6.29–89.08)

WPI (0-19)

4.91±2.95 (1–18)

SS scale (0-39)

3.94±2.35 (1–10)

BDI (0-21)

9.88±9.26 (0–38)

BAI (0-21)

10.86±9.91 (0–55)

Menopause situation

Premenopausal

85 (%79.4)

N (%)

Perimenopausal

10 (%9.3)

Postmenopausal

12 (%11.2)

Working status

Housewife

N (%)

Working

56 (%52.3)

Student

5 (%4.7)

1990 ACR+

3 (%2.8)

2010 ACR+

3 (%2.8)

Both of them+

16 (%15)

None

85 (79.4)

ACR Fibromyalgia Classification Criterion N (%)

46 (%43)

FMS: Fibromyalgia syndrome, VAS: Visual analog scale, BMI: Body mass index, FIQ: Fibromyalgia Impact Questionnaire, WPI: Widespread Pain Index, SS: Symptom Severity, BDI: Back Depression Inventory, BAI: Back Anxiety Inventory, ACR: American Collage of Rheumatology

doi: 10.5455/medscience.2018.07.8884

The demographic and clinical data of patients with FMS diagnosis (n:22) and patients without FMS (n:85) according to the 1990 and 2010 ACR FMS classification criteria are shown in Table 2. The mean age of the FMS group was 44.00±9.20, while the mean age of the non-FMS group was 41.39±10.73 and there was no statistical difference between them (p˃0,05). There was no significant difference between the two groups in terms of height, weight and BMI (p˃0,05). Mean duration of chest pain was 7.82±5.82 months in the FMS group and significantly higher in the non-FMS group (2.26±2.07) (p<0.001) (Table 2). The mean VAS scores evaluated by patients and doctors were significantly higher than those of non-FMS group (p<0.001). Among the other clinical and functional evaluation parameters of FMS, the number of tender

Med Science 2019;8(1):58-62

points, WPI, SS and FIQ values were high in the FMS group, which was statistically significant (p<0.001) (Table2). In the FMS group, 15(68.2%) patients were in the perimenopausal period and 7(31.8%) were in the peri and postmenopausal period. In the nonFMS group, 70(82.4%) were premenopausal and 15(17.6%) were in the peri- and postmenopausal period (Table 2). In the FMSgroup with NCCP, correlations between chest pain VAS scores and clinical parameters are shown in Table 3.There was a positive correlation between the VAS pain scores evaluated by the physician and the BAI, BDI, pain duration and height (p<0.05) (Table 3), while the VAS pain scores evaluated by the patient were positively correlated with SS scale, FIQ, BDI scores and height ).

Table 2. Comparison of demographic and clinical parameters between non-cardiac chest painful FMS group and non-FMS group

Age (years) Height (cm) Weight (kg) BMI (kg/cm2) Pain duration (month) Patient’s pain assessment (0-100 mm VAS) Physician’s pain assessment (0-100 mm VAS) Tender point count (0-18)

FMS Group (n:22)

Non FMS Group (n:85)

44±9.20 (29–61) 161.54±5.82 (150–173) 72.90±13.29 (51–96) 27.97±5.23 (19.80–39.50) 7.82±5.82 (2–20) 69.5±19.8 (2–100)

41.39±10.73 (20–65) 162.37±5.49 (150–172) 69.08±11.14 (47–94) 26.22±4.17 (17.27–40.17) 2.26±2.07 (1–10) 39.3±23.8 (1–90)

0.318 0.408 0.181 0.118 <0.001 <0.001

55.9±15.0 (2–80) 12.18±2.92 (6-18)

26.7±22.9 (0–70) 4.15±3.20 (0-10)

<0.001 <0.001

FIQ (0-100) WPI (0-19) SS scale (0-39) BDI (0-21) BAI (0-21) Menopause situation N (%)

59.56±16.26 (28.19–89.08) 35.42±16.7 (6.29 –67.52) <0.001 9±3.52 (5–18) 3.85±1.53 (1–10) <0.001 6.73±2.14 (2–10) 3.22±1.81 (1–8) <0.001 21.18±11.74 (6–55) 8.19±7.38 (0–32) <0.001 19.45±9.48 (6–38) 7.40±7.45 (0–31) <0.001 Premenopausal 15 (%68.2) 70 (%82.4) 0.335 Perimenopausal 3 (%13.6) 7 (%8.2) Postmenopausal 4 (%18.2) 8 (%9.4) Working status Housewife 16 (%72.7) 30 (%35.3) 0.006 <0.05 N (%) Working 5 (%22.7) 51 (%60) Student 1 (%4.5) 4 (%4.7) ACR Fibromyalgia Classification 1990 ACR+ 3 (%13.6) 0 (%0) <0.001 Criterion N (%) 2010 ACR+ 3 (%13.6) 0 (%0) Both of them+ 16 (%72.7) 0 (%0) None 0 (%0) 85 (%100) FMS: Fibromyalgia syndrome, VAS: Visual analog scale, BMI: Body mass index, FIQ: Fibromyalgia Impact Questionnaire, WPI: Widespread Pain Index, SS: Symptom Severity, BDI: Back Depression Inventory, BAI: Back Anxiety Inventory, ACR: American Collage of Rheumatology Table 3. Correlations chest pain and clinical parameters in Group without fibromyalgia

Tender point count (0-18)

Patient’s pain assessment (0-100 mm VAS) r p 0.038 0.860

Physician’s pain assessment (0-100 mm VAS) r p -0.075 0.742

WPI

-0.067

0.766

-0.115

0.610

SS scale

0.557

0.007*

0.394

0.069

FIQ

0.890

0.000*

0.749

0.000*

BAI (0-21)

0.417

0.054

0.447

0.037*

BDI (0-21)

0.554

0.008*

0.496

0.019*

Pain duration (month)

0.235

0.293

0.057

0.800

Age (years)

0.128

0.569

-0.161

0.473

Height (cm)

0.503

0.017*

0.491

0.020*

Weight (kg)

-0.024

0.917

0.149

0.508

BMI (kg/cm2)

-0.175

0.435

-0.029

0.899

WPI: Widespread Pain Index, SS: Symptom Severity, FIQ: Fibromyalgia Impact Questionnaire, BAI: Back Anxiety Inventory, BDI: Back Depression Inventory, BMI: Body mass index

doi: 10.5455/medscience.2018.07.8884

Med Science 2019;8(1):58-62

Discussion

Conclusion

Reported first caserelated to FMS with no visceral origin of chest pain is a 52-year-old obese female. The patient had compression and chest pain on the left side of the chest and was followed up as myocardial infarction. However, it was determined later that this angina type pain in the patient was caused by spasm of the lefthanded spinae and left trapezius muscle groups [14].

The frequency of FMS in patients with NCCP is similar to the frequency of FMS in the general population. In patients with NCCP, FMS is a diagnosis that should be kept in mind. The criteria of ACR 1990 and 2010 are not superior to each other in the diagnosis of FMS in patients with NCCP. The application of both criteria in the FMS diagnosis place seems to be more advantageous in terms of not skipping FMS diagnosis. New studies are needed to determine the diagnostic criteria of FMS and its sensitivity and to revise existing diagnostic criteria. In these conditions the clinician’s opinion is still important in the FMS definition.

There are several studies reporting the prevalence of FMS in NCCP patients. In a study conducted by Wise et al. 100 NCCP reported a 5% prevalence of FMS in the patient [15]. Ho and colleagues examined whether the presence of FMS or chest wall sensitivity in patients with pre-coronary artery chest pain helped to distinguish between cardiac and NCCP. In conclusion, 19% of patients with normal coronary angiograms received FMS diagnosis according to ACR criteria but 3% of patients with abnormal angiogram had FMS diagnosis [16]. In our study, the prevalence of ACRs meeting the FMS classification criteria of 1990 was 3%, and the prevalence of ACRs meeting the 2010 FMS classification criteria was 3%. The ratio of those who met both the 1990 and 2010 criteria was 15%. It was seen that 79.4% of the patients did not meet any of the 1990 and 2010 FMS classification criteria for ACR. In a study conducted by Öncü et al. 100 patients with widespread pain were included in the study. Sensitivity and specificity of ACR 2010 diagnostic criteria were found as 81% and 85% in3rd month and 88% and 86% respectively in 12th month. In this study, the sensitivity and specificity of the ACR 2010 diagnostic criteria at baseline and follow-up were high compared to the 1990 classification criteria, suggesting that the ACR 2010 diagnostic criteria should be chosen in clinical follow-up [17]. In our study, patients with NCCP had similar results with ACR 1990 and ACR 2010 diagnostic criteria. As far as we could investigate, we think that this is the first and only study to evaluate the ACR’s1990 and 2010 FMS classification criteria in NCCP patients. FMS is a syndrome characterized by widespread pain in the community with a prevalence of 1 to 5 percent. In all ethnic groups, 85-90% of patients can be seen in all ages and genders, and women are 40-60 years old. In our study, the FMS prevalence (3%) in patients with NCCP was found to be consistent with the general FMS prevalence (1-5%) in the population [18,19]. The mean age of NCCP patients included in this study is around 42 and this age group is within range. In Kim et al.’s study, there was a positive correlation between the number of tender points and the WPI score and between the SS scale score and the FIQ score [20]. In the study performed by Segura-Jiménez et al. there was a positive correlation between the number of tender points and WPI score and SS scale score [21]. In our study, the number of tender points, WPI, SS and FIQ values of the other clinical and functional evaluation parameters of FMS were high in the FMS group, which was statistically significant. In addition, there was a positive correlation between the VAS pain scores evaluated by the physician and the BAI, BDI, duration of pain and height while there was a positive correlation between the VAS pain scores evaluated by the patient and SS scale, FIQ, BDI scores and height.

Limitation This study has some limitations. First of all,the patients in the focus of the study consist of only female sex, for it is the profile of patients admitted to the cause of the outpatient clinic. It was observed that among the patients who applied to polyclinics, the number of women was much higher than that of men. Patient generalization with male FMS is not appropriate for the results obtained, but to be very dominant female gender in FMS makes these restrictions disregardable. Another limitation is the crosssectional study of the work and a relatively low number of patients. However, to be wide of the exclusion criteria has caused the number of patients to be restricted. Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Before the study, permissions were obtained from local ethical committee. Arif Gülkesen ORCID: 0000-0002-3008-7333

Referance 1.

Wolfe F, Smyte HA, Yunus MB, et al. The American College of Rheumatology 1990 Criteria for the classification of fibromyalgia: report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33:160-72.

Yunus MB, İnanıcı F. Fibromyalgia syndrome: clinical features, diagnoses, and biopathophysiologic mechanisms. In: RachlinES, Rachlin IS eds, Myofascial Pain and Fibromyalgia. Trigger Point Management. Mosby, St Louis. 2002, pp. 3-31.

Yunus MB, Kalyan-Raman UP, Masi AT, et al. Electron microscopic studies of muscle biopsy in primary fibromyalgia syndrome; a controlled and blinded study. J Rheumatol. 1989;16:97-101.

Simms RW. Fibromyalgia is not a muscle disorder. Am J Sci. 1998;315:346-50.

Sprott H, Bradley LA, Oh SJ, et al. Immuno histochemical and molecular studies of serotonin, substance P, galanin, pituitary adenylyl cyclaseactivating polypeptide and secretoneurin in fibromiyalgic muscle tissue. Arthritis Rheum. 1998;41:1689-94.

Şendur ÖF. Ağrılı Kas Sendromları. In: Oğuz H, Dursun E, Dursun N eds,Tıbbı Rehabilitasyon, Nobel Tıp Kitabevi, İstanbul, 2004;1221-38.

Çapacı K, Hepgüler S. Fibromiyalji Sendromu: Etiyopatogenez. Ege Fiz Tıp ve Reh Der 1998;4:219-225.

Ramos JA. The great deceiver: a case of central sensitization presenting as carcinoid syndrome. AA Case Rep. 2016;6:364-5.

Bradley LA, Alarcon GS. Fibromyalgia. In: Arthritis and Allied Conditions, Kopman WJed, Lippncott Williams&Wilkins, Philadelphia 2001:1812-44.

10. Sim J, Madden S. Illness experience in fibromyalgia syndrome: a metasynthesis of qualitative studies. Soc Sci Med. 2008;67:57-67.

doi: 10.5455/medscience.2018.07.8884 11. Aaron LA, Burke MM, Buchwald D. Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arc Intern Med. 2000;160:221-7. 12. Aaron LA, Buchwald D. A review of the evidence for overlap among unexplained clinical conditions. Ann Intern Med. 2001;134:868-81. 13. Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American college of rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res. 2010;62:600-10. 14. Patton IJ, Williamson JA. Fibrositis as a factor in the differential diagnosis of visceral pain. Can Med Assoc J 1948;58:162-6. 15. Wise CM, Semble EL, Dalton CB. Musculoskeletal chest wall syndromes inpatients with noncardiac chest pain: a study of 100 patients. Arch Phys Med Rehabil. 1992;73:147-9.

Med Science 2019;8(1):58-62

16. Ho M, Walker S, McGarry F, et al. Chest wall tenderness is unhelpful in the diagnosis of recurrent chest pain. QJM. 2001;94:267-70. 17. Oncu J, Iliser R, Kuran B. Do new diagnostic criteria for fibromyalgia provide treatment opportunity to those previously untreated? J Back Musculoskelet Rehabil. 2013;26:437-43. 18. Yunus MB, Masi AT. Juvenile primary fibromyalgia syndrome. Arthritis Rheum. 1985;28:139-44. 19. Yunus MB, Holt GS, Masi AT, et al. Fibromyalgia syndrome among the elderly: comparison with younger patients. J Am Geriatr Soc. 1988;32:987-95. 20. Kim SM, Lee SH, Kim HR. Korean J Pain. 2012;25:173-82. 21. Segura-JimĂŠnez V, Aparicio VA, Ă lvarez-Gallardo IC, et al. Rheumatology Oxford. 2014;53:1803-11.

Available online at www.medicinescience.org

ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):63-6

Comparison of patient specific quality assurance tests done with using different dosimetric systems for intensity modulated radiotherapy treatment plans Kamil Erkan Ozgen1, Sukran Eskici Oztep2, Mehmet Bahadir Celik2, Eda Bengi Yilmaz3, Mehmet Kabadayi2 2

1 Ege University, Faculty of Medicine, Department of Radiation Oncology, Izmir, Turkey Mersin City Training and Research Hospital, Department of Radiation Oncology, Mersin, Turkey 3 Mersin University, Faculty of Medicine, Department of Radiation Oncology,Mersin, Turkey

Received 15 July 2018; Accepted 01 August 2018 Available online 31.08.2018 with doi: 10.5455/medscience.2018.07.8873 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Intensity modulated radiotherapy is the developed technique of 3 dimensional conformal radiation therapy. In this method, irradiated fields can be seperated into many subfields that are called segments. Each segments’ radiation dose can be adjusted. Intensity modulated radiotherapy plans have complex segments and high gradient dose regions. Therefore, quality assurance of intensity modulated radiotherapy plans is very important. The aim of this study is to perform quality assurance tests of intensity modulated radiotherapy plans by using different dosimetric systems and compare of results. Intensity modulated radiotherapy treatment plans of thirty patients’ quality assurance were tested using Matrixx and Delta4. Then, gamma pass rates that were determined as a result of the gamma analysis done using gamma pass-fail criteria that had values of different dose difference and distance to agreement. In our study, the differences between the mean values of gamma pass rates determined before were statistically examined and there was significant difference between two dosimetric systems. Keywords: Intensity modulated radiotherapy, Matrixx, Delta4, Gamma analysis

Introduction Intensity modulated radiotherapy (IMRT) is different from 2 Dimensional (D) conventional and 3D conformal radiotherapy methods and different dosimetric confirmations are needed. In all the centers using this technique in the world, performing dosimetric quality control for patient has become a protocol [1,2] Dosimetric quality control procedures such as Matrixx and Delta4 are being used [3,4]. In this study, the dosimetric quality controls of 30 patients with IMRT were performed using 2D Matrixx and 3D Delta 4 dosimetric systems. The dose maps obtained from the treatment planning system were compared with the dosimetric measurement results. Advantages and disadvantages of the dosimetric systems used have been identified. Thus, it was aimed to establish a quality control program when the dosimetric accuracy of IMRT plans was determined. Material and Methods In this study; the dosimetric validation of the treatment plans of 30 patients with different anatomic localized tumors approved for IMRT planning was performed. Treatment plans were prepared using the Monaco treatment planning system with static IMRT *Coresponding Author: Sukran Eskici Oztep, Mersin City Training and Research Hospital, Department of Radiation Oncology, Mersin, Turkey E-mail: dreskici@hotmail.com

(step and shoot) technique [5]. Computer tomography (CT) images of 30 patients, including 10 prostate cancer, 10 head and neck cancer, and 10 brain tumor patients and the plans were clinically approved. Dosimetric quality control procedures were performed using IMRT Matrixx and Scandidos Delta4 phantom [6-8]. The dose maps from the treatment planning system and the absolute dose values were compared. Dose maps; The OmniProI’mRT program for Matrixx, a 2D dosimetric system, was evaluated using the gamma (γ) analysis method over the Scandidos Delta4 program for Delta4, a 3D dosimetric system. The mean gamma analysis of the dosimetric systems was statistically analyzed using a one-way analysis of variance to determine whether there was a significant difference in percentages between the two [9]. Results In our study, the differences between the mean values of gamma pass rates determined before were statistically examined and there was significant difference between two dosimetric systems (p=0.001). There wasn’t significant difference between two systems in terms of mean values of gamma pass rates that were determined as a result of the gamma analysis performed for 10 patients with brain tumors (p=0,326). However, there were significant differences 63

doi: 10.5455/medscience.2018.07.8873

between two systems in terms of mean values of gamma pass rates that were determined as a result of gamma analysis performed for 10 patients with head and neck cancer (p=0,032) and 10 patients with prostate cancer (p=0.008). Also the mean values of gamma pass rates were determined higher for Matrixx system (Table 1). That was statistically supported that there were significant differences between two systems in terms of mean values of gamma pass rates which were determined as a result of gamma analysis performed using different pass-fail criteria that had values of different dose difference and distance-to-agreement (DTA). There were significant differences between two systems in terms of mean values of gamma pass rates that were determined as a result of gamma analysis done using pass-fail criteria %2/2mm

Med Science 2019;8(1):63-6

(p=0.000), %3/2mm (p=0.002), %3/4mm (p=0.002) and %3/5mm (p=0.016) (Table 2,3) (Figure 1,2). Table 1. Statistical analysis of gamma pass rates obtained after gamma analysis of treatment regions for two dosimetric systems Treatment Area Brain Head and Neck Prostate

Dosimetric system

Average (%)

Standard Deviation

Matrixx

99,620

0,3795

Delta4

99,500

0,4163

Matrixx

98,980

1,0881

Delta4

97,690

1,8818

Matrixx

99,240

1,2002

Delta4

97,640

1,5643

Table 2 The comparison of gamma pass rates obtained after gamma analysis with criteria with different dose differences and DTA values resulted in quality control measurements of 30 patients with Matrixx Patient No

%2/2mm (%)

%3/2mm (%)

%3/3mm (%)

%3/4mm (%)

%3/5mm (%)

97,7

98,9

99,8

100,0

99,0

99,4

99,9

100,0

96,2

97,5

99,0

99,4

99,5

99,0

99,6

99,9

100,0

96,0

97,2

99,2

99,5

99,7

98,2

99,1

100,0

97,1

98,5

99,4

99,7

100,0

97,4

98,7

99,8

100,0

97,7

98,5

100,0

95,6

97,3

99,2

99,5

99,8

98,6

99,4

99,9

100,0

94,4

98,2

99,6

99,9

100,0

94,5

96,4

99,0

99,5

99,6

95,3

98,1

99,5

99,7

99,8

96,1

98,3

99,6

100,0

93,8

95,1

96,5

97,2

97,9

94,6

97,9

99,3

99,5

99,6

92,0

95,8

98,8

99,1

95,9

98,6

99,9

100,0

91,6

96,0

97,7

99,2

99,4

97,6

98,8

99,8

99,9

98,7

99,3

99,9

100,0

95,6

96,7

98,6

98,8

99,9

98,4

99,0

99,8

99,9

100,0

97,4

99,2

99,8

100,0

98,4

99,0

99,7

100,0

96,1

97,7

99,8

100,0

96,7

98,0

99,6

100,0

94,0

95,0

96,0

96,8

98,0

95,5

98,2

99,4

99,7

99,9

* The lines filled with the grey color belong to the plans that failed gamma analysis.

doi: 10.5455/medscience.2018.07.8873

Med Science 2019;8(1):63-6

Table 2 Comparison of gamma pass rates obtained after gamma analysis with criteria with different dose differences and DTA values resulting in quality control measurements of 30 patients with Delta4 Patient No

%2/2mm (%)

%3/2mm (%)

%3/3mm (%)

%3/4mm (%)

%3/5mm (%)

88,6

96,6

99,1

99,6

99,8

100,0

96,9

99,0

99,6

100,0

95,9

98,6

99,8

98,0

98,7

99,0

100,0

99,4

99,9

100,0

98,8

99,5

99,6

100,0

98,8

99,1

99,8

100,0

98,6

99,1

99,2

99,5

99,8

97,5

97,9

98,9

99,8

94,0

98,2

99,6

99,7

91,7

97,7

99,3

99,8

99,9

89,9

93,6

96,5

97,4

97,9

88,8

91,9

95,5

96,4

96,6

93,1

96,3

99,1

99,8

99,9

90,1

92,9

95,5

96,0

99,7

80,1

89,3

95,3

96,6

96,7

82,2

93,3

97,1

98,5

99,0

94,7

98,0

99,6

99,9

91,7

97,6

99,4

99,5

99,7

93,5

97,5

99,8

100,0

91,9

94,3

96,6

97,5

98,2

84,7

90,6

95,5

96,8

98,1

87,8

92,1

96,1

97,3

97,9

91,5

96,2

98,0

98,8

98,9

92,2

97,1

99,6

100,0

91,6

96,9

98,2

99,1

99,4

94,1

97,3

97,9

98,2

98,8

87,8

92,3

95,8

96,7

97,9

93,3

98,0

98,9

99,7

100,0

* The lines filled with the grey color belong to the plans that failed gamma analysis.

Figure 1. Graphical representation of gamma pass rates obtained using different dose criteria of 30 patients for the matrix

Figure 2. Graphic representation of gamma pass rates obtained using different dose criteria of 30 patients for Delta

doi: 10.5455/medscience.2018.07.8873

It was shown that both Matrixx and Delta4 dosimetric systems were successful in gamma analysis and applicable for the dosimetric verification of the IMRT treatment plans. Discussion According to the results obtained from this study, it is revealed that Matrixx being 2D dosimetric method and Delta4 being 3D dosimetric method is applicable for the measurements that are performed in order to in spect the dosimetric accuracy of IMRT treatment plans. In our study, gamma analysis of 30 patients’ IMRT treatment plans using the ‘γ evaluation method’ which is composite analysis of 3 mm DTA and %3 dose difference (DD) were figured out regarding gamma passing rate (GP%) and also it was observed that the dose distributions are with in acceptable tolerances (γ≤1). As a consequence of comparison of quality accuracy data with dosimetric methods, it was statistically verified that there was a significant difference in GP % between the methods. Furthermore GP % obtained from Matrixx method that is used to treatment of 30 patients are higher than GP % obtained from Delta4 method that is used to treatment of the same 30 patients. It should be also noted that the main reasons of variance of GP % can be that Matrixx averages there reference doses, Matrixx’s gantry and collimator angles were set at 0 degrees to whole area, besides these Matrixx performs dose distribution by collecting the whole field. Accurate reading of Delta4, reading errors for all areas by performing irradiation at all gentle angles, and precise reading in high dose gradient regions, resulting in a large number of unsuccessful gamma analysis points in the whole volume, so that the gamma penetration percentage is lower than the Matrixx percent obtained causes. Classifying the cases of patients as brain tumor, head and neck cancer and prostate cancer, the dose validation of IMRT pretreatment applied patients with brain tumor, no difference is seen in GP % between the methods, which are Matrixx, and Delta4. Being size of planned area small and having homogeneous dose distribution is the main reason of the similarity of measurements. Since head and neck and prostate cancer patients have wide and high dose gradient range unlike the brain tumor cases, it was founded that quality assurance (QA) measurements acquired by using two dosimetric methods had a meaningful deviations and GP % accomplished from Delta4 method was lower than Matrixx IMRT method.

Med Science 2019;8(1):63-6

As a result of gamma analysis by applied varient 3 mm DTA and %3 dose difference, it was supported statistically that there is significant alteration between two methods. Moreover it should be noted that GP % values of IMRT treatment plan prepared to 30 patients was higher in the Matrixx method. The main reason for the difference is that Delta4 is better able to detect points because it performs more accurate reading at smaller DTA values. It should be pointed that with the decrease in DTA value, gamma-passing rate also decreased. Conclusion It was indicated that both Matrixx and Delta4 dosimetric methods work out dosimetric verification of IMRT treatment plan. Competing interests The authors declare that they have no competing interest. Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Before the study, permissions were obtained from local ethical committee. Kamil Erkan Ozgen ORCID: 0000-0002-8375-5155} Sukran Eskici Oztep ORCID: 0000-0002-9776-8651 Mehmet Bahadir Celik ORCID: 0000000224027828 Eda Bengi Yilmaz ORCID: 0000-0002-5299-8672 Mehmet Kabadayi ORCID: 0000-0003-1745-9822

References 1.

Meyer JL. New Technologies in the Radiotherapy Clinic. In: IMRT, IGRT, SBRT-Advances in the Treatment Planning and Delivery of Radiotherapy Department of Radiation Oncology. Karger, Basel, 2007;1-58.

Podgorsak EB. Intensity modulated radiotherapy. In: Radiation oncology physics: A hand-book for teachers and students. IAEA, Vienna, 2005;534-8.

Radyoterapi Tedavi Planlarının Dozimetrik Doğrulaması. http://medikalfizik. org/uploads/files/Radyoterapi Tedavi Planlarının Dozimetrik Doğrula-ması. pdf

Chandraraj V, Esquivel C, Papanikolaou N. Comparison of four commercial devices for Rapid Arc and sliding window IMRT QA. J Appl Clin Med Phys. 2011:12;338–49.

Kawrakow I, Fippel, M. Investigation of variance reduction techniques for Monte Carlo pho-ton dose calculation using XVMC. Phys Med Biol. 2000:45;2163-83.

User’s Guide to the SP34 QA Phantom. Scanditronix Wellhöfer, Germany, 2003.

User Manual of I’mRT MatriXX. Scanditronix Wellhöfer, Germany, 2003.

Delta4: Getting Started. ScandiDos AB, 2009.

DA Low, JF Dempsey. Evaluation of the gamma dose distribution comparison method. Me-dical Physics. 2003:30:2455-64.

Available online at www.medicinescience.org

ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):67-71

Evaluation of impulsivity and complex attention functions of subjects with substance use: Sample from Adiyaman province Ali Kustepe1, Aysun Kalenderoglu2, Mustafa Celik3, Esra Kaya Bozkurt1, Mehmet Hamdi Orum2, Sukru Uguz4 Adiyaman University Training and Research Hospital, Clinic of Psychologist, Adiyaman, Turkey 2 Adiyaman University, Faculty of Medicine, Department of Psychiatry, Adiyaman, Turkey 3 Private Yuzyil Hospital, Clinic of Psychiatry, Istanbul, Turkey 4 Cag University, Faculty of Science and Literature, Psychology, Mersin, Turkey

Received 18 July 2018; Accepted 05 August2018 Available online 25.10.2018 with doi:10.5455/medscience.2018.07.8917 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The aim of this research is to compare impulsivity and complex attention functions in individuals with substance use disorders to those who do not use substance. Design of this study was a case-control study. Universe of this study was patients with substance use who admitted to psychiatry department of our hospital. Among them, 33 (94.3%) males and 2 females between 18-65 years of age formed the study sample. Randomly selected 23 (92.0%) males and 2 (8%) females without any substance use disorders who were similar to the study group according to age and sex formed the control group. A statistically significant difference was found between the two groups in terms of Barratt’s total impulsivity score, motor impulsivity, and non-plan point scores (p˂0.05). There were two statistically significant differences (p˂0.05) between two groups in terms of Trail Making Part B, Trail Making Part B / Trail Making Part A, Trail Making Part B - Trail Making Part A, Trail Making Part B + Trail Making Part A. Subjects using substances have difficulties with concentration, delaying gratification, making appropriate decisions, and inhibiting responses. Another important finding of this study was higher levels of disturbance in complex attention function in subjects with substance use. According to this result, subjects with substance use have difficulties in changing between different stimulating sets, following consecutive stimuli and mental flexibility. Long term follow-up studies are needed to understand the reciprocal relations between substance use, impulsivity, and complex attention. Keywords: Substance use disorder, impulsivity, complex attention

Introduction Substance abuse has emerged as an important biopsychosocial problem since human beings have realized that certain substances change their own mood and feel different, even though they are not permanent [1]. Although the existence of a special personality for addiction is rejected, individuals with substance use disorders differ from controls in terms of some personality traits such as impulsivity and search for novelty. Dependents are often people whose internal tensions are too high and whose lives are not satisfactory to them [2]. Impulsivity includes a variety of behaviors that are overly risky, unsuitable for the environment, not well planned, immature

*Coresponding Author: Mehmet Hamdi Orum, Adiyaman University, Faculty of Medicine, Department of Psychiatry, Adiyaman, Turkey E-mail: mhorum@hotmail.com

and often resulting in undesirable consequences. Impulsivity is manifested by carelessness, impatience, searching for excitement, seeking pleasure, taking risks, low probability of harm, and extroversion. Impulsivity is also one of the core manifestations of many psychiatric disorders [3]. It is generally accepted that impulsive actions consist of three dimensions. First; not to use existing information to think about the consequences of behavior. Latter; not to give up a small bonus at that moment for a great prize to be earned later. The third is; cannot suppress established powerful motor reactions [4]. When these three dimensions are evaluated together, it can be said that the impulse disrupts the ability to assess a certain situation and respond flexibly to this situation [5]. In the literature, there are many studies that examined the relationship between impulsivity and substance use. A study of the relationship between cannabis use and alcohol abuse behavior and impulsivity level in university students revealed that the students who were exposed to cannabis and excessive drinking 67

doi: 10.5455/medscience.2018.07.8917

behaviors had a higher level of impulsivity and novelty seeking behavior [2,6]. Kollins [7] said individuals who had higher rates of impulsivity started smoking, drinking alcohol and using cannabis earlier. A study by Vonmoos et al. [8] found that recreational cocaine-using and dependent cocaine users were more impulsive and likely to seek excitement when compared to the control group. Even if the difference between the impulsivity levels of those who use and those who do not use the substance is revealed, this does not clarify the cause-effect relationship between substance use and impulsivity [9]. Three hypotheses have been proposed to explain the relationship between impulsivity and substance addiction. First, the high level of impulsivity has led to substance abuse and drug addiction. Second, substance use has increased the level of impulsivity. The third is that impulsivity and substance use are related to a third factor [10]. Attention is the conscious actuation of the psychological functions that occur with perception, thinking and imagination. Complex attention, which is a frontal executive function, consists of attention maintenance, concentration, persistence, exclusion of distracting stimuli, and inhibition of inappropriate response tendency [11]. In the study by Davies et al. [12], the duration of the Trail Making Test Part A (TMT-A) for substance abuse was found to be similar to that of the control group. In the same study, Trail Making Test Part B (TMT-B) duration was reported to be longer than control group. Konrad et al. [13] found that the duration of TMT-A and TMT-B of treated alcoholic dependents was longer than the control group. However, this difference was not found to be significant. The prevalence of substance use disorders appears to have increased significantly over the years with various causes [1]. This has led to the need to conduct research on addiction and to identify a number of measures to prevent addiction. It is thought that our study will enhance the level of knowledge about the factors predisposing to substance use disorders and contribute to the development of treatment programs for the groups at risk. Material and Methods Study Design and Participants Design of this study was a case-control study. Universe of this study was patients with substance use who admitted to psychiatry department of our hospital (between 01/03/2016 and 31/05/2016). The patient group included 33 (94.28%) males and 2 (5.72%) females between 18-65 years of age. There was no significant difference between the universe and the sample in terms of gender (p = 0.369). The mean age of the universe was 23,27±4,63 while the mean age of the sample was 24,51±5,34. There was no significant difference between the two groups (p = 0.259). The patients were not taking any medication. Patients who used substances in the last month were excluded from the study. Randomly selected 23 (92.0%) males and 2 (8%) females without any substance use disorders who were similar to the study group according to age and sex formed the control group. This study was approved by the Ethics Committee of Adiyaman University (Date: 23.03.2016, Protocol Number: 2016/2-6). Assessment Sociodemographic Form A form containing sociodemographic and clinical information was

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filled in by the researcher. Age, gender, education level, marital status, job, number of hospitalizations, additional psychiatric diagnosis, history of forensic prosecution, attempt to quit substance, alcohol-substance type were used as variables in the questionnaire. Trail Making Test Trail Making Test (TMT), originally developed by psychologists studying in the United States Army, is a widely used neuropsychological tests worldwide. TMT which measures complex attention, working memory, planning and set change from executive functions requires motor skills and visual-spatial processing. TMT consists of two forms, A and B. In both forms, stimulant substances are scattered on the test form. In the first part, the subject combines the numbers in random order starting from 1 on the page. In the second part, both numbers and letters of the alphabet are scattered randomly on the paper, and the subject moves from 1 to A by drawing a number of letters from 2 to B. The TMT practice material, consisting of four pages of A4 size, contains exercise and test pages for each of the A and B forms. TMT Turkey normative study for 20-49 years of age, made by Turkes et al [14]. Barratt Impulsiveness Scale It is a 4-point likert type measure consisting of 30 items and three sub-factors. Factors; motor impulsivity, non-planning, attentionrelated impulsivity. The Turkish validity and reliability study of the scale was performed by Gulec et al [15]. Statistical Analysis Windows SPSS 21.0 program (Statistical Package for the Social Sciences Inc.) was used for statistical analysis. Mean, standard deviation, percent, and median were used as descriptive statistics. It was investigated by the Kolmogorov Smirnov test that the variables exhibited normal distribution (p> 0.05). Independent sample t test was used to compare the time to TMT-A, attention related impulsivity, Barratt impulsivity scale total score, and the time to TMT-B / TMT-A variables which exhibit normal distribution. Mann-Whitney U test was used to compare TMT-A error, TMT-A correction, TMT-B time, TMT-B error, TMT-B correction, TMT-A time + TMT-B time, TMT-B – TMT-A, motor impulsivity, and unintended impulsivity variables which not exhibit normal distribution. In comparing categorical variables, chi-square test was used. Statistical significance level was accepted as p<0.05 for all values. Results The identifier properties of the individuals are shown in Table 1. There were no significant differences in terms of age, gender, marital status, and working status (p˃0.05). There was a significant difference in terms of education status. The education level of control group was higher than the control group (p=0.005). The mean age of the patient group was 17.2±4.17 years, the mean number of quitting substance use attempt was 4.62±4.52 times, and the mean duration without substance use was 112.37±137.77 days. Additional psychiatric diagnosis was present in 3 (8.6%) persons with substance use disorder and 32 (91.4%) had no additional psychiatric diagnosis. Twenty-two (62.9%) persons with substance use disorders had a history of criminal prosecution, while 13 (37.1%) had no criminal history. While 5 (14.3%) had 68

doi: 10.5455/medscience.2018.07.8917

a history of hospitalization, 30 (85.7%) did not have a history of hospitalization. In terms of number of substance, 17 (48.6%) were using one substance, 17 (48.6%) were using two substances, and 1 (2.9%) were using four substances. The substances used by the group with substance use disorder, the duration of use, the first substance they used and the substances they preferred were shown on the table (Table 2). The participants’ values for the Barratt Impulsivity Scale were shown on the table (Table 3). A statistically significant difference was found between the two groups in terms of Barratt’s total impulsivity score, motor impulsivity and non-planning scores (p˂0.05). The values of the participant’s TMTs were shown on the table (Table 4). There were statistically significant differences (p˂0.05) between two groups in terms of TMT-B time, TMT-B time / TMT-A time, TMT-B time - TMT-A time, TMT-B time + TMT-A time.

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Table 1. Sociodemographic Data Patient

Control

n (%)

33 (94.3)

23 (92.0)

2 (5.7)

2 (8.0)

Yes

26 (74.3)

16 (64.0)

9 (25.7)

9 (36.0)

8 (22.9)

6 (24.0)

Male Female

p value 0,726

Working status 0,391

Marital Status Married Single

0,918

27 (27.1)

19 (76.0)

Mean±SD

p value

Age

24,51 ± 5,34

23,44 ± 4,54

0,418

Education (Years)

9,97 ± 1,90

11,32 ± 1,57

0,005*

*p<0.05 Statistical Analysis: Chi-square Note: SD: Standard deviation

Table 2. Substance Use Characteristics Substance

n (%)

Duration of Substance Use (Mean±SD)

Preferred Substance n (%)

Synthetic Cannabinoid

3 (8.6)

28.00±6.92

1 (2.9)

3 (8.6)

Marijuana

26 (74.3)

45,69±30.63

24 (68.6)

11 (31.4)

Alcohol

6 (17.1)

60,50±58.18

4 (11.4)

3 (8.6)

Heroin

13 (37.1)

36,31±21.97

4 (11.4)

13 (37.1)

Volatiles

1 (2.9)

12.00±0.00

0 (0.0)

1 (2.9)

Ecstasy

6 (17.1)

44.00±27.01

2 (5.7)

4 (11.4)

*p<0.05 Statistical Analysis: Descriptive statistics (Mean, percentage, standard deviation) Note: SD: Standard Deviation

Table 3. Barratt Impulsiveness Scale Results Patient

Table 4. Trail Making Test A and Trail Making Test B Patient

Control

(Mean±SD)

TMT-A Time

40.91±14.26

37.04±10.74

0.254

TMT-A Error

0.11±0.32

0.08±0.27

0.665

TMT-A Correction

0.17±0.51

0.20±0.40

0.432

TMT-B Time

86.68±32.66

65.04±17.57

0.002*

TMT-B Error

0.85±0.73

0.56±0.65

0.115

TMT-B Correction

0.25±0.61

0.08±0.27

0.195

TMT-B Time / TMT-A Time

2.16±0.53

1.78±0.28

0.001*

TMT-B Time - TMT-A Time

45.77±25.28

28.00±10.26

0.001*

TMT-B Time + TMT-A Time

127.60±43.60

102.08±27.05

0.010*

Barratt Impulsivity Total Score

66.37±13.22

59.40±9.70

0.029*

Control p value

(Mean±SD)

Motor Impulsiveness

13.34±2.63

11.96±1.94

0.030*

Do Not Plan

22.05±3.58

19.84±2.32

0.015*

Attention-related Impulsivity

30.97±8.13

27.60±6.46

0.091

Barratt Impulsivity Total Score

66.37±13.22

59.40±9.70

0.029*

*p<0.05 Statistical Analysis: Independent samples t test Note: SD: Standard Deviation

p value

*p<0.05 Statistical Analysis: Independent samples t test Note: SD: Standard Deviation

doi: 10.5455/medscience.2018.07.8917

Discussion The impulsivity level and complex attention functions of individuals with substance use disorder in our study were compared with healthy controls. Gender distribution in the study is in accordance with the literature. In Asan et al. [16]’s study, 283 (93.7%) of the 302 patients with alcohol and substance use were male and 19 (6.3%) were female. In a similar study, 104 (93.7%) males and 7 females (6.3%) were found to have alcohol and substance use among 111 people [17]. According to these results, it is thought that substance use disorder can be affected by gender and it is seen more frequently in men than in women. However, this difference may be due to the fact that men are more likely to apply for treatment. The mean age of the patient group and the literature are also compatible [16]. When the findings obtained in the study and the literature information are evaluated together, it is considered that substance use negatively affects the working life of the individual. Also, findings in the study are parallel to the literature and it is thought that substance use affects the marital status [17]. The age of starting to use the substance varies according to the type of substance used. In a study, substance use before age 20 was reported as 76.6% [17]. Köksal [18] reported that 63.5% of the patients in the study had experienced past or continuing legal problems related to substance use. Findings related to the forensic problem in this study are similar to other studies. In the findings, it is considered that the people with substance use have more legal problems than the general population. According to our study, it is thought that the first substance used by those with substance use disorder is marijuana. Marijuana may be a “door-opening” substance in transition to other substances [17]. One of the important findings of this study is that the impulsivity level of the group with substance use disorder is higher than the healthy control group. Bozkurt [19] found that the Barratt impulsivity scale for alcohol and heroin addicts had higher scores on attention impulsivity, motor impulsivity, unplanned impulsivity subscales, and total impulsivity scores than the control group. Caliskan [20] found no significant difference in the Barratt impulsivity scale total score, motor impulsivity, attention impulsivity and unplanned impulsivity subscales between the groups with and without cannabis in the last 3 urine samples. Ersche et al. [21] reported that substance addicts scored higher on all subscales of the Barratt impulsiveness scale. Koksal [18] found that the group using heroin had a higher impulsivity score than those who used bonzai. The group with substance use disorder completed TMT-B in longer duration than healthy controls. TMT-B measures complex attention function. Rosenberg et al. [22] performed TMT, Stroop test, Verbal Fluency tests and found that all of the tests resulted in a significant loss of performance in the drug-using group. Unal [23] reported that volatile substance users completed TMT-A significantly later than the control group. According to our study, complex attention is more impaired in the patient group than in the controls. Subjects using substances have difficulties with concentration, delaying gratification, making appropriate decisions, and inhibiting responses. Moral development involves many processes related to executive functions. Some of them include reasoning ability, empathy ability, evaluating emotional cues, looking at events from different perspectives, internalizing correct behavior

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patterns, providing personal supervision and delaying reactions. Inadequacies in these areas cause behavior problems. Disorders related to working memory may occur in persons with substance use disorders. These are features such as making conclusions, making preparations, foresight and mimicry from complex events. For example, repetitive errors in neuropsychological tests are associated with deterioration in these processes. Another managerial function, the emotional regulation system, includes the control of emotions, motivation and alertness. Reconstruction and fragmentation of learned behaviors are also another managerial function in substance dependence. These disorders, which are described in executive functions, cause problems in the subjects of analysis and synthesis. The information obtained from longitudinal studies also focused on problems such as rapid response, focus on focus, and mood variability [24-26]. As a result; the level of impulsivity of substance users was found to be higher than the healthy control group. This result can be interpreted as impulsivity makes people tend to use substances, or it can be interpreted as substance use increases impulsivity. Another important consequence of the study is that patients with substance use has higher impaired complex attention than healthy controls. This finding may be a factor that triggers the use of the substance or it may be a result of the use of the substance. This is the first study to investigate the complex attention of the executive functioning of patients with substance use disorder in our country with the trail making test. Limitations Major limitation of this study is its cross-sectional design. A prospective design starting from early periods of substance use with regular follow-up scale evaluations would yield more convincing results about nature of addiction. The lack of standardized scales to make a clinical diagnosis is another limitation of this study. It is thought that there may be a relation between the scale used and education level. However, a significant difference was found between our groups in terms of education level. It is thought that the study can be repeated with study groups where the level of education is similar. The number of women in this study is low in both groups. It is difficult to adapt the results obtained for this reason to women. It may be useful to conduct studies that have a high percentage of women. Conclusion As a result; the level of impulsivity of substance users was found to be higher than the healthy control group. This result can be interpreted as impulsivity makes people tend to use substances, or it can be interpreted as substance use increases impulsivity. Another important consequence of the study is that patients with substance use has higher impaired complex attention than healthy controls. This finding may be a factor that triggers the use of the substance or it may be a result of the use of the substance. This is the first study to investigate the complex attention of the executive functioning of patients with substance use disorder in our country with the trail making test. Acknowledgements This study is the master’s thesis of Ali Kustepe (Cag University School Number: 201410079) dated January 2017 from the authors. The thesis study was approved by the Cag University Institute of Social Sciences, Department of Psychology, under the name “Evaluation of Impulsivity and Complex Attention Functions of Subjects with Substance Use: Sample from Adiyaman Province”.

doi: 10.5455/medscience.2018.07.8917 Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Before the study, permissions were obtained from local ethical committee. Ali Kustepe ORCID:0000-0001-9734-5360 Aysun Kalenderoglu ORCID:0000-0002-8216-8610 Mustafa Celik ORCID:0000-0003-4228-0445 Esra Kaya Bozkurt ORCID:0000-0002-7515-1132 Mehmet Hamdi Orum ORCID:0000-0002-4154-0738 Sukru Uguz ORCID:0000-0001-7940-2165

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Kollins SH. Delay discounting is associated with substance use in college students. Addict Behav. 2002;28:1167-73.

Vonmoos M, Hulka LM, Preller KH, et al. Differences in self-reported and behavioral measures of impulsivity in recreational and dependent cocaine users. Drug Alcohol Dependence. 2013;133:61-70.

De Wit H. Impulsivity as a determinant and consequence of drug use: A review of underlying processes. Addict Biol. 2009;14:22-31.

10. Perry JL, Carroll ME. The role of impulsive behaviour in drug abuse. Psychopharmacology (Berl). 2008;200:1-26.

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13. Konrad A, Vucurevic G, Lorscheider M, et al. Broad disruption of brain white matter microstructure and relationship with neuropsychological performance in male patients with severe alcohol Dependence. Alcohol Alcoholism. 2012;47:118-26. 14. Türkeş N, Can H, Kurt M, ve ark. İz Sürme Testi’nin 20-49 yaş aralığında Türkiye için norm belirleme çalışması. Türk Psikiyatri Dergisi. 2015;26:18996. 15. Güleç H, Tamam L, Güleç MY, et al. Barratt Dürtüsellik Ölçeği-11 (BIS11)’nin Türkçe uyarlamasının psikometrik özellikleri. Klinik Psikofarmakoloji Bülteni. 2008;18:251-8. 16. Asan Ö, Tıkır B, Okay İT, ve ark. Bir AMATEM birimine başvuran alkol ve madde kullanım bozukluğu olan hastaların sosyodemografik ve klinik özellikleri. Bağımlılık Dergisi. 2015;16:1-8. 17. Türkmen SN, Kumaşoğlu Ç, Akyol T. Alkol ve Madde Bağımlılığı Tedavi ve Eğitim Merkezi (AMATEM) biriminde yatan bireylerde içselleştirilmiş damgalanma ve yaşam kalitesi. Bağımlılık Dergisi. 2015;16:182-91. 18. Köksal B. Madde bağımlılarında dürtüsellik ve saldırganlığın incelenmesi. Yüksek Lisans Tezi, İstanbul, 2016 19. Bozkurt M. Alkol ve eroin bağımlılığı olan iki ayrı grupta dürtüsellik ve agresyonun kişilik özellikleri ile ilişkisi. Tıpta Uzmanlık Tezi, Bakırköy Prof. Dr. Mazhar Osman Ruh Sağlığı ve Sinir Hastalıkları Eğitim ve Araştırma Hastanesi, İstanbul, 2012. 20. Çalışkan N. Denetimli serbestlik tedbiri ile tedavi kararı verilen kannabis kullanıcılarında dürtüsellik ve benlik saygısı düzeylerinin takip sonuçları ile ilişkisi. Uzmanlık Tezi, Ankara Numune Eğitim ve Araştırma Hastanesi, Ankara, 2015. 21. Ersche KD, Turton AJ, Pradhan S, Bullmore ET, Robbins TW. Drug addiction endophenotypes: Impulsive versus sensation-seeking personality traits. Biol Psychiatry. 2010;68:770-3. 22. Rosenberg N, Grigsby J, Dreisbach J, et al. Neuropsychologic impairment and MRI abnormalities associated with chronic solvent abuse. Clin Toxicol. 2012;40:21-34. 23. Ünal E. Uçucu madde kullanım bozukluğu olan ergenlerde dikkat, bellek, yürütücü işlevler ve vizyospasyal fonksiyonların değerlendirilmesi. Tıpta Uzmanlık Tezi, Bakırköy Prof. Dr. Mazhar Osman Ruh Sağlığı ve Sinir Hastalıkları Eğitim ve Araştırma Hastanesi, İstanbul, 2011. 24. Yazıhan-Torun N, Özşahin A, Sütçigil L. Dikkat eksikliği hiperaktivite bozukluğunun yetişkinlikteki yansımaları. Klinik Psikiyatri. 2009;12:43-50.

11. Karakas S. A descriptive frame work for in Formation processing: An integrative approach. In: Basar E, Hari R, Lopes Da Silva, Schürmann M, eds, Brain Alpha Activity: New Aspects and Functional Correlates. International Journal of Psycho physiology. 1999;26:353-68.

25. Orum MH, Kara MZ, Egilmez OB. Relationship between immune cells and alcohol dependents and controls: what about the lymphocyte-related ratios? J Immunoassay Immunochem. 2018;39:348-50.

12. Davies SJC, Pandit SA, Feeney A, et al. Is there cognitive impairment in clinically, healthy abstinent alcohol dependence? Alcohol Alcoholism. 2005;40:498-503.

26. Turhan E, İnandı T, Özer C, ve ark. Üniversite öğrencilerinde madde kullanımı, şiddet ve bazı psikolojik özellikler. Türkiye Halk Sağlığı Dergisi. 2011;9:33-44.

Available online at www.medicinescience.org

ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):72-6

Risk of adenomyosis according to the type of previous uterine surgery Gamze Yilmaz1, Emre Erdem Tas2, Ayse Filiz Yavuz2 2

1 Ankara Ataturk Training andResearchHospital, Department of Obstetricsand Gynecology, Ankara, Turkey Ankara Yildirim Beyazit University Faculty of Medicine, Department of Obstetrics and Gynecology, Ankara, Turkey

Received 06 July 2018; Accepted 07 August 2018 Available online 11.10.2018 with doi:10.5455/medscience.2018.07.8900 Copyright ÂŠ 2019 by authors and Medicine Science Publishing Inc. Abstract This study aimed to ascertain whether previous uterine surgery has a role in the etiology of adenomyosis; to determine the incidence of uterine surgery in adenomyosis cases; and to assess the risk of adenomyosis according to the type of uterine surgery. The study included 1481 patients who had a hysterectomy due to any indication in a single center between January 2004 and December 2014. It was approved by the Ethical Rewiew Board of Ankara Yildirim Beyazit University Faculty of Medicine. Patients with and without adenomyosis were divided into two groups and compared according to age, parity, and history of previous uterine surgery. Previous uterine surgeries were also separately compared. A p-value less than 0.05 was considered statistically significant.We found that 63.4% of adenomyosis patients and 40.6% of non-adenomyosis patients underwent at least one uterine surgery. In patients with similar age and parity, those who underwent a uterine surgery were 2.494 times more at risk of being diagnosed with adenomyosis. A separate analysis of surgeries showed that previous myomectomy and Dilatation and Curetege were associated with an increased risk of adenomyosis while Cesarean-section had no significant effect. It was observed that previous uterine surgeries increase the risk for adenomyosis. Patients who had one more uterine surgery were more likely to develop adenomyosis. Keywords: Adenomyosis, risk factors, dilatation and curettage, uterine myomectomy, cesarean section

Introduction Adenomyosis is defined as the presence of ectopic endometrial glands and stroma in myometrial tissue [1,2]. In the past two decades, it was diagnosed by the pathological examination of hysterectomy, but it can now be detected through advanced imaging modalities without the need for surgery. The prevalence of adenomyosis varies in many clinics; studies have reported a prevalence of 5-70% and an average incidence of 20-30% in hysterectomy cases [3-6]. There are wide variations in incidence due to racial, ethnic, or geographical differences. However, it was not clarified whether variations stem from individual factors or from differences in diagnostic criteria [5]. None of the symptoms observed in adenomyosis are specific; symptoms can also be associated with other concomitant pathologies (leiomyoma, endometriosis, endometrial polyp, etc.). Thus, it is difficult to identify patients with adenomyosis alone and to clarify their clinical phenotype. It is generally associated with menorrhagia, abnormal uterine bleeding, chronic pelvic pain, *Coresponding Author: Gamze Yilmaz, Ankara Ataturk Training andResearchHospital, Department of Obstetricsand Gynecology, Ankara, Turkey E-mail: gamze_u@hotmail.com

dysmenorrhea, and dyspareunia; however, the accuracy of these associations is controversial [4,5]. The etiology of adenomyosis is still unclear; however, age, multiparity, previous uterine surgeries, smoking, tamoxifen and antidepressant use can be influential [710]. This study aimed to identify whether a previous uterine surgery (Cesarean-section [C-section], myomectomy, Dilatation and Curettage [D&C], and hysteroscopy) has a role in the etiology of adenomyosis; to determine the incidence of uterine surgery in adenomyosis cases; and to assess the risk of adenomyosis according to the type of surgery. Material and Methods The study included 1481 patients who had a hysterectomy due to any indication in a training and research hospital between January 2004 and December 2014. Patient data were obtained from the Hospital Information Management System, archive files, and through contact with patients when necessary. Patient files were routinely scanned to identify age, gravidity, parity, the number of abortion, previous uterine surgeries (C-section, myomectomy, D&C, and hysteroscopy), hysterectomy indications, and the presence or absence of adenomyosis in pathology reports. The 72

doi: 10.5455/medscience.2018.07.8900

patients were excluded from the study if sufficient information were not avaliable from the patient files or though contact by telephone.

Med Science 2019;8(1):72-6

The research was retrospectively conducted. The normality of the research variables was analyzed using the Shapiro-Wilk test. Continuous variables were expressed as mean ± standard deviation (mean ± SD) and median (IQR: interquartile range). Numbers (percentages) were used to show patients who underwent at least one uterine surgery, those who did not undergo uterine surgery, and patients’ history of a previous myomectomy, C-section, D&C and hysteroscopy.

In terms of previous uterine surgery, 63.4% (n=189) of adenomyosis patients and 40.6% (n=480) of non-adenomyosis patients underwent at least one uterine surgery. Thus, the rates of previous uterine surgery were different between the diagnostic groups (χ2=50.173, p<0.001). Similarly, a statistically significant difference was also found between the rates of previous D&C in the diagnostic groups (χ2=70.051, p<0.001). The diagnostic groups were similar in terms of the history of myomectomy and C-section (p>0.05). None of the adenomyosis patients and 99.7% (n=1176) of the non-adenomyosis patients had a hysteroscopy. No statistical inference was found on the presence of a previous hysteroscopy (Table-2).

The Mann-Whitney U test was used to compare variables including age, parity, the number of C-section, etc. according to patients with and without adenomyosis. Chi-square tests were used for the analysis of categorical variables in diagnostic groups, such as previous uterine surgery. Logistic regression analysis was used to determine the effects of the history of uterine surgery on the diagnosis of adenomyosis. In the analysis results, the odds ratio (OR) and the 95% confidence interval (CI) of OR were explained using a Wald statistic and p-value. P<0.05 was accepted as statistically significant.

In terms of previous uterine surgery in general, age and parity had no significant effect among the factors affecting the diagnosis of adenomyosis, while the presence of previous uterine surgery had a significant effect (p<0.001) . Among patients with similar age and parity, those who underwent a uterine surgery were 2.494 times more likely to be at risk of being diagnosed with adenomyosis compared to those who did not undergo uterine surgery (Table-3). In the same group, patients who had undergone one more uterine surgery were at 47% higher risk of being diagnosed with adenomyosis (Table 4).

Statistical analysis and calculations were performed using IBM SPSS Statistics 21.0 (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.).

Considering the patients’ history of previous uterine surgery in detail, age and parity again had no significant effect on the diagnosis of adenomyosis while the presence of previous myomectomy and D&C had a significant effect (p<0.05) Among the patients with similar age, parity, and previous D&C history, those who underwent a myomectomy were 2.304 times more likely to be at risk of being diagnosed with adenomyosis compared to those who did not(Table 5). Among the patients with similar age, parity, and previous myomectomy history, those who underwent D&C were 2.941 times more likely to be at risk of being diagnosed with adenomyosis compared to those who did not (p<0.001).

Results The mean age for 298 patients diagnosed with adenomyosis was calculated as 50.87 ± 7.84 years and 1183 patients diagnosed with diseases other than adenomyosis was 52.05±9.53 years. The number of previous C-sections, and the number of previous hysteroscopies were not different (p>0.05). Adenomyosis patients were found to have a significantly higher number of previous myomectomy and D&C (Table-1,p<0.05).

Table 1. Distribution of age, parity and the number of uterine surgeries according to the diagnostic groups (Adenomyosis vs. others) Pathology Report Adenomyosis (n=298)

Other (n=1183)

Age mean ± SD

50.87±7.84

52.05±9.53

Median (IQR)

49.00 (7.00)

49.00 (10.00)

mean ± SD

3.11±1.60

3.06±1.89

Median (IQR)

3.00 (2.00)

mean ± SD

0.04±0.79

0.02±0.16

Median (IQR)

0.00 (0.00)

mean ± SD

0.21±0.63

0.17±0.52

Median (IQR)

0.00 (0.00)

mean ± SD

1.27±1.52

0.55±1.04

Median (IQR)

1.00 (2.00)

0.00 (1.00)

mean ± SD

0.01±0.11

Median (IQR)

0.00 (0.00)

Parity

Myomectomy

C-section

D&C

Hysteroscopy

Test Statistic

1.100

0.271

1.817

0.069

2.029

0.042

1.322

0.186

9.258

<0.001

1.006

0.314

Abbreviations: C-Section: Cesarean-section; D&C: Dilatation and Curetege.

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Table 1. Distribution of age, parity and the number of uterine surgeries according to the diagnostic groups (Adenomyosis vs. others) Pathology Report Adenomyosis n (%) Other n (%) Uterine surgery +

109 (36.6) 189 (63.4)

703 (59.4) 480 (40.6)

287 (96.3) 11 (3.7)

1162 (98.2) 21 (1.8)

258 (86.6) 40 (13.4)

1055 (89.3) 126 (10.7)

129 (43.3) 169 (56.7)

820 (69.3) 363 (30.7)

298 (100.0) 0 (0.0)

1176 (99.7) 4 (0.3)

Myomectomy

C-section

D&C

Histerescopy

Test Statistic

50.173

<0.001

3.2771

0.070

1.811

0.178

70.051

<0.001

Table 3. Factors affecting the diagnosis of adenomyosis (considering previous uterine surgery) % 95 CI of OR B

Wald

Lower Limit

Upper Limit

Age

-0.011

0.008

1.777

0.182

0.989

0.974

1.005

Parity

0.048

0.040

1.453

0.228

1.049

0.971

1.133

(underwent)

0.914

0.135

45.513

<0.001

2.494

1.913

3.253

Constant

-1.444

0.417

12.001

0.001

0.236

Uterine Surgery

Table 4. Factors affecting the diagnosis of adenomyosis (Considering the number of uterine surgery performed) % 95 CI of OR B

Wald

Lower Limit

Upper Limit

Age

-0.015

0.008

3.248

0.072

0.985

0.969

1.001

Parity

0.044

0.040

1.200

0.273

1.045

0.966

1.130

UterineSurgery (number)

0.385

0.046

70.395

<0.001

1.470

1.344

1.609

Constant

-1.164

0.409

8.090

0.004

0.312

Abbreviations: CI: confidence interval; OR: odds ratio Table 5. Factors affecting the diagnosis of adenomyosis (considering previous uterine surgery in detail) % 95 CI of OR B

Wald

Lower Limit

Upper Limit

Age

-0.015

0.008

3.388

0.066

0.985

0.969

1.001

Parity

0.038

0.040

0.894

0.344

1.039

0.960

1.124

Myomectomy (underwent)

0.835

0.392

4.541

0.033

2.304

1.069

4.964

D&C (underwent)

1.079

0.133

65.289

<0.001

2.941

2.264

3.820

Constant

-1.198

0.414

8.357

0.004

0.302

Abbreviations: CI: confidence interval; D&C: Dilatation and Curettage, OR: odds ratio

C-section had no significant effect on the diagnosis of adenomyosis. Considering the number of all uterine surgeries that the patients underwent, age and the number of previous D&C had a significant effect on the diagnosis of adenomyosis, while parity had no significant effect . Among the patients with similar parity and a similar number of previous D&C, those who were one year older had a 2.0% (CI: 0.3% â&#x20AC;&#x201C; 3.6%) lower risk of being diagnosed with adenomyosis . Among the patients with similar age and parity,

those who underwent one more previous D&C were at 53.4% (CI: 69.3% â&#x20AC;&#x201C; 38.9%) higher risk of being diagnosed with adenomyosis. Age and the number of previous D&C had a significant effect on the diagnosis of adenomyosis (Table 6). Among the patients with similar age, parity, and a similar number of previous myomectomies and C-sections, those who underwent one more previous D&C were at 53.9% higher risk of being diagnosed with adenomyosis (OR=1.539). 74

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Table 6. Factors affecting the diagnosis of adenomyosis (considering the number of all previous uterine surgeries) B SE Wald p OR Age -0.018 0.008 4.479 0.034 0.982 Parity 0.040 0.041 0.953 0.329 1.040 Myomectomy (number) 0.484 0.362 1.788 0.181 1.623 C-section (number) 0.176 0.114 2.367 0.124 1.192 D&C (number) <0.001 0.431 0.051 72.538 1.539 Constant 0.018 -0.991 0.420 5.569 0.371 Abbreviations: CI: confidence interval; C-Section: Cesarean-section; D&C: Dilatation and Curettage, OR: odds ratio

Discussion Studies in the literature are inconsistent on whether a previous uterine surgery has an effect on the etiology of adenomyosis. The present study treated uterine surgeries both under a general category and separately under four sub-categories including myomectomy, C-section, hysteroscopy, and D&C. Considering patients â&#x20AC;&#x2122; history of uterine surgery, 63.4% of adenomyosis patients and 40.6% of non-adenomyosis patients underwent at least one uterine surgery. Considering the history of previous uterine surgery in general, the presence of previous uterine surgery was found to be significant among the factors affecting a diagnosis of adenomyosis. Additionally, the number of previous surgeries has a statistically significant correlation with an increased risk. Among the patients with similar age and parity, those who had a uterine surgery were 2.4 times more likely to be at risk of being diagnosed with adenomyosis compared to those who did not have. In the same group, patients who had one more uterine surgery were at 47% (CI: 34.4% â&#x20AC;&#x201C;60.9%) higher risk of being diagnosed with adenomyosis. The literature includes research results that are parallel with the present study [5,10,11]. However, it also includes research emphasizing that there is no correlation [4,9,11]. Panganamamula et al. hypothesized that adenomyosis arises from the invasion of endometrial glands into myometrium depending on the surgical destruction of the endomyometrial border. They observed an increased risk of adenomyosis with previous uterine surgery; however, they found no statistically significant correlation when they analyzed previous surgeries individually (C-section, myomectomy, endometrial ablation, and D&C) [10]. Bergolt et al. also reported no increased risk with C-section and myomectomy [4]. In two separate studies in 2010 and 2012, Taran et al. also supported that there is no risk increase [7,8]. Considering patientsâ&#x20AC;&#x2122; history of previous uterine surgeries in detail, the present study found that a previous myomectomy and D&C history had a significant effect on the diagnosis of adenomyosis. Among the patients with similar age, parity, and previous D&C history, those who had a myomectomy were 2.304 times more likely to be at risk of being diagnosed with adenomyosis compared to those who did not have a myomectomy. Kazemi et al. have recently reported that previous uterine surgeries increased the risk of adenomyosis and no adenomyosis patients underwent a myomectomy; thus, they did not find a specific risk related to myomectomy [11]. The present study found that the diagnostic groups (i.e. adenomyosis and non-adenomyosis patients) were similar in terms of having a C-section. C-section had no significant effect on the diagnosis of adenomyosis. The literature includes a few studies assessing the correlation between C-section and adenomyosis.

% 95 CI of OR Lower Limit Upper Limit 0.966 0.999 0.961 1.126 0.798 3.301 0.953 1.491 1.393 1.699

Curtis et al. retrospectively surveyed 1850 patients and found no significant correlation between C-section and adenomyosis) [12]. This result was later supported by a number of studies [9,13]. There are, however, different results. Vavilis et al. (1997), Levgur et al. (2000), and Whitted et al. (2010) argued that a previous C-section is associated with an increased prevalence of adenomyosis [14-16]. Kazemi et al. (2014) have more recently reported that a previous C-section is the most common surgery that increases the risk of adenomyosis [11]. Literature studies have mostly focused on D&C when investigating risk factors for adenomyosis. The present study found that D&C increased the risk of adenomyosis. Among the patients with similar age, parity, and previous myomectomy history, those who had D&C were 2.9 times more at risk of being diagnosed with adenomyosis compared to those who did not. Among the patients with similar age and parity, those who had one more previous D&C were at 53% higher risk of being diagnosed with adenomyosis. Parazzini et al. found an increased risk of adenomyosis in D&C cases other than pregnancy and reported in a later study that patients who underwent D&C for pregnancy termination were at higher risk of adenomyosis compared to those who did not undergo D&C for pregnancy termination [3,6]. Similarly, Levgur et al. and Taran et al. also reported an increased risk [7,16]. Curtis et al. indicated an increased risk in sharp curettage cases for pregnancy termination (especially before 1975) but did not find an increased risk in D&C cases other than pregnancy [12]. The general opinion in the literature is that a previous D&C, whether for pregnancy termination or not, increases the risk of adenomyosis. The present study did not include the reasons for having D&C but considered, in general, the likelihood of disruption of the endometrialmyometrial junction. The literature includes no research on the correlation between hysteroscopy and adenomyosis. The present study found no statistically significant difference between two diagnostic groups in terms of the number of previous hysteroscopies. Conclusion Although this study has some limitations, such as its retrospective, single-center design ,unknown whether uterine cavity was damaged during myomectomy and it was conducted on patients who underwent hysterectomy; it supports the notion that the presence of previous uterine surgeries increases the risk of adenomyosis. Furthermore, we identified that patients who had undergone one more uterine surgery were at 47% higher risk of being diagnosed with adenomyosis. Although; cesarean section damages entire endometrial layer, increase risk for adenomyosis was not determined.

doi: 10.5455/medscience.2018.07.8900 Competing interests The authors declare that they have no competing interest

Med Science 2019;8(1):72-6

Taran FA,Weaver AL, Coddington CC,et al. Understanding adenomyosis: a case control study. Fertil Steril. 2010; 94: 1223-8.

Ethical approval This present research was accepted by local ethics committee and informed consent forms and permits were obtained from all participants before joining the study.

Taran FA,Wallwiener M, Kabashi D, et al. Clinical characteristics indicating adenomyosis at the time of hysterectomy: a retrospective study in 291 patients. Arch Gynecol Obstet. 2012;285:1571–6.

Gamze Yilmaz ORCID: 0000-0001-8021-7653 Emre Erdem Tas ORCID: 0000-0001-6043-2700 Ayse Filiz Yavuz ORCID: 0000-0003-3699-7757

Templeman C, Marshall SF, Ursin G, et al. Adenomyosis and endometriosis in the California Teachers Study. Fertil Steril. 2008; 90:415-24.

10. Panganamamula UR, Harmanlı OH, Isık -Akbay EF, et al. İs prior uterine surgery a risk factor for adenomyosis. Obstet Gynecol. 20014;104:1034-8.

Financial Disclosure The financial support for this study was provided by the investigators themselves.

Reference 1.

Siegler AM ,Camilien L. Adenomyosis J Reprod Med. 1994:39; 841-53.

Hendrickson MR, Kempson RL. Non-neoplastic conditions of the myometrium and uterine serosa H. Fox (Ed.), Haines and Taylor obstetrical and gynecological pathology (3rd edition), Churchill Livingstone, Edinburgh, London, Melbourne and New York (1987), pp. 405-10.

Parazzini F, Vercellini P, Panazza S,et al. Risk factors for adenomyosis. Hum Reprod. 1997;12:1275-9.

Bergholt T, Eriksen L, Berendt N, et al. Prevalence and risk factors of adenomyosis at hysterectomy. Hum Reprod. 2001;16: 2418-21.

Vercellini P, Vigano P, Somigliana,et al. Adenomyosis: epidemiological factors. Best Pract Res Clin Obstet Gynaecol. 2006;20:465-77.

Parazzini F, Mais V, Cipriani S,et al. Determinants of adenomyosis in women who underwent hysterectomy for benign gynecological conditions: results from a prospective multicentric study in Italy. Eur J Obstet Gynecol Reprod Biol. 2009;143:103-6.

11. Kazemi E, Alavi A, Aalinehad Fet al. Evaluation of the relationship between prior uterine surgery and the incidence of adenomyosis in the Shariati Hospital in Bandar-Abbas ,Iran,from 2001 to 2011. Electron Physician. 2014;6:912-8. 12. Curtis KM, Hillis SD, Marchbanks PA, et al. Disruption of the endometrialmyometrial border during pregnancy as a risk factor for adenomyosis. Am J Obstet Gynecol. 2002;187:543–4. 13. Farquhar C, Brosens I. Medical and surgical management of adenomyosis. Best Pract Res Clin Obstet Gynaecol 2006;20:603-16. 14. Vavilis D, Agorastos T, Tzafetas J, et al. Adenomyosis at hysterectomy: prevalence and relationship to operative findings and reproductive and menstrual factors. Clin Exp Obstet Gynecol. 1997;24:36-8. 15. Whitted R, Verma U, Voigl B, et al. Does cesarean delivery increase the prevalence of adenomyosis? A retrospective review. Obstet Gynecol. 2000;95:S83. 16. Levgur M, Abadi MA, Tucker A. Adenomyosis: symptoms, histology, and pregnancy terminations.Obstet Gynecol. 2000;95:688-91.

Available online at www.medicinescience.org

ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):77-80

Epidemiology of Blastocystis spp. in primary school students at a central village of Ordu province Ulku Karaman1, Zeynep Koloren2, Emine Ayaz2, Umit Gur2 1 Ordu University, Faculty of Medicine, Department of Parasitology, Ordu,Turkey Ordu University, Faculty of Arts and Sciences, Department of Molecular Biology and Genetics, Ordu,Turkey

Received 02 July 2018; Accepted 07 August 2018 Available online 18.10.2018 with doi:10.5455/medscience.2018.07.8912 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Blastocystis spp. is one of the most common intestinal parasites in humans and its pathogenicity is still controversial. The epidemiology of this parasite varies depending on the socio-cultural, socio-economic and geographic circumstances. In this study, Blastocystis spp. was investigated in stool samples of a Primary School students’ in a Central Village in Ordu province who did not have any intestinal complaints. Before starting work, we were granted permission from National Education Directorate and the School Board. Blastocystis spp. was investigated in Primary School Students’ stool samples by direct microscopy and Trichrome staining. The stool samples which showed any form of Blastocystis spp. were evaluated as “microscopically positive” regardless of the number per microscope field. Eighty and 85 of the 165 students participating in working were male and female, respectively. As a result of the microscopic investigation, 45 (27.3%) students were identified as positive. Eighteen of the positive students (40%) were male and 27 (60%) were female. Direct microscopic inspection, sedimentation and permanent staining are routine methods used in diagnosis of Blastocystis spp. This study also evaluated trichrome staining for each stool samples. In our research, this parasite was identified in 27.3% of asymptomatic Primary School students’ stool samples. This suggests the parasite is relatively common in the region. Blastocystis spp. infects via the fecal-oral route. As a result, we presented recommendations for the enhancing personal hygiene, social education and the provision of water treatment for the students to protect themselves from infection with Blastocystis spp. Keywords: Blastocystis spp., Epidemiology, Ordu, Primary school students

Introduction Blastocystis spp. which is defined in 1988 by Zierdt can be caused complication in gastrointestinal tract in many animal and human [1]. There are different opinions about pathogenicity, genetic diversity, host spectrum, and treatment options, although the knowledge of parasite morphology for long time [2]. There are many zoonotic genotypes in humans [3]. There are studies in the literature supporting the pathogen of Blastocystis [4-6], whereas, some authors have reported that Blastocystis spp. is not responsible the clinical symptoms of blastocystosis [7,8]. Tan [3] asserts that some populations may be more susceptible to infection with Blastocystis spp. and risk factors of this parasite are immunodeficiency, journey to the tropics, animal low hygiene, contact with contaminated water and food. It is reported that in the rare cases, detection of Blastocystis spp. is only amoeboid form can be shown severe diarrhea and while Blastocystis spp. can lead to *Coresponding Author: Ulku Karaman, Ordu University, Faculty of Medicine, Department of Parasitology, Ordu,Turkey E-mail: ulkukaraman44@hotmail.com

protracted and recurrent diarrhea in immunocompromised persons, especially AIDS patients [9]. In addition, Blastocystis infections cause symptoms such as diarrhea, abdominal pain, discomfort, bloating, gas, cramps, vomiting, dehydration, anorexia, insomnia, and nausea, lack of appetite, weight loss, fatigue, itching and tenesmus [10]. Blastocystis spp. has taken in the first row within the gastrointestinal protozoa in epidemiologic study, as well [6,11,12]. The economic developments, increasing human migration, environmental and demographic changes have been reported to be effective in the distribution of parasite. Subtropical climatic zone which is also including Turkey and evolves the proliferation of parasitic disease pathogens provides condition of optimal temperate climate [13]. Nowadays, the prevalence of parasite is different rates in developing countries and developed countries. The prevalence of Blastocystis spp. is the most common gastrointestinal protozoan with 1.5-10% in developed countries, while they are at the rate of 30-50% in developing countries. This situation have been connected to low hygiene, contacting with animals and contaminated water and food 77

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[2,14]. It has been reported that the prevalence of this parasite was 1% in Japan [15], 40.9% in Brazil [16] and 33.3% in Egypt [17] while, the rate of this parasite ranged from 0.48-44.4% in Turkey [13,18]. Recent studies suggest that it is impossible to explain the relationship between Blastocystis and irritable bowel syndrome when intestinal microbiota is not considered. Researchers have suggested that the environment may become a condition that supports or does not support the multiplication of Blastocystis due to the changing intestinal flora in chronic bowel diseases [19]. Meta-genomic analysis in a retrospective study Blastocystis was detected in 20% of patients with ulcerative colitis (UC), but not in Crohnâ&#x20AC;&#x2122;s disease [20].

Figure 1. Blastocystis vacuolar form by Trichrome staining (100X magnification)

According to our best reached knowledge, many researches were reported regarding as intestinal pathogens in different sites of Turkey. However, this research is the first for the detection on epidemiology of the intestinal parasites in children in Ordu province. In this study, Blastocystis spp. was investigated in stool samples of Primary School students who did not have any intestinal complaints at a Central Village in Ordu province of Black Sea Region in Turkey. Material and Methods Before starting work, we were granted permission from National Education Directorate and the School Board. The research was conducted in Department of Medical Parasitology laboratory at School of Medicine in Ordu University by examining 5-14 age group of 165 childrenâ&#x20AC;&#x2122;s stool samples collected from Kokenli Elementary School in Ordu province between the periods of February, 2015-March, 2015. The cover-sealed containers for stools were used for each specimen in research. The class teachers described how to take stool samples for students and it should not be at a rate of no more than 1/3 of the stools container. Fresh stool samples were examined without waiting after reached to the laboratory. The stools were macroscopically evaluated for the color, consistency, whether the presence of blood and mucus and parasitic. The stools slides were examined by direct microscopy and trichrome staining. All slides were screened by the use of direct microscopy under X10 and X40 magnifications and stained slides have been assessed by scanning 100 magnification. Results In the study, 80 and 85 out of 165 students participating in this research were male and female, respectively. As a result of the microscopic investigation, 45 (27.3%) students were identified as positive. Eighteen of the positive students were found to be male and 27 were female. Blastocystis spp. found over 5 in each field was evaluated as positive. Sixty percent of women and 40% of men has been found to be infecting with parasites. The parasites were found to be in the same samples by Trichrome stain.

Figure 2. Blastocystis vacuolar form by Trichrome staining (100X magnification)

Discussion Blastocystis spp. is one of the most common intestinal protozoa in humans. In nature there are many genotypes and human is the host for many zoonotic genotypes [3,21]. The pleomorphic structure of parasite and the lack of standardized diagnostic methods lead to misinterpretation in data about Blastocystis spp. The complexity about the pathogenesis of this parasite have originated from the presence of pathogenic and nonpathogenic genotypes [22]. Epidemiological, in vivo and in vitro studies related with parasite reinforce its the pathogen data [23]. The methods used in the routine diagnosis of Blastocystis spp. have been reported as directly screen, condensation and permanent staining. When directly screen comparing with condensation and Trichrome staining, these methods are reported to be more sensitive than directly screen [6]. Korkmaz et al [12] reported that the difficulty can be experienced in direct microscopic examination of blastocystosis because of different sizes and different morphological types of them and confusable with yeast and leukocytes by inexperienced persons. Even though, the authors found that the presence of the parasite 78

doi: 10.5455/medscience.2018.07.8912

with trichrome staining higher than native-lugols, this method is also time consuming, laborious, and requires experience. In this study, both directly screen and trichrome staining method were used together. Mumcuoğlu [24] reported that Blastocystis is found to be positive in 16 patients (29.1%) with irritable bowel syndrome were treated with direct microscopy, 18 (32.7%) with trichrome staining and culture method. Control group 2 without gastrointestinal system complaints; Blastocystis spp. was detected in 1 person (2.0%) by direct microscopy and Trichrome staining and in 3 persons (6%) by culture method. In control group 1, no other pathogens were found in all six patients who were detected 5 and up Blastocystis spp. on direct microscope. In addition to this situation, because of the absence of post-treatment complaints, reported that Blastocystis spp. Is a pathogen that needs to be evaluated by complaints and microscopy adherence? Korkmaz et al [12] reported the occurrence of Blastocystis spp. in a total of 350 stool samples belonging to patients with diarrhea (n=157) and non-diarrhea (n=193) by native-lugol examination, tricrome staining and direct fluorescent antibody (DFA) methods. Researchers; Blastocystis spp. were found in culture of a total 66 (19%) fecal specimens which were 26 of diarrhea patients (16.6%) and 40 of non-diarrhea patients (21%). Blastocystis spp. was found to be positive in samples with12% (42/350) Native-lugol, 17% (58/350) Trichrome staining and 19% (66/350) DFA method. In our study, Native-lugol and Trichrome staining were also used for diagnostic purposes of Blastocystis spp.

Med Science 2019;8(1):77-80

In the resource information reached with parasite epidemiology, the prevalence of this parasite was found to be with 1.5-10% in developed countries, while it was between 30-50% in the developing countries [25]. In America (USA?) and Brazil, the prevalence of Blastocystis was found to be with 18% and 26.5%, respectively [26,27], while, Blastocystis infection rate in Vietnamese pregnant women is reported as 20.4% [28]. In our country, the prevalence of Blastocystis spp. had been reported at ranging from 0.48-44.4% [13,18,29,30]. The prevalence of Blastocystis spp. was found to be with 0.48% in Kütahya [30], 2.1% in Istanbul [31], 22% in Ankara [32], 4,38% in Izmir [11], 7% in Eskişehir [33], 7.64% in Manisa [34], 23.2% in Kocaeli [35], 23.57% in Bursa [36]. According to Korkmaz et al. [12], Blastocystis spp. isolation have been reported in a total of 19% of the stool sample culture with 16.6% of patients with diarrhea and 21% of non-with diarrhea. Twelve percent of the stool samples are positive by native-lugols, 17% and 19% of them were positive by trichrome staining and DFA method, respectively. In this study, parasite was detected in children who not to go to the doctor because of any complaints. Conclusion This study represented that this parasite is relatively common in this region. Enhancing personal hygiene and public education and the provision of water treatment are necessary to protect themselves from Blastocystis infection. Acknowledgements We thank 2nd grade students in Faculty of Medicine for sample collection.

It has been reported that parasites may be opportunistic pathogens in children and those with immunosuppression and should be monitored more carefully [25]. In people with Blastocystis infection, clinical findings are considered to be due to many factors such as Blastocystis genotype, microbiota, host immune response, Blastocystis concentration and other accompanying infection [19]. Blastocystis infection has been associated with numerous gastrointestinal and some dermatological symptoms (abdominal pain, diarrhea, constipation, weakness, vomiting, headache, dermatological manifestations, joint pain and psychiatric findings) in studies that have identified Blastocystis as pathogenic [26].

Competing interests The authors declare that they have no competing interest

In this study, according to anamnesis, it was determined that the parasitized children have digestive system disorders. However, they have reported that they did not go to the doctor with the reasons for their complaints. This can be explained by the fact that the treatment of children should be taken into consideration.

Tan TC, Suresh KG. Predominance of amoeboid forms of Blastocystis hominis in isolates from symptomatic patients. Parasitol Res. 2006; 98:189193.

Roberts T, Stark D, Harkness J, et al. Update on the pathogenic potential and treatment options for Blastocystis sp., Gut Pathog. 2014;6-17.

Mumcuoglu [24], Blastocystis spp. has found to be with 6 (7.5%), 8 (10.0%) and 15 (18.8%) of patients in the control group 1 with acute gastroenteritis complaints by direct microscopy, Trichrome staining and culture method, respectively. In addition, Blastocystis spp. has found to be with 1 (2.0%) and 3 (6%) of patients in the control group 2 with non-acute gastroenteritis complaints by direct microscopy, Trichrome staining and culture method, respectively. Blastocystis spp. has been identified in all of 6 patients in the control group 1 by direct microscopy in each field with the number of its 5 and up. But, no other pathogens were found in direct microscopy. Blastocystis spp. should be assessed by taking into consideration with microscope data and patient’s complaints.

Tan KS. New insights on classification, identification, and clinical relevance of Blastocystis spp. Clin Microbiol Rev. 2008;21:639-65.

Leder KM, Hellard E, Sinclair MI, et al. No correlation between clinical symptoms and Blastocystis hominis in immunocompetent individuals. J Gastroenterol Hepatol. 2005;20:1390-4.

Andiran N, Acikgoz ZC, Turkay S, et al. Blastocystis hominis, an emerging and imitating cause of acute abdomen in children. J Pediatr Surg. 2006;41:1489-91.

Ozcakir O, Gureser S, Erguven S, et al. Characteristics of Blastocystis hominis infection in a Turkish university hospital. Turkey Parazitol J. 2007;31:277-82.

Muller RA, Minshevv BH. Blastocystis hominis: an organism in search of a disease. Rev Inf Dis. 1988;10:930-8.

Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Before the study, permissions were obtained from local ethical committee. Ulku Karaman ORCID: 0000-0001-7027-1613 Zeynep Koloren ORCID: 0000-0003-3982-5459 Emine Ayaz ORCID:0000-0001-9708-2716 Umit Gur ORCID:0000-0002-1511-1147

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Senay H, MacPherson D. Blastocystis hominis: epidemiology and natural history. J Inf Dis. 1990;162:987-90.

Windsor JJ, Whiteside TM, Chalmers RM, et al. Blastocystis hominis: a common yet neglected human parasite. Brit J Biomed Sci. 2001;58:129-30.

10. Godekmerdan A. Prevalence of Blastocystis hominis in patients presenting dispensary and its relationship with gastro-intestinal complaints. Erciyes University Institute of Health Sciences. 1995;4:5-13. 11. Inceboz T, Usluca S, Over L, et al. The epidemiology research of Blastocystis hominis in the Dokuz Eylul University Medical Faculty Hospital between 2005 and 2009. Turkey Parazitol J. 2011;35:72-6. 12. Kormaz GA, Doğruman ALF, Mumcuoğlu I. Investigation of stool specimens of Blastocystis sp. by microscopic, culture and molecular methods. Mikrobiol Bul. 2015 49:85-97. 13. Akdemir C, Helvaci R. Evaluation of parasitology laboratory results of a group of people older than 15 years of age in Kutahya. Turkey Parazitol J. 2007;31:37-40.

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1999;18:436-9. 24. Mumcuoğlu I, Coskun FA, Aksu N, et al. Role of Dientamoeba fragilis and Blastocystis spp. in irritable bowel syndrome. Turkey Parazitol J. 2013;37:73-7. 25. Stenzel DJ, Boreham PF. Blastocystis hominis revisited. Clin Microbiol Rev. 1996;9:563-84. 26. Nascimento SA, Moitinho Mda L. Blastocystis hominis and other intestinal parasites in a community of Pitanga City, Paraná State, Brazil. Rev Inst Med Trop S Paulo 2005;47:213-7. 27. Eassa SM, Ali HS, El Masry SA, et al. Blastocystis hominis among immunocompromised and immunocompetent children in Alexandria, Egypt. Ann Clin Laboratory Res. 2016;4. 28. Hameed DM, Hassanin OM, Zuel-Fakkar NM. Association of Blastocystis hominis genetic subtypes with urticaria. Parasitol Res. 2011;108:553-60. 29. Amin OM. The epidemiology of Blastocystis hominis in the United States. Res J Parasitol. 2006;1:1-10.

14. 14.Alfellani MA, Stensvold CR, Vidal-Lapiedra A, et al. Variable geographic distribution of Blastocystis subtypes and its potential implications. Acta Trop. 2013;126:11-8.

30. Cheng HS, Haung ZF, Lan WH, et al. Epidemiology of Blastocystis hominis and other intestinal parasites in a Vietnamese female immigrant population in Southern Taiwan, Kaohsiung. J Med Sci. 2006;22:166-70.

15. Hirata T, Nakamura H, Kinjo N, et al. Prevalence of Blastocystis hominis and Strongyloides stercoralis infection in Okinawa, Japan. Parasitol Res. 2007;101:1717-9.

31. Celik T, Daldal N, Karaman U, et al. Incidence of intestinal parasites among Primary School Children in Malatya. Turkey Parazitol J. 2006;30:35-8.

16. Aguiar J I, Goncalves AQ, Sodre FC, et al. Intestinal protozoa and helminths among Terena indians in the State of Mato Grosso do Sul: high prevalence of Blastocystis hominis. Rev Soc Bras Med Trop. 2007;40: 631-4. 17. Rayan HZ, Ismail OA, El Gayar EK. Prevalence and clinical features of Dientamoeba fragilis infections in patients suspected to have intestinal parasitic infection. J Egypt Soc Parasitol. 2007;37:599-608. 18. Atambay M, Karaman U, Aycan O, et al. The frequency of intestinal parasites and head lice among students of the Aksemsettin Primary School for deaf students. Turkey Parazitol J. 2007; 31:62-5. 19. Stensvold CR, Clark CG. Current status of Blastocystis: A personal view. Parasitology International 2016;65:763-71. 20. Andersen LO, Bonde I, Nielsen HB, et al. A retrospective metagenomics approach to studying Blastocystis. FEMS Microbiol Ecol. 2015;91. 21. Noël C, Dufernez F, Gerbod D, et al. Molecular phylogenies of Blastocystis isolates from different hosts: implications for genetic diversity, identification of species, and zoonosis. J Clin Microbiol. 2005;43:348-355. 22. Clark CG. Extensive genetic diversity in Blastocystis hominis. Mol Biochem Parasitol. 1997;87:79-83. 23. Giacometti A, Cirioni O, Fiorentini A, et al. Irritable bowel syndrome in patients with Blastocystis hominis infection. Eur J Clin Microbiol Infect Dis.

32. Malatyali E, Ozcelik S. Isolation of Blastocystis sp. from human hosts and in vitro determination of different morphological forms. Turkey Parazitol J. 2011;35:19-22. 33. Koksal F, Baslanti I, Samasti M. A retrospective evaluation of the prevalence of intestinal parasites in İstanbul, Turkey. Turkey Parazitol J. 2010;34:16671. 34. Gulmez D, Saribas Z, Akyon Y, et al. The results of Hacettepe University Faculty of Medicine Parasitology Laboratory in 2003-2012: Evaluation of 10 Years. Turkey Parazitol J. 2013;37:97-101. 35. Dogan N, Demirustu C, Aybey A. The Prevalence of intestinal parasites according to the distribution of the patients’ gender and parasite species for five years at the Osmangazi University Medical Faculty. Turkey Parazitol J. 2008;32:120-5. 36. Duzyol D, Kilimcioğlu AA, Cengiz Ozyurt B, et al. Incidence of intestinal parasites detected in the Department of Parasitology in Celal Bayar University Hospital between 2006 and 2010. Turkey Parazitol J. 2012;36:147-51. 37. 35.Tamer GS, Caliskan S, Willke A. Distribution of intestinal parasites among patients who presented at the Parasitology Laboratory of the Kocaeli University School of Medicine Hospital. Turkey Parazitol J. 2008;32:126-9. 38. Alver O, Oral B, Tore O. The distribution of intestinal parasites detected in the Uludag University Medical School Hospital between 2005 and 2008. Turkey Parazitol J. 2011;35:194-8.

Available online at www.medicinescience.org

ORIJINAL ARTICLE

Medicine Science International Medical Journal

Medicine Science 2019;8(1):81-7

Smoking patterns and cessation counseling practices among physicians in Turkey Cigdem Tekin1, Gulsen Gunes2, Erkay Nacar2, Burak Mete2, Ertan Unver2 1

Inonu University, Health Vocational Scholl, Department of Home Care Services,Malatya, Turkey 2 Inonu University, Faculty of Medicine, Department of Public Health, Malatya, Turkey Received 04 August 2018; Accepted 07 August 2018 Available online 08.08.2018 with doi: 10.5455/medscience.2018.07.8867 Copyright © 2019 by authors and Medicine Science Publishing Inc.

Abstract By this study we aimed to determine the frequency of smoking of physicians, whether they evaluate their patients in terms of smoking, and their traits of 5A step method use in an attempt to provide consultancy service to their patients. The research is a descriptive study. The size of the minimum sample was determined to be 251. The survey constituted of sections which examined demographic features and the implementations of the physicians on smoking cessation and 5A practices. Twenty one percent of the physicians stated to smoke every day, 8% of them stated to smoke occasionally. Considering the familiarity with 5A practices for those cases willing to quit smoking, 20.1% of the physicians stated to be familiar, and 79.9% of them stated not to be familiar. When the 5A practices according to the specialists of the physicians are considered, while ‘pulmonology’ physicians have scored significantly the highest average point. The vast majority of physicians don’t know the implication 5A and don’t applicate the implications. Keywords: Physicians, patient, cigarette, 5A aplications, cigarette counseling

Introduction According to the WHO( World Health Organization) data, cigarette consumption, ranking forth among the risks that threaten human health, also ranks second among the causes of death. One out of every ten deaths is caused by smoking [1,2]. According to the World Health Organization (WHO) report, 10 million people died in 20th century due to tobacco epidemic, and if immediate measures are not taken, there will be more than 8 million deaths each year by the year 2030, and 80% of these deaths are estimated to occur in developing countries [3]. Cigarette smoking also leads to 71% of the deaths due to lung cancer, 42% of the deaths due to chronic respiratory system diseases, and approximately 10% of the deaths due to cardiovascular system diseases [4]. It has become mandatory to provide active prevention and active treatment services in view of such a major health problem. In this regard, physicians are anticipated to protect people who have never smoked; especially children and juveniles, to treat those who smoke, and to prevent those who quit smoking from taking up smoking [5,6].

*Coresponding Author: Gulsen Gunes, Inonu University, Faculty of Medicine, Department of Public Health, Malatya, Turkey E-mail: gulsen.gunes@inonu.edu.tr

Although there are reliable evidences about the harms of tobacco use, a small portion of the smokers are actually aware of the health risks of smoking. People in general know that smoking is harmful but they are rarely aware of the actual harm of this addiction [7]. The smoking statuses of the cases that consult to health institutions should be interrogated no matter which reason they may have come for [8]. That “asking and learning the smoking habits” of the individuals and that physicians “giving recommendations” about cessation lead to rise in the rates of smoking cessation [9]. The role of the physicians in smoking cessation ranks number two following the individual himself [10]. It has been determined that approximately 70% of people who smoke refer to a physician for any reason, but physicians guide and make suggestions to approximately only 15% of them about the harms of smoking [11]. The physicians, as they have a significant place in public health protection, should take patient’s smoking history on each contact and should make suggestions about smoking cessation. According to patient assessment recommended by the National Cancer Institute about smoking, smoking should be inquired, cessation should be recommended, cessation should be aided and monitoring studies should be conducted [12]. By this study we aimed to determine the frequency of smoking of those physicians who serve in city center of Malatya, whether they evaluate their patients in terms of smoking, and whether they encourage the patients about cessation and their traits of 5A step method use in an attempt to provide consultancy service to their patients. 81

doi: 10.5455/medscience.2018.07.8867

Material and Method Setting The research, which was conducted in 2015 covering the period of January - April, is a descriptive study. Nine hundred and five physicians who served in the province of Malatya; Turgut Ozal Medical Center Hospital, Public Hospital and Private Hospitals, comprised the target population of the study. The formula N.t2.p.q/ d2(N-1)+t2.p.q applied in case the number of individuals in the target group is known for the selection of the sample. The size of the minimum sample was determined to be 251. The target population was stratified with regard to the institutions where the physicians worked, the academic title of the physicians and the status of being a practitioner, and the stratified sampling method was utilized. Eighty-seven percent of the sample was reached. A survey was filled by the physicians who had not been on leave of absence and by those who agreed to answer the questionnaire. A written permission was received from the Inonu University Medical Faculty Ethics Committee for the study to be performed.

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the physicians, 51.3% of them worked between 11 to 20 years at highest rate. Twenty one percent of the physicians stated to smoke every day, 8% of them stated to smoke occasionally, 71% of them stated that they did not smoke. Considering the familiarity with 5A practices which are recommended by WHO for those cases willing to quit smoking, 20.1% of the physicians stated to be familiar, and 79.9% of them stated not to be familiar (Table 1). Table 1. Socio-demographic characteristics of the participants Number (n)

Women

24.8

Men

176

75.2

25-34

12.4

35-44

140

59.8

45-54

23.1

Subjects and data collection The survey constituted of sections, which has been developed upon literature knowledge, which examined demographic features and the implementations of the physicians on smoking cessation, and 5A practices. The 5A practices are implementations for cigarette cessation of which WHO recommends. The recommended 5As for those cases which are willing to quit smoking are: Asking every patient whether he/she has smoked within the last month (ask), advising to quit smoking (advise), assessing about willingness of smoking cessation (assess), assisting in the consideration of smoking cessation and attempt of cessation (assist), arranging a monitoring program to prevent relapse (arrange) [13,14]. The answers to the questions were summed up in 7-Point Likert Scale as: “never (1)”, “seldom (2)”, “at times (3)”, “fifty-fifty (4)”, “usually (5)”, “mostly (6)”, “always (7)”. Higher scores indicate that those physicians implemented the 5A practices on their patients more often.

≥ 55

4.7

Married

220

94.0

Single

5.6

Other

0.4

Private sector

27.8

Public hospital

30.3

Universty

20.5

Family practition center

21.4

Internal medicine

136

59.1

Surgery medicine

40.9

Professor(

9.4

Analysis The data collection tools about the research were computerized after conducted as a survey, by checking each data set and excluding the incomplete answers from the study. In the statistical analyses, with the Kolmogorov-Smirnov test (K-S); the Student’s t and One Way Anova tests have been utilized for the data which correlate with the normal distribution, and Mann-Whitney U and Kruskall Wallis tests have been utilized for those data which do not correlate with the normal distribution, and in all assessments, p<0.05 has been accepted to be significant.

Associate Professor

6.8

Assistant Professor

3.8

Specialist

130

55.6

General practitioner

24.4

≤10

24.8

11-20

120

51.3

21-30

20.5

≥31

3.4

Smokers

Sometimes smoker

Non-smoker

159

Yes

20.1

179

79.9

Results Out of the physicians that have participated in the research, 24.8% are female, 75.2% are male. The average age of the participants are 41.23±6.56 and 94% of the individuals are married. Out of the physicians that have participated in the research, 27.8% serve at private sectors, 30% serve at public hospitals, 20.5% serve at universities, 21.4% serve at family health centers. Fifty nine point one percent of the physicians work in internal medicine, 40.9% of them works in medical surgery. Out of the participant physicians; 55.6% are specialist doctors, 24.4% are general practitioners, 9.4% are professors, 6.8% are associate professors, 3.8% are assistant professors. Considering the working years of

Socio-demographic characteristics Gender

Age

Marital Status

The Occupy Institution

Department

Degree

Years worked

Smoking status

The knowing status of 5A

For the first practice of 5A practices; ‘Ask’, 17.9% of the physicians have given the answer ‘mostly I do’, for ‘Advice’, 33.2% of them have given the answer ‘I always do’, for ‘Assess’, 29.6% of them have given the answer ‘I seldom do’, for ‘Arrange’, 49.8% of them have given the answer ‘I never do’ (Table 2). 82

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Table 2. The rate of 5A smoking cessation practices of physicians n

Ask

223

10.3

16.1

16.6

9.9

16.1

17.9

13.0

1% 4.11

Advise

223

6.7

5.8

9.9

7.2

23.3

13.9

33.2

5.09

Assess

223

13.0

29.6

19.7

11.7

10.3

8.5

7.2

3.31

Assist

223

18.4

22.4

13.0

9.9

14.8

12.6

9.0

3.54

Arrange

223

49.8

23.3

8.5

4.5

7.2

4.5

2.2

2.18

1 indicates never, 7 indicates always

When the 5A practices according to the specialists of the physicians are considered, while ‘pulmonology’ physicians have scored significantly the highest average point with the question of ‘How often did you ask or assess about the smoking status of your

patients whom you take anamnesis or whom you examine within the last month?’, ‘orthopedics’ physicians have scored the lowest point (Table 3).

Table 3. Physicians’ 5A smoking cessation practices by medical department Medical departments

Ask

Advise

Assess

Assist

Arrange

General internal medicine

5.12

5.88

3.61

4.36

2.45

Neurology

3.73

4.55

2.18

2.91

1.18

Ophthalmology

2.50

3.20

2.20

1.80

1.40

Orthopaedics

2.33b

3.67

2.67

2.22

1.33

Brain surgery

3.00

3.80

2.40

2.80

1.10

Psychiatry

4.33

4.67

3.67

Pulmonary medicine

6.83a

6.83

6.50a

5.00a

General surgery

3.45

5.00

2.27

2.91

1.36

Infectious diseases

4.00

5.33

4.67

5.00

2.00

Cardiovascular surgery

5.50

5.25

3.25

4.00

3.75

Dermatology

2.63

4.00

2.00

2.13

1.13

Anesthesiology

3.80

3.20

2.00

1.20

1.00b

Urology

4.30

5.70

4.50

3.90

1.60

Otolaryngology

5.00

6.50

3.38

4.00

2.38

Respiratory surgery

6.50

7.00a

6.00

5.50

3.50

Physical medicine and rehabilitation

3.60

5.00

3.40

2.00

Cardiology

6.00

6.50

4.25

5.00

2.00

Pediatric

3.00

4.50

3.00

2.25

Obstetrics and gynecology

4.22

5.00

3.22

3.56

2.56

Emergency

4.30

4.90

3.10

3.40

2.10

Family practition center

4.14

5.37

3.59

3.80

2.69

Plastic surgery

4.00

5.00

2.00b

1.00b

227

223

Total

When the Smoking Cessation Practice Total Scores according to Socio-demographical characteristics of the physicians are considered, there has been no significant variation determined in the points scored considering the gender, marital status and smoking status. When the age groups are considered, the average scores of the physicians who are between the ages of 45-54 have been determined to be significantly higher. When the institutions at which the physicians work are considered, the average scores of those physicians who work at university hospital have been determined to be significantly higher. The average score of Internal Medicine has been determined to be significantly higher than that of Surgery. The average score of the physicians whose term of employment is

of 21-30 years has been determined to be significantly higher than that of the other groups (Table 4). When the scores received by the physicians according to their titles are considered, those who have the title of Assistant Professor Doctor have been determined to score significantly higher (Table 5). As far as Gender and Smoking Status are concerned, the nonsmoker male physicians have been determined to score significantly higher with the questions ‘How often did you recommend smoking cessation?’ and ‘Did you assist in the smoking cessation?’ (such as; naming days, recommending medications, referring to smoking cessation outpatient clinics) from the Smoking Cessation Practices (Table6). 83

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Table 4. The comparison of the scores of smoking cessation according to socio-demographical characteristics of physicians n

Min

Medyan

Max

Women

16.50

Men

169

18.00

25-34

15.00

35-44

136

17.00

45-54

21.00

≥ 55

13.00

Married

210

17.50

Single

14.00

Private sector

15.00

Public hospital

16.50

Universty

22.50

Family practition center

20.00

Internal medicine

127

19.00

Surgical medicine

16.00

≤10

15.00

11-20

115

18.00

21-30

21.00

≥31

12.00

Smokers

15.00

Sometimes smoker

16.50

Non-smoker

158

19.00

Gender 0.49*

Age

0.037**

Marital Status 0.191*

The Occupy Institution

0.001**

Department 0.009*

Years worked

0.009*

Smoking status 0.063**

*Mann-Whitney U **Kruskal Wallis Table 5. The comparison of smoking cessation practice score means according to socio-demographical characteristics of the physicians Characteristics

5A Practices X±SS

Professor

21.89 ± 7.13

Associate Professor

21.46 ± 9.28

Degree

Assistant Professor

22.44 ± 8.94

Specialista

125

16.52 ± 7.34

General practitioner

19.36 ± 6.66

Yes

21.60 ± 8.41

178

17.38 ± 7.13

The knowing status of 5A

a the group that makes the difference * independent t test **One Way Anova Table 6. Smoking cessation practice of physicians according to gender and smoking status Smoking Cessation Practice

Women Smokers

Men

Non-smoker

Smokers

Non-smoker

Ask

4.36

4.00

0.50

3.69

4.31

0.06

Advise

4.86

5.03

0.77

4.63

5.34

0.02

Assess

2.50

3.33

0.13

3.14

3.47

0.26

Assist

3.29

3.45

0.78

3.04

3.81

0.02

Arrange

1.71

2.33

0.24

1.92

2.31

0.11

Regular smokers + sometimes smokers. chi-square test

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When the statements about smoking cessation practices of the physicians who smoke and those who do not are considered, the physicians who do not smoke scored significantly higher with

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the statements of ‘ In my opinion, to make people quit smoking is difficult’ and ‘In my opinion to give consultation for smoking cessation ends in failure’ (Table 7).

Table 7. Smoking cessation attitudes of physicians according to smoking status Smokera AO±SS

Non-smoker AO±SS

If patients cannot quit on their own, there is little that I can do

2.80±1.00

2.56±1.08

0.12

It is difficult for me to get people to quit

2.34±0.97

2.67±1.14

0.03

Counseling for cessation is not an efficient use of my time

3.23±1.15

3.53±1.08

0.06

Cessation counseling improves my relationship with patients

2.58±0.96

2.26±0.88

0.01

Helping with smoking cessation makes me feel useful to patients

2.29±0.87

2.16±0.89

0.32

I find counseling patients about smoking cessation to be frustrating

3.51±0.92

3.80±0.91

0.03

Regular smokers + sometimes smokers. independent t test

Discussion I Physicians by their public image, have a substantial role in the community in both prevention of starting smoking and also encouraging smoking cessation [15, 16]. Out of the physicians who participated in the study, 29% smoke (including those who smoke occasionally) and 71% of them have stated that they do not smoke. Still, in our study 25.9% of female physicians and 30% of male physicians have stated that they smoke. In a study which Gunes et al. conducted in 2005 over a similar population, 37.5% of the physicians stated that they smoked [17]. Kosku et al. (2003) reported the smoking rate of the female physicians to be 29% and of the male physicians to be 41% [18]. Temel et al. (2004) reported in their study established the smoking rate to be 57% in males, and 43% in females [19]. In the study Aslan et al. conducted in 2008 similar to our study, was found to be 26% [11]. Demir et al. (2013) in the research which they conducted, stated that 30.5% of the participant physicians smoked [20]. In the study which we conducted, the smoking rate of the physicians have been found to be parallel with but relatively lower than the other research results. Since the other studies were conducted earlier as of date, it gave rise to the thought of that as time elapsed, the studies concerning the battle against smoking in Turkey have had an effect on physicians. This has aroused the idea that the physicians who take an active role in the battle against smoking are to succeed primarily on their own behalf and then for their patients. Also, according to Global Adult Tobacco Research report 2012, the tobacco use prevalence in Turkey between the years 2008 and 2012 fell from 31.2% to 27.1%. The decrease occurred in both men (from 47.9% to 41.5%) and in women (from 15.2% to 13.1%).This alteration means a reduction in smoking frequency of 13.4% (13.5% in men, 13.7% in women) [21]. Our study is also such as to verify these data. The 5A (Ask, Advise, Assess, Assist, Arrange) strategy is recommended to be implemented on the approach to the patients who are willing to be successful on smoking cessation treatment [22,23]. As familiarity with 5A practices of the participant physicians are considered, it is established that with a low rate, 20.1% of them are familiar, and 79.9% of them are not. Out of those participant physicians in the study, 47% have stated to question their patients routinely about whether they smoke or not (always, mostly, usually), as for 42.6% have stated to question at times (half and half, occasionally, sometimes). Ten point three per cent of the physicians on the other hand, have never questioned

about smoking statuses of their patients. As to in the study of Gunes et al. this rate was similarly found to be 10.9% [17]. In another study that was conducted, it was determined that 61.5% of the physicians regularly questioned about the smoking status of their patients, 25.7% of them questioned occasionally, and 12.8% of them did not question at all [24]. The most important step in 5A strategy is the step “Ask”. That every physician asking questions about smoking to every patient increases the smoking cessation rate twice [14]. We expect the ‘Ask’ strategy to be practiced with a higher rate. In our study, 70.4% of the physicians have stated to give recommendations about smoking cessation to their patients regularly (always, mostly, usually), 22.9% of them have stated to give recommendations occasionally (fifty-fifty, at times, sometimes), 6.7% of the physicians, on the other hand, have stated not to give any recommendations to their patients. In a study that was conducted in 2013, 71.5% of the physicians stated to recommend their patients to quit smoking [20]. As to the study of Cirit et al., 50.5% of the physicians stated to recommend their patients to quit smoking ‘regularly’, 17.3% of the physicians stated to do so ‘occasionally’ [24]. This data of our study is similar to that of Demir et al. and higher than that of Cirit et al. When the years in which the studies were conducted are considered, it might be claimed that, in time, the emphasis to be placed on the subject and the sensibility of the physicians have increased. Out of the participant physicians in the study, 36.4% have stated to assist (Assist) in smoking cessation regularly (always, mostly, usually), 45.3% have stated to assist occasionally (fifty-fifty, at times, sometimes), as for 18.4% of the physicians have stated to not to provide any support to their patients. In the study of Gunes et al. 13.1% of the physicians have stated to support the patients regularly, 33.1% of them have stated to support occasionally, 53.8% of them on the other hand, have stated to not to have any guidance on supporting [17]. While in our study the support and guidance services are given to eight out of every ten patients, in the study of Gunes et al. support is given to five out of every ten patients. This variation between the studies have shown that, in the course of time, naming days to quit smoking, recommending medications, referring to a smoking cessation outpatient clinic have been successful in the battle against smoking. In the study, considering the scores received by the physicians from the 5A practices according to their specialists, while pulmonology 85

doi: 10.5455/medscience.2018.07.8867

and thoracic surgery specialists scored the highest; plastic surgery, orthopedics and ophthalmology specialists scored the lowest [17]. In our study, there has been no significant difference found between the smoking cessation practice scores of the physicians and their genders and marital statuses. Also in similar studies that have been conducted, there has been no significant difference found between the gender of the physicians and the smoking cessation practices [17,20]. In our study, the scores on smoking cessation practices of the physicians who work in the university hospital have been found to be significantly higher than of those who work in the other institutions. When the conclusions of the scanned meta-analyses of 42 studies which were published between 1972-2012 by Stead et al. [25] about the effectiveness of giving recommendations on smoking cessation are considered, the institution to give the most frequent recommendations has been observed as the first step health institutions. It is considered to stem from the application rates of more patients with high risk due to smoking applying to university hospitals in different branches, and the smoking cessation services being provided by two different units (Public Health Dpt., and Family Doctors Dpt.) of the university hospitals in the city where the study has been planned. The reason why academician doctors work in the university hospitals might be that academician doctors are more sensible with their patients in respect of smoking. In our study, the physicians who work in internal medicine have been found to implement the smoking cessation practices more than those of surgical medicine. In a study that was conducted, the physicians who worked in internal medicine again were found to recommend their patients to quit smoking and to assess the extent of their eagerness with significantly higher rate than those of surgical medical sciences [17]. This could be interpreted as the internal medicine physicians placing more emphasis on preventive health services. While there is no significant difference in terms of 5A practices between smoker and non-smoker female participant physicians, there has been found a significant difference between male physicians. Non-smoker male physicians have been found to recommend and to support their patients to quit smoking with a higher rate. Also in the study of Gunes, non-smoker male physicians have been observed to implement the 5A practices on their patients with a higher rate [17]. While in our study, there is no significant difference between implementing the 5A practices and the smoking status of the physicians, in the study of Uysal et al. the physicians who do not smoke have been stated to implement the 5A practices on their patients with a higher rate [26]. In another study that has been conducted, there has been no significant difference found about the attitudes between those physicians who smoke and those who do not smoke [27]. When considering the smoking cessation practices of the physicians with regard to their smoking statuses, those participant physicians

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who do not smoke consider it to be difficult to quit smoking, as far as they have observed, for those patients who consulted to them and it to end in failure to give consultation. Those physicians who smoke on the other hand, have stated that giving consultation enhance their communication with their patients. Conclusion IThe most successful countries in decreasing the smoking rate and decreasing its consumption are those where the physicians are most active in the battle against smoking and where the smoking rate among the physicians is at the lowest degree [28]. Three out of every ten physicians who participated in our study were established to smoke. Smoking of physicians have a negative effect on the communities which a battle against tobacco, and decrease the faith of the individuals who want to quit smoking. In this sense, considering the smoking status of the physicians to be one of the most effective factors upon the community, it is advisable that primarily physicians and physician candidates to be trained and in-service-training to be given systematically about smoking cessation practices throughout their medical training. In our study, it has been determined that four out of every five physicians is not familiar with the 5A practices of smoking cessation and 10% of the physicians have never inquired the smoking status. By adding a section that is obligatory to be filled to the anamnesis form of the physicians, the smoking statuses of the patients could be inquired and thus support services could be provided to those who are willing to quit smoking or at least awareness could be created in regard to the issue. Recommendations The battle against smoking, which is the leading cause of chronic diseases and related disabilities and deaths, should be undertaken not only by smoking cessation outpatient clinics which are introduced specifically for this purpose but also by all health institutions. Also by providing training about this topic for the physicians who work on the first step that is significant for preventive medicine, 5A practices should be attempted to be increased on the first step. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval For this study, ethical approvals from the ethics committee of the university with legal permits from the authorities in Turkey have been taken. Ă&#x2021;igdem Tekin ORCID: 0000-0001-9038-1924 Gulsen Gunes ORCID: 0000-0003-2021-7103 Erkay Nacar ORCID: 0000-0002-7046-4551 Burak Mete ORCID: 0000-0002-0780-6176 Ertan Unver ORCID: 0000-0002-4049-0054

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Pai M, Mohan A, Dheda K, et. al. Lethal interaction: the colliding epidemics of tobacco and tuberculosis. Expert Rev Anti Infect Ther. 2007;5:385-91.

Bates M.N, Khalakdina A, Pai M, et. al. Risk of tuberculosis from exposure to tobacco smoke: A systematic review and metaanalysis. Arch Intern Med. 2007;167:335-42.

World Health Organization, and Research for International Tobacco Control. WHO report on the global tobacco epidemic, 2008: the MPOWER package.

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Alwan A. Global status report on noncommunicable diseases 2010. World Health Organization. 2011.

Karlıkaya C, Öztuna F, Aytemur SZ, et al. Tobacco control. Toraks Dergisi. 2006;51-64.

Üçer H, Keten HS, Ersoy Ö, et al. Knowledge, attitudes and practices of family physicians about smoking cessation. Turkish Journal of Family Practice. 2014;18:58-62.

Hammond D, Fong GT, McNeill A, et al. Effectiveness of cigarette warning labels in informing smokers about the risks of smoking: findings from the International Tobacco Control (ITC) Four Country Survey. Tobacco Control. 2006;15:319-25.

Uzaslan E. Sigarayı bırakma yöntemleri. Sted. 2003;12:166.

Pazarlı P. Sigara bırakma süreci ve bu süreçteki olguların tanımı, tütün ve tütün kontrolü. Aves yayıncılık, İstanbul, 2010;445-50.

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Ozal Med Cent 4. 1997;407–12. 17. Gunes G, Karaoğlu L, Genc M, et al. University hospital physicians’ attitudes and practices for smoking cessation counseling in Malatya, Turkey. Patient Education and Counseling. 2005;147–53. 18. Kosku N, Kosku M, Çıkrıkçıoğlu U, et al. Smoking Habits and attitudes of the members of the thoracic society. Turkish Thor J. 2003;4,3,223-30. 19. Temel A, Dilbaz N, Bayam G, et al. The Relationship between the smoking habits and the frequency of quiting and dependent personality traits among health professionals in a training hospital. J Dependence. 2004;5:16-22. 20. Demir C, Şimşek Z. Physicians’ smoking cessation behavior and related factors. TAF Preventive Medicine Bulletin. 2013;12:501-10. 21. Turkey global adult tobacco survey 2012. Anıl Matbaa, Ankara, 2014. 22. Özge C. Sigara bırakma tedavisinde 5A ve 5R kavramları, tütün ve tütün kontrolü. Aves yayıncılık, İstanbul, Turkey. 2010.

10. Yorgancıoğlu A, Esen A. Nicotine dependence and physicians. Toraks Dergisi. 2000;1:90-95.

23. Vidrine JI, Shete S, Cao Y, et al. Ask-Advise-Connect: a new approach to smoking treatment delivery in health care settings. JAMA Intern Med. 2013;173:458-64.

11. Aslan D, Bilir N, Özcebe H, et al. Türkiye’de sağlık çalışanlarının sigara içme durumu ve etkileyen faktörler. Sağlık Bakanlığı, Ankara, 2007;5-61.

24. Cirit M, Orman A, Ünlü M. Smoking habits among physicians in Afyon. Turkish Thora J. 2002;3:253-6.

12. Rennard SI, Daughton DM. Smoking cessation. Chest. 2000;117,360-4.

25. Stead LF, Buitrago D, Preciado N, et al. Physician advice for smoking cessation. Cochrane Database Syst Rev. 2013;5:165.

13. WHO Information fact sheets. Fact Sheet No. 221. Tobacco health facts. http://www.who.int/inffs/en/fact221.html. April 1999 14. Fiore, Michael C. Treating tobacco use and dependence. Rockville, MD: US department of health and human services. Public health service. 2000;000032. 15. Rigotti NA, Torndike AN. Reducing the health burden of tobacco use: what’s the doctor’s role. Mayo Clin Proc. 2001;76,121–3. 16. Gunes G, Pehlivan E, Egri M, et al. Prevalence of smoking in doctors, nurses and medical faculty students working in Turgut Özal Medical Center. J Turgut

26. Uysal MA, Dilmen N, Karasulu L, et al. Smoking habits among physicians in Istanbul and their attitudes regarding anti-smoking legislation. Tuberculosis and Thorax. 2007;55:350-5. 27. Özer ÖA. Smoking status and the behaviours, about quitting smoking, of the medical doctors giving primary care services in Eskişehir. Eskişehir University of Medical Sciences, Eskişehir, 2012. 28. Altıntaş H, Bozdağ G, Polat C, et al. Smoking attitude and behaviour of a public organisation data processing centre workers. J Dependence. 2006;7:310.

Available online at www.medicinescience.org

ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):88-92

Diagnostic utility of chest pain characteristics in discriminating obstructive coronary artery disease: A ‘Historic’ Dilemma Demet Ozkaramanli Gur Namik Kemal University Research and Education Hospital, Department of Cardiology, Tekirdag, Turkey Received 29 July 2018; Accepted 11 August 2018 Available online 26.09.2018 with doi:10.5455/medscience.2018.07.8882 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Chest pain (CP) is the major presenting symptom of coronary artery disease (CAD) wherein history remains to be a fundamental and challenging diagnostic step. Despite the clarity of ‘typical’ CP characteristics in guidelines; interpretation and description of CP by patients are open to wide variations. The aim of this study was to define the components of CP that most closely associate to presence of obstructive CAD and determine the influence of gender on CP features. Herein, consecutive patients with suspected stable CAD who were scheduled for a coronary angiography(CAG) were prospectively enrolled. The data on demographic and pain characteristics were collected by a questionnaire. Patients were categorized into ‘CAD’ and ‘Normal’ groups with respect to presence of obstructive CAD in CAG. Among 402 patients, 86 had chest discomfort or equivalent symptoms but denied ‘CP’. Patients with CAD were more commonly male; with older age, lower BMI, more frequent prior revascularization, clopidogrel use, higher creatinine and lower HDL levels. When classical features of CP such as quality; location, duration, relationship to exertion were compared; stabbing/sharp pain, CP related to cold or emotional stress and CP that radiates to back were significant factors against CAD; while absence of precipitating factors was related to CAD. Yet, none of the features of typical angina pectoris were significantly related to presence of CAD. Determinants of CAD were; prior revascularization (OR= 22.7, p=0.021), body mass index (OR=1.4, p=0.007), clopidogrel use(OR=55.5, p=0.018) and blood glucose (OR=1.02, p=0.046) in women; and age (OR=1.2, p=0.029) was the single predictor of CAD in men. This study demonstrated no association between classical features of typical CP and presence of CAD in patients with stable angina pectoris. Clinical factors that influenced presence of CAD in different genders were also different. Keywords: Chest pain, typical angina pectoris, coronary artery disease

Introduction Chest pain (CP) is the major presenting symptom of patients with coronary artery disease (CAD) at the outpatient and/or emergency clinics. [1] Nevertheless, not all patients presenting with CP are of cardiac origin. Physical, psychological and socio-economic factors play significant role in perception and description of pain by patients. [2] Physicians, on the other hand, have to rely on patients’ description of pain, to proceed with the diagnostic steps. Herein, history remains to be the fundamental and the most challenging diagnostic step. Angina pectoris is the CP of ischemic origin. [3] The characteristics of typical angina pectoris are clearly outlined in the guidelines and are distinct in terms of quality, duration and location. [1] Diagnosis and treatment of coronary artery disease depends on the correct interpretation of CP as a symptom. This, however, is not straightforward; as CP is a subjective symptom with many influencing factors. Several studies failed to prove discriminatory *Coresponding Author: Demet Ozkaramanli Gür , Namik Kemal University Research and Education Hospital, Department of Cardiology, Tekirdag, Turkey E-mail: dozkarm@yahoo.com

value of CP characteristics on prediction of significant CAD in acute coronary syndromes. [4-6] The data on chronic angina pectoris is limited, and there is no literature published in Turkish population. This study aimed to define the features of the CP in patients with obstructive CAD and determine the components that most closely associate to presence of obstructive CAD. We also sought to evaluate whether CP characteristics differed among genders. Material and Methods A total of 402 consecutive patients with CP and suspected stable CAD who were scheduled for a routine coronary angiography (CAG) were prospectively enrolled. Patients with episodes of CP suggestive of unstable angina pectoris such as new (within 2 weeks) onset, those with rest angina, with acute coronary syndromes or recent (within 6 months) revascularization were not included to the study. Patient enrollment was started after approval from local Ethics Committee and covered a period between September 2017 and January 2018. The data on demographic characteristics and features of CP were evaluated by a questionnaire, prior to the coronary angiography. 88

doi: 10.5455/medscience.2018.07.8882

The biochemical parameters such as fasting blood glucose, white blood cell (WBC) count, hemoglobin (Hb), Platelet count(PLT) creatinine, low density lipoprotein (LDL), high density lipoprotein (HDL), total cholesterol (TC) and triglyceride were recorded. Weight and height were measured to calculate body mass index (BMI; kg/m2). Patients were categorized into ‘obstructive CAD’ and ‘Normal’ groups with respect to presence of CAD that causes luminal stenosis of ≥50% on coronary angiogram. CP questionnaire The questionnaire was divided into two parts wherein the first part consisted of questions about the demographic data with possible influence on perception of CP such as level of education, working status, history of cardiovascular risk factors, history of prior revascularization and drugs used. The second part of the questionnaire was about important features of CP such as quality, location, duration, precipitating and relieving factors, radiation, number of locations that pain radiates, accompanying symptoms and the severity graded by the patient. Guidelines of stable coronary artery disease classifies stable angina pectoris according to the following 3 criteria [1]: 1. Substernal chest discomfort of characteristic quality and duration 2. Provoked by exercise or emotional stress 3. Relieved by rest or nitrates. In ‘typical’ angina pectoris, CP features fulfill all three criteria while those that fulfill 2 are classified as ‘atypical’ CP and those that fulfill one or none are classified as ‘noncardiac’. We, therefore,

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utilized the same criteria in the CP questionnaire. Statistical Analysis The categorical variables were expressed as percentages (%, n) and continuous variables were expresses as mean ± standard deviation or as median (min-max) as appropriate. The normality of distribution in continuous variables were tested by KolmogorovSmirnov test. The ‘Obstructive CAD’ and ‘Normal’ groups were compared using either independent samples t test in case or Mann Whitney U test as appropriate. The categorical variables were compared by Chi-Square. Pearson’s Chi square was used when the expected frequencies in the 2x2 contingency tables were >25; A continuity correction chi square was used when the expected frequencies were between 5 and 25 and Fisher’s exact test was used when the expected frequencies were <5. With stratifying study group by gender and setting presence of obstructive CAD as the dependent variable, multivariate logistic regression analysis was conducted. All variables that had p ≤ 0.10 in the univariate analyses were included into the model, by stepwise method, to determine the predictors of presence of obstructive CAD. A p value of <0.05 was considered significant. Results Of 402 patients (48% women; mean age 61.2 ±10.9 years), 86 patients negatively replied to the question on whether they had experienced chest pain before. These patients denied to have ‘CP’ but complained of subtle chest discomfort (59.3%), dyspnea (25.6%), fatigue (11%), sweating (1.9%) and syncope (1.9%). The data on patients without chest pain are presented in Table 1.

Table 1. Baseline characteristics of the patients who denied to have CP Baseline Characteristics

Overall study opulation n=86

Obstructive CAD n=44

Normal n=42

p value

Age, years Female Gender, %(n)

63.7±11.4 40.7 (35) 73.3(63) 10.5(9) 16.3(14) 26.7(23) 28.5(18.3-44.4) 48.8(42) 26.7(23) 32.6(28) 25.6(22) 48.8(42) 43(37) 50(43) 17.4(15) 41.9(36) 47.7(41) 15.1(13) 27.9(24) 19.8(17) 4.7(4) 3.5(3) 111(68-379) 7.5(3.7-12.7) 13.2(9-17.7) 237.5(121-457) 0.9(0.6-6.8) 104(27-357) 44(25-99) 183(98-439) 158(14.2-527) 25.6 (22) 0.01(1) 0.01 (1) 25.6 (11) 59.3 (51)

64.5±10.8 29.5(13) 77.3(34) 11.4(5) 11.4(5) 20.5(9) 28.4(18.3-44.4) 50(22) 25(11) 31.8(14) 27.3(12) 47.7(21) 63.6(28) 65.9(29) 27.3(12) 47.7(21) 59.1(26) 20.5(9) 34.1(15) 20.5(9) 6.8(3) 4.5(2) 114(87-356) 7.3(4.1-11.5) 13.3(9-16.6) 220(141-432) 0.88(0.59-2.0) 102(27-176) 43(25-99) 183(101-275) 167.5 (14.2-527) 22.7(10) 0.02(1) 9.1(4) 65.9(29)

63±12.1 52.4(22) 69(29) 9.5(4) 21.4(42) 33.3(14) 29.3(20.9-42.5) 47.6(20) 28.6(12) 33.3(14) 23.8(10) 50(21) 21.4(9) 33.3(14) 7.1(3) 35.7(15) 35.7(15) 9.5(4) 21.4(9) 19(8) 2.4(1) 2.4(1) 110(68-379) 7.6(3.7-12.7) 13.2(9.1-17.7) 262(121-457) 0.91(0.56-6.8) 106(40.8-358) 45(29-80) 194(98-439) 149(60-518) 28.6(12) 0.02(1) 16.7(7) 52.4(22)

0.55 0.053* 0.44

Education, %(n) Work status, %(n) BMI, kg/m2 Hypertension, %(n) Diabetes mellitus, %(n) Hyperlipidemia, %(n) Smoking status, %(n) Family history, %(n) Prior revascularization, %(n) Medications, %(n)

Glucose White blood cell, x103 Hemoglobin, gr/dL Platelet, x103 Creatinine LDL, mg/dL HDL, mg/dL T. cholesterol, mg/dL Trigliceride, mg/dL Predominant symptom

Primary school High school University

ASA Clopidogrel Beta blockers RAAS blockers CCB Statin OAD Insulin Nitrates

Dyspnea Pre/syncope Sweating Fatigue Chest discomfort

0.26 0.27 0.99 0.89 1 0.90 1 <0.001 0.05 0.03 0.36 0.051 0.26 0.28 1 0.61* 1* 0.44 0.19 0.61 0.019 0.56 0.71 0.38 0.82 0.13 0.41

CAD: Coronary artery disease, BMI: Body mass index, ASA: Acetylsalicylic acid, RAAS: renin-angiotensin-aldosterone system, CCB: calcium channel blockers, OAD: oral antidiabetic drugs, LDL: low density lipoprotein, HDL: high density lipoprotein. Categorical variables are compared by continuity correction chi square; continuous variables are compared by independent samples t test or Mann Whitney U as appropriate. *indicates p values calculated by Fishers exact test

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Med Science 2019;8(1):88-92

Table 2. Baseline characteristics of patients with chest pain Baseline Characteristics

Overall study populationn=316

Obstructive CAD n=165

Normal n=151

p value

Age Female Gender, %(n)

60.4±10.7 50(158)

62.9±10.3 35.8(59)

57.7±10.5 65.6(99)

<0.001 <0.001

Primary school

85.1(269)

86.1(142)

84.1(127)

0.9

High school

11.1(35)

10.9(18)

11.3(17)

University

3.8(12)

3(5)

4.6(7)

Work status, %(n)

30.4(96)

30.3(50)

30.5(46)

0.97

BMI

29.2 (18.5-48.8)

28.2 (19.4-45.5)

31.1 (18.5-48.8)

0.004

Hypertension, %(n)

54.7(173)

55.2(91)

54.3(82)

0.88

Diabetes mellitus, %(n)

30.7(97)

31.5(52)

29.8(45)

0.74

Hyperlipidemia, %(n)

31.6(100)

30.9(51)

32.5(49)

0.76

Current Smoker, %(n)

28.5(90)

28.4(41)

32.5(49)

0.13

Family history, %(n)

55.4(175)

51.5(85)

59.6(90)

0.149

55.8(92)

32.5(49)

<0.001

Education, %(n)

Prior revascularization, %(n) Medications, %(n)

ASA

50.3(159)

54.5(90)

45.7(69)

0.11

Clopidogrel

22.5(71)

33.9(56)

9.9(15)

<0.001

Beta blockers

51.3(162)

50.9(84)

51.7(78)

0.89

RAAS blockers

41.5(131)

45.5(75)

37.1(56)

0.13

CCB

16.5(52)

14.5(24)

18.5(28)

0.33

Statin

26.3(83)

30.3(50)

21.9(33)

0.09

OAD

21.5(68)

21.2(35)

21.9(33)

0.89

Insulin

8.2(26)

9.1(15)

7.3(11)

0.70*

Nitrates

4.7(15)

5.5(9)

4(6)

0.72*

Glucose

112(62-419)

113(77-419)

110(62-346)

0.07

White blood cell, x103

7.2(3.4-15.5)

7.3(3.4-15.5)

7.2(3.5-14.4)

0.50

Hemoglobin, gr/dL

13.4(9.2-18.6)

13.5(9.2-18.6)

13.3(9.7-18)

0.50

Platelet, x103

243(108-547)

231(114-475)

259(108-547)

0.051

Creatinine

0.85(0.5-2.2)

0.87(0.54-2.2)

0.81(0.52-1.56)

0.02

LDL, mg/dL

116(25-269)

114(25-269)

116(28-247.5)

0.46

HDL, mg/dL

44(21-104.5)

42(21-104.5)

46.1(25-93.2)

0.013

T. cholesterol, mg/dL

198(96-356)

193(110-359)

202(96-353)

0.33

Trigliceride, mg/dL

171(48-743)

176(48-722)

167(54-743)

0.74

CAD: Coronary artery disease, BMI: Body mass index, ASA: Acetylsalicylic acid, RAAS: renin-angiotensin-aldosterone system, CCB: calcium channel blockers, OAD: oral antidiabetic drugs, LDL: low density lipoprotein, HDL: high density lipoprotein. Categorical variables are compared by chi square; continuous variables are compared by independent samples t test or Mann Whitney U as appropriate. * indicates p values calculated by continuity correction.

Among 86 patients who denied to have CP, 51% (n=44) was revealed to have obstructive CAD. Patients in obstructive CAD group differed from normal group, only in terms of prior revascularization; there were more patients with prior revascularization in obstructive CAD group. Patients with obstructive CAD but no CP also had more frequent clopidogrel use and lower platelet number than normal CAG patients. The presenting symptom of 78.6%(n=316) of patients was CP. The baseline characteristics of these patients are presented in Table 2. When compared to patients with normal CAG; obstructive CAD patients were more frequently male (35.8 vs 65.7%, p<0.001), with older age (62.9±10.3 vs 57.7±10.5, p<0.001), lower BMI (28.2 vs 31.1 kg/m2, p=0.004), more common prior revascularization (55.8 vs 32.5%, p<0.001) and clopidogrel use (33.9 vs 9.9%, p<0.001), higher creatinine (0.85 vs 0.81, p=0.02) and lower HDL(42 vs 46.1 mg/dL, p=0.013). There was no statistically significant difference in terms of cardiovascular risk factors such as diabetes, hypertension, hyperlipidemia, smoking; the medications; or the biochemical parameters such as WBC, Hb, PLT, LDL, TC and TG between patients with and without obstructive CAD (p>0.05).

Table 3 summarizes the pain characteristics of patients with CP. Notably, most patients described typical angina pectoris in terms of quality, location, duration and related factors. Nevertheless, only 52.2% of CAG revealed obstructive CAD. CP characteristics of patients with and without CAD were comparable in terms of localization, duration, relieving factors, accompanying symptoms and severity of pain (p>0.05). Patients with obstructive CAD, however, less frequently had stabbing/sharp pain (7.3 vs 15.2%, p=0.03) , CP that is precipitated by cold (24.8 vs 37.7%, p=0.013) or emotional stress(47.9 vs 68.2%, p<0.001), and that radiates to back (42.4 vs 55.6%, p=0.014). As previous studies have established the role of gender as a significant predictor of CP characteristics; we have stratified patient population by gender to determine the predictors of presence of CAD. Logistic regression analysis showed that prior revascularization (OR= 22.7, p=0.021), body mass index (OR=1.4, p=0.007), clopidogrel use(OR=55.5, p=0.018) and blood glucose (OR=1.02, p=0.046) were significant predictors of CAD in women while age (OR=1.2, p=0.029) was the single predictor of CAD in men. 90

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Table 3. Characteristics of chest pain in patients with and without CAD Characteristics of chest pain Quality, %(n)

Localization, %(n)

Duration, %(n)

Precipitating factors, %(n)

Relieving factors, %(n)

Radiation, %(n)

Accompanying symptoms , %(n)

Scale

Overall study population n=316

Obstructive CAD n=165

Normal n=151

p value

squezing/pressure* ache/burn needling stabbing/sharp anterior thorax* epigastric back few seconds <5 min* 5-10 min* 30 min< hours none identified exercise* cold* emotional stress* none rest* nitrates* none

46.5(147) 21.2(67) 21.2(67) 11.1(35) 94(297) 2.8(9) 3.2(10) 20.3(64) 34.2(108) 25(79) 12(38) 6.3(20) 18.4(58) 67.7(214) 31(98) 57.6(182) 15.8(50) 79.1(250) 5.1(16) 21.2(32)

47.3(78) 21.8(36) 23.6(39) 7.3(12) 93.3(154) 2.4(4) 4.2(7) 20(33) 36.4(60) 23.5(39) 13.3(22) 5.5(9) 23.6(39) 64.2(106) 24.8(41) 47.9(79) 17.6(29) 77(127) 5.5(9) 26.1(43)

45.7(69) 20.5(31) 18.5(28) 15.2(23) 94.7(143) 3.3(5) 2(3) 20.5(31) 31.8(48) 26.5(40) 10.6(16) 7.3(11) 12.6(19) 71.5(108) 37.7(57) 68.2(103) 13.9(21) 81.5(123) 4.6(7) 21.2(32)

0.77 0.78 0.26 0.03 0.78 0.74 0.34 0.80

back shoulders arms jaw None Dyspnea nausea pre/syncope cold sweating fatigue

48.4(153) 26.6(84) 41.5(131) 24.7(78) 18(57) 49.1(155) 19.9(63) 11.7(37) 50.9(161) 63.9(202) 5(1-10)

42.4(70) 25.5(42) 38.8(64) 23(38) 20(33) 46.1(76) 20(33) 9.1(15) 49.1(81) 63(104) 5(2-10)

55.6(84) 27.8(42) 44.4(67) 26.5(40) 15.4(24) 52.3(79) 19.9(30) 14.6(22) 53(80) 64.9(98) 5(1-10)

0.014 0.58 0.26 0.43 0.34 0.26 0.97 0.18 0.49 0.72 0.9

0.011 0.167 0.013 <0.001 0.61

0.4

* indicates the features on typical angina pectoris. CAD: Coronary artery disease

Discussion This study has demonstrated that classical features of typical angina pectoris were not associated with obstructive CAD in patients with stable angina pectoris. Moreover, pain that is radiates to back or that is exacerbated by cold or emotional stress was associated with absence of CAD. Logistic regression analysis proved that clinical factors which influenced presence of CAD were different between the two genders and none of the CP characteristics was independently associated with CAD in either gender. The characteristics of CP that favors angina pectoris was defined long ago and have been used in clinical practice since then [1,7,8]. Nevertheless, CP is a subjective symptom for which the utility of this classification is questionable [9]. Carlton et al have studied the discriminatory value of ‘typicality of CP’ in acute CP patients and showed that it was not of value in acute coronary syndromes [4]. This was also proved by a study, in which categorical definition of typical CP yielded very low sensitivity and specificity. (48% and 66% respectively) in patients with acute CP [5]. Sepehrvand et al have gone one step further, omitted CP characteristics and tested the accuracy of different management protocols in the emergency setting ignoring CP features. They showed that management protocols performed well without CP characteristics in decision-

making [6]. The data on the chronic stable CP is scarce and there is no published data in Turkish population indeed. Comparison of CP features between patients with and without CAD showed that, most of the features of chronic stable CP were similar between the two groups. An exception was the stabbing/ sharp pain that is already known to be an unusual symptom in the CAD. Although pain ‘exacerbated by emotional stress or cold’ constitutes one of the components of typical angina pectoris, it was less common in CAD patients in our study. Previous studies suggested that patients with non-obstructive CAD and psychological stress have greater incidence of persistent chest pain [10,11]. Concomitant stress, my have therefore, triggered the anginal symptoms in patients without CAD in our study as well. Pain that radiates to back was also found to be associated with absence of CAD in the present study. Radiation of angina to the back is a common presentation that can easily be misinterpreted for back pain. In logistic regression analysis, when all clinical factors were evaluated together with the CP characteristics, this study evidenced that, none of the pain characteristics were among significant predictors of CAD. Gender is a major cardiovascular risk factor. It has shown to profoundly influence perception and description of CP [12-14]. We 91

doi: 10.5455/medscience.2018.07.8882

therefore have analyzed current data in men and women separately, in an effort to describe the predictors of CAD precisely. Among all clinical and CP characteristics, age was the single, independent, significant predictor of CAD in male patients. For women, the p value for age in regression analysis was 0.07 and it did not reach statistical significance. The mean age of women and men with CP was 61± 10.3 vs 59.9± 11.2. (p>0.05) In women, significant predictors of CAD were found to be prior revascularization (for longer than 6 months), clopidogrel use, blood glucose and BMI. Need for repeat revascularization after an initial procedure is a common outcome of percutaneous coronary interventions as clearly demonstrated by the SYNTAX trial [15]. Clopidogrel use was independently associated with CAD; as patients with more severe anginal symptoms may have been prescribed to have clopidogrel. Blood glucose was also positively associated with CAD. Higher BMI seemed to be protective of CAD in women; as previously demonstrated by obesity paradox [16,17]. Nevertheless, BMI is not a good surrogate of obesity and cannot discriminate the subtypes of obesity and adipose tissue with varying metabolic rates [18]. Another important finding in our study was high percentage of patients who denied to have ‘CP’. They described chest discomfort using different terminology. Considerable amount of these patients without CP had indeed CAD revealed by CAG. These patients with atypical symptoms are those with worse prognosis.[19] The major limitation of the study was the fact that study population consisted only of patients with CP who were referred to CAG. This was inevitable since there is no study to have CAG for all patients presenting with CP. Moreover, CAG has provided a gold standard method to conclude on presence of CAD. Conclusion This study has several clinical implications to the clinical practice as we have demonstrated no association between classical features of typical CP and presence of CAD in patients with stable angina pectoris. Pain that radiates to back; that is exacerbated by cold or emotional stress was associated with absence of CAD, in the present study. Different clinical factors influenced presence of CAD in different genders; yet none of the CP characteristics was independently associated with CAD in either gender. Acknowledgments The abstract of this study is submitted to the 34. National Congress of Turkish Society of Cardiology Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Before the study, permissions were obtained from local ethical committee. Demet Ozkaramanlı Gur ORCID: 0000-0003-2542-8196

References 1.

Task Force Members, Montalescot G, Sechtem U, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the

Med Science 2019;8(1):88-92

management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34:2949–3003. 2.

Lenfant C. Chest pain of cardiac and noncardiac origin. Metabolism. 2010;59:41-6.

Khan IA, Mehta NJ. Initial historical descriptions of the angina pectoris. J Emerg Med. 2002;22:295-8.

Carlton EW, Than M, Cullen L, et al. Chest pain typicality’ in suspected acute coronary syndromes and the impact of clinical experience. Am J Med. 2015;128:1109-16.

das Virgens CM, Lemos L, Noya-Rabelo M, et al. Accuracy of gestalt perception of acute chest pain in predictingcoronary artery disease. World J Cardiol. 2017:26;9:241-7.

Sepehrvand N, Zheng Y, Armstrong PW, et al. Identifying low risk patients for early discharge from emergency department without using subjective descriptions of chest pain: insights from providing rapid out of hospital acute cardiovascular treatment (PROACT) 3 and 4 Trials. Acad Emerg Med. 2017;24:691-700.

Tamura A, Naono S, Torigoe K, et al. Gender differences in symptoms during 60-second balloon occlusion of the coronary artery. Am J Cardiol. 2013;111:1751-4.

Diamond GA, Forrester JS. Analysis of probability as an aid in the clinical diagnosis of coronary-artery disease. N Engl J Med. 1979;300:1350-8.

Rovai D, Neglia D, Lorenzoni V, et al. Limitations of chest pain categorization models to predict coronary artery disease. Am J Cardiol. 2015;116:504-7.

10. Wheeler A, Schrader G, Tucker G, et al. Prevalence of depression in patients with chest pain and non-obstructive coronary artery disease. Am J Cardiol. 2013;112:656-9. 11. Mommersteeg PM, Pot I, Aarnoudse W, et al. Type D personality and patientperceived health in nonsignificant coronary artery disease: the TWeesteden mIld STenosis (TWIST) study. Qual Life Res. 2013;22:2041-50. 12. Tamura A, Naono S, Torigoe K, et al .Gender differences in symptoms during 60-second balloon occlusion of the coronary artery. Am J Cardiol. 2013;111:1751-4. 13. Philpott S, Boynton PM, Feder G, et al. Gender differences in descriptions of angina symptoms and health problems immediately prior to angiography: the ACRE study. Appropriateness of coronary revascularization study. Soc Sci Med. 2001;52:1565-75. 14. Granot M, Goldstein-Ferber S, Azzam ZS. Gender differences in the perception of chest pain. J Pain Symptom Manage. 2004;27:149-55. 15. Parasca CA, Head SJ, Milojevic M, et al. Incidence, characteristics, predictors, and outcomes of repeat revascularization after percutaneous coronary intervention and coronary artery bypass grafting: The SYNTAX Trial at 5 Years. JACC Cardiovasc Interv. 2016;9:2493-507. 16. Braun N, Gomes F, Schütz P. “The obesity paradox” in disease: Is the protective effect of obesity true? Swiss Med Wkly. 2015;145:142-65. 17. Lavie CJ, McAuley PA, Church TS, et al. Obesity and cardiovascular diseases: implications regarding fitness, fatness, and severity in the obesity paradox. J Am Coll Cardiol. 2014;63:1345-54. 18. Goyal A, Nimmakayala KR, Zonszein J. Is there a paradox in obesity? Cardiol Rev. 2014;22:163-70. 19. Grosmaitre P, Le Vavasseur O, Yachouh E, et al. Significance of atypical symptoms for the diagnosis and management of myocardial infarction in elderly patients admitted to emergency departments. Arch Cardiovasc Dis. 2013;106:586-92.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):93-6

The better choice for measuring the gonial angle of different skeletal malocclusion types: Orthopantomograms or lateral cephalograms? Tugba Haliloglu Ozkan1, Selim Arici1, Enes Ozkan2 2

1 Ondokuz Mayıs University, Faculty of Dentistry, Department of Orthodontics, Samsun, Turkey Bafra Oral and Dental Health Hospital, Department of Oral and Maxillofacial Surgery, Samsun, Turkey

Received 21 June 2018; Accepted 26 August 2018 Available online 10.01.2019 with doi:10.5455/medscience.2018.07.8907 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The aim of this study was to highlight the current dilemma of gonial angle measurement on orthopantomograms and lateral cephalograms of adults with different skeletal malocclusion types. The sample consisted of 50 Class I, 50 Class II and 50 Class III (25 males and 25 females for each group) orthopantomograms and cephalograms obtained from previously treated orthodontic patients. For each malocclusion group, the angle between Tweed’s mandibular plane and the tangent from the line running along the gonion to the distal point of the condyle was measured on the right and left sides on orthopantomograms and the superimposed images of the mandible on cephalograms. Paired t-test demonstrated no significant difference between the values of gonial angles determined by cephalograms and orthopantomograms in Cl I patients. Pearson correlation also showed a high correlation between gonial angle values measured on the two diagnostic tools in Cl I patients. In Cl II and Cl III patients, statistical analysis showed a significant difference between the gonial angles defined by cephalograms and orthopantomograms. Orthopantomograms can be used for determining gonial angle as accurately as cephalograms in Cl I patients. Hovewer, orthopantomograms are not appropriate tools for measuring the gonial angle in Cl II and Cl III patients. Keywords: Gonial angle, orthopantomogram, cephalogram

Introduction Evaluation of growth pattern is of critical importance in orthodontic diagnosis and treatment planning. The gonial angle is a significant indicator to assess mandibular steepness and the growth pattern in patients; giving deserving information about vertical positions of the jaws and facial asymmetry. [1] It is a valuable marker while giving distinctive decision of orthodontic treatment or orthognatic surgery in an orthodontic patient. The downward and backward rotation of the mandible is called as a high angle in patients who showed increase of gonial angle. A low angle describes upward and forward rotation of mandible that appears decreased of gonial angle on patients. [2] The gonial angle is one of the determinative factor while specifying treatment approaches like extraction decision in Cl II patients and surgery decision in Cl III patients. [3]

*Coresponding Author: Tugba Haliloglu Ozkan , Ondokuz Mayıs University, Faculty of Dentistry, Department of Orthodontics, Samsun, Turkey E-mail: dttuuba@gmail.com

The gonial angle can be measured on both orthopantomograms and cephalograms. Orthopantomogram is frequently used in orthodontic practice to provide important information about the teeth, their axial inclinations, maturation periods and surrounding tissues [4]; and also has relatively low radiation exposure. [5] Cephalograms can provide information about vertical, sagittal and transversal relations of the upper and lower jaws according to the skull base; the relationship between the upper and lower jaws, and the inclination of the teeth. However, the right and left sides can not be displayed separately in these x-rays, so it is insufficient to give definite information. [6] Although the gonial angle is usually measured from cephalograms, panoramic radiographs is being used gradually for jaw evaluation. [7] Some studies have shown that the left and right gonial angles can be separately measured by orthopantomogram which is a simple and repeatable radiographic method. [4] Hovewer, there is a lack of research in the literature examining orthopantomograms’ ability of determining skeletal patterns. If proven, the accuracy of orthopantomograms to determine gonial angle would provide clinicians to evaluate growth pattern of a patient without the need for an extra x-ray; and also helps general dentists while directing the patients to specialists. 93

doi: 10.5455/medscience.2018.07.8907

Med Science 2019;8(1):93-6

Therefore, the aim of this study was to compare the efficiency of orthopantomograms and cephalograms in the measurement of gonial angles for all skeletal malocclusion types. Material and Methods Patients A total of 150 orthopantomograms and 150 cephalograms (50 Cl I, 50 Cl II, 50 Cl III for each group) of patients referred to our orthodontic department were selected. The study was approved by the Institutional Ethical Committee of Ondokuz Mayıs University. Subjects with a craniofacial malformation or a facial asymmetry; or radiographs with technical or exposure faults were excluded from the study. All radiographs were obtained with the same digital machine (Sirona, XG 3, Munchen, Germany) at the Oral and Maxillofacial Radiology department of OMU Dental Faculty. The radiographs had to be taken by the same apparatus and same technician, and patients in natural head position. The skeletal pattern of the subjects were detected measuring SNA, SNB and ANB angles on the cephalograms in the sagittal plane; and then grouped with respect to skeletal malocclusion types. In both radiographs, the gonial angle is determined from two tangents which were drawn from the inferior border of the mandible (Tweed’s mandibular plane) and posterior borders of condyle and ramus of both sides, considering that the symphysis was not visible on orthopantomograms (Figure 1-Figure 2) The gonial angles were measured by using a software programme (Turcasoft, Samsun, 2012) and recorded. To determine the intraexaminer error, all measurements were repeated by the same examiner 2 weeks apart, and Dahlberg’s formula was used. Error variance was found not to exceed 0,24° in all the measurements. Statistical analyzes The SPSS for Windows statistical package version 23.0 (SPSS Inc., Chicago, IL) was used for all descriptive statistics and analyses. The level of significance was set to P<.05. Since the data were normally distributed, multiple comparison tests (ANOVA) and Tukey tests were used to determine differences among and between the three groups. Independent t-test was performed for comparison of orthopantomogram and cephalometric measurements. Mean values and standard deviations were calculated for all the parameters. Pearson correlation was applied for comparing the correlation of different variables. Statistical power analysis was performed to calculate the number of samples for %96 confidence interval.

Figure 1. Measurement of the gonial angle in orthopantomogram

Figure 2. Measurement of the gonial angle in cephalogram

Results Statistical power analysis was used to determine the required number of samples as the power of the test at 97%. The study sample consisted of 150 subjects that were distributed homogenous into three groups in terms of age and gender. The groups were classified as follows: Cl I 50 subjects (mean age:17,77± 2,42), Cl II 50 subjects (mean age: 17,81±2,52), Cl III 50 subjects (mean age: 17,50±2,43). Each group consisted of 25 males and 25 females. Tables 1, 2 and 3 compare the mean value and standard deviation of the gonial angle measured by orthopantomogram and cephalogram in different genders and different types of malocclusion. Comparison of the Gonial Angle Between Right and Left Sides of Orthopantomograms In orthopantomograms, the mean value of the right gonial angle was 127,93°, with a standard deviation of 8,22°, and the mean value of the left gonial angle was 127,84° with a standard deviation of 8,24° in Cl I patients; with no statisticaly significant difference (Table 1). Similarly, no significant difference was found between the right and left gonial angles measured in orthopantomograms of Cl II and Cl III patients (P = 0.712) Comparison of the Gonial Angle Between Orthopantomograms and Cephalograms In Cl I patients, the mean value of the gonial angle was measured 127,89±7,96° in orthopantomogram and 127,77±7,87° in cephalogram. No statistically significant difference was observed with respect to the diagnostic tool used. (p=0,774) In addition, a high correlation was found between the orthopantomogram and cephalogram gonial angle measurements (r=931). In Cl II patients, 94

doi: 10.5455/medscience.2018.07.8907

the mean value of gonial angle was measured 127,07±6,42° in orthopantomogram and 129,75±7,30° in cephalogram. In Cl III patients, the mean value of gonial angle was measured 131,97±6,31° in orthopantomogram and 132,92±6,95° in cephalogram. The differences between the measurements were found statisticaly significant for both Cl II (p=0,00) and Cl III (p=0,41) patients. (Table 2) Comparison of the Gonial Angle Between Genders In Cl I patients, the mean values of the external gonial angle in orthopantomogram measured between females and males were 127,49±7,76° and 128,28±8,30, respectively. The difference was not statisticaly significant. (p=0,686) There was also no gender difference in the gonial angle value in cephalograms. Further, no statistically significant difference was observed between females

Med Science 2019;8(1):93-6

and males in the gonial angle measured using these 2 diagnostic tools in both Cl II and Cl III patients. (Table 3) Table 1. Comparison of the gonial angle between right and left sides of orthopantomograms

Cl I

Cl II

Cl III

Mean-st.dv

p value

Right

127.93±8.22

Left

127.84±8.24

Right

126.24±6.39

Left

127.89±6.65

Right

131.58±6.62

132.36±6.83

0.881

0.208

0.563

Table 2. Comparison of the gonial angle between orthopantomograms and cephalograms Cl I Mean-st.dv OPG

127.89±7.96

CEPH

127.77±7.87

Cl II p value

Mean-st.dv

Cl III p value

127.07±6.42

0.774

p value

131.97±6.31

0.000

129.75±7.30

Mean-st.dv

0.041

132.92±6.95

st.dv: standart deviation

Table 3. Comparison of the gonial angle between genders Cl I Mean-st.dv OPG

CEPH

Male

128.28±8.30

Female

127.49±7.76

Male

128.33±8.53

Female

127.20±7.28

Cl II p value 0.686

0.279

Mean-st.dv 126.90±6.96 127.24±5.96 128.64±7.39

Cl III p value 0.853

0.287

Mean-st.dv 132.06±6.55 131.87±6.20 132.75±7.54

p value 0.916

0.860

st.dv: standart deviation

Discussion This study was performed to assess and compare the measurement of the gonial angle in orthopantomograms and cephalograms in adult patients with different skeletal malocclusion types. There is a certain variation in the size of the gonial angle depending on the measurement method used. [7] Gonial angle can be measured either by drawing the horizontal side of the gonial angle formed by the tangent to the lower border of the mandible or a line passing through the gnathion. Because of the limited visibility of the gnathion in an orthopantomogram, it might result in an inaccurate measurement of the gonial angle. [8] Although the majority of studies have shown that orthopantomogram is a reliable and accurate method to determine the gonial angle [4,6,8], the majority of the samples used in these studies were not allocated according to their skeletal malocclusions. Okşayan et al. [9] concluded that orthopantomogram results were as reliable as lateral cephalograms in all Angle classifications. Hovewer, in the present study, orthopantomogram measurements were similar

with the cephalometric measurements just in Cl I patients. The gonial angle value showed a significant difference between the two radiographs in Cl II and Cl III patients. Researchers revealed a great individual variation in gonial angle distortion and showed that the gonial angle differs by age and different types of malocclusion. [10-12] In orthopantomograms, magnification does change from the anterior region to the posterior region of the dentition and the object depth. [13] Considering the sagittal relationship in Cl II and Cl III patients viewing from the frontal plane, it could be suggested that the changing depth of the mandible could affect the gonial angle size. Therefore, significance between the gonial angle measurements in Cl II and Cl III patients may be due to the distortion in radiographs. In our study, gender did not have a considerable effect on the gonial angle in both radiographs. Similar results were obtained by Shahabi et al. [14] and Upadhyay et al. [15]; who concluded that no gender differences was found between the two type of radiographs. Some previous studies have reported a difference in gonial angle value between genders. [9,16,17] Larazabal et 95

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al. [18] stated that gender differences in the gonial angle value depended on the age of the patients. Ghosh et al. [19], Bhardwaj et al. [20], Huumonen et al. [21], and Xie and Ainamo [22] reported that females had a larger gonial angle, which might be due to the impact of masticatory forces. As a result of our study, the gonial angle value was not statisticaly significantly different between the right and left sides of orthopantomograms, which is in agreement with the results of the previous studies. [4,8,14] Orthopantomograms are useful tools to determine growth direction through the measurement of the gonial angle and therefore to establish vertical growth problems. Orthopantomograms also provide more accurate information about both right and left sides of gonial angles of a patient avoiding the influence of the superimposed images found on cephalograms. [9] The ability to detect the growth direction from the orthopantomograms will be beneficial because the majority of dentists require this diagnostic tool during routine dental examinations. Conclusion Orthopantomograms, which is an already available tool, can be recommended for the determination of the gonial angle just in Cl I patients. Hovewer, cephalograms still appears the better choice for the accurate measurement of the gonial angle in Cl II and Cl III patients. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval This work has been approved by the Institutional Review Board. Tugba Haliloglu Ozkan ORCID: 0000-0003-1180-8534 Selim Arici ORCID: 0000-0001-8890-2065 Enes Ozkan ORCID: 0000-0002-8182-9042

References 1.

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J Pharm Bioallied Sci. 2017;9:92-5. 7.

Mattila K, Altonen M, Haavikko K. Determination of the gonial angle from the orthopantomogram. Angle Orthod 1997;47:107-10.

8- Radhakrishnan PD, Sapna Varma NK, Ajith VV. Dilemma of gonial angle measurement: Panoramic radiograph or lateral cephalogram. Imaging Sci Dent. 2017;47:93-7.

Okşayan R, Aktan AM, Sökücü O, Haştar E, Ciftci ME. Does the panoramic radiography have the power to identify the gonial angle in orthodontics? ScientificWorld Journal. 2012;2012:219708.

10. Slagsvold O, Pedersen K. Gonial angle distortion in lateral head films: a methodologic study. Am J Orthod. 1977;71:554-64. 11. Altonen M, Haavikko K, Mattila K. Developmental position of lower third molar in relation to gonial angle and lower second molar. Angle orthod. 1977;47:249-55-8. 12. Ranta R, Altonen M. A comparative study of gonial angle and growth of the lower third molar in cleft lip and palate. An orthopantomographical study. Scand J Plast Reconstr Surg. 1978;12:273-8. 13. Stramotas S, Geenty JP, Petocz P, Darendeliler MA. Accuracy of linear and angular measurements on panoramic radiographs taken at various positions in vitro. Eur J Orthod. 2002;24:43-52. 14. Shahabi M, Ramazanzadeh BA, Mokhber N. Comparison between the external gonial angle in panoramic radiographs and lateral cephalograms of adult patients with Class I malocclusion. J Oral Sci. 2009;51:425-9. 15. Upadhyay RB, Upadhyay J, Agrawal P, Rao NN. Analysis of gonial angle in relation to age, gender, and dentition status by radiological and anthropometric methods. J Forensic Dent Sci. 2012;4:29-33. 16. Raustia AM, Salonen MA. Gonial angles and condylar and ramus height of the mandible in complete denture wearers--a panoramic radiograph study. J Oral Rehabil. 1997;24:512-6.

Xiao D, Gao H, Ren Y. Craniofacial morphological characteristics of Chinese adults with normal occlusion and different skeletal divergence. Eur J Orthod. 2011;33:198-204.

17. Ceylan G, Yanikoglu N, Yilmaz AB, et al. Changes in the mandibular angle in the dentulous and edentulous states. J Prosthet Dent. 1998;80:680-4.

Nanda SK. Growth patterns in subjects with long and short faces. Am J Orthod Dentofacial Orthop. 1990;98:247-58.

18. Larrazabal-Moron C, Sanchis-Gimeno JA. Gonial angle growth patterns according to age and gender. Ann Anat. 2018;215:93-6.

Tahmina K, Tanaka E, Tanne K. Craniofacial morphology in orthodontically treated patients of class III malocclusion with stable and unstable treatment outcomes. Am J Orthod Dentofacial Orthop. 2000;117:681-90.

19. Ghosh S, Vengal M, Pai KM, et al. Remodeling of the antegonial angle region in the human mandible: a panoramic radiographic cross-sectional study. Med Oral Patol Oral Cir Bucal. 2010;15:802-7.

Zangouei-Booshehri M, Aghili HA, Abasi M, et al. Agreement between panoramic and lateral cephalometric radiographs for measuring the gonial angle. Iran J Radiol. 2012;9:178-82.

20. Bhardwaj D, Kumar JS, Mohan M. Radiographic evaluation of mandible to predict the gender and age. J Clin Diagn Res. 2014;8:66-9.

Gavala S, Donta C, Tsiklakis K, et al. Radiation dose reduction in direct digital panoramic radiography. Eur J Radiol 2009;71:42-8.

Kumar SS, Thailavathy V, Srinivasan D, et al. Comparison of Orthopantomogram and Lateral Cephalogram for Mandibular Measurements.

21. Huumonen S, Sipilä K, Haikola B, et al. Influence of edentulousness on gonial angle, ramus and condylar height. J Oral Rehabil. 2010;37:34- 8. 22. Xie QF, Ainamo A. Correlation of gonial angle size with cortical thickness, height of the mandibular residual body, and duration of edentulism. J Prosthet Dent 2004;91:477-82.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):97-101

Investigation of the relationship between pain threshold and joint position sense in the cervical region Ceyhun Turkmen, Nezire Kose, Hatice Cetin, Esra Dulger, Sevil Bilgin Hacettepe University, Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation, Ankara, Turkey Received 13 April 2018; Accepted 01 September 2018 Available online 08.11.2018 with doi:10.5455/medscience.2018.07.8918 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract This study was performed to investigate whether there is a relationship between cervical region pain threshold and joint position sense (JPS) in healthy subjects. The subjects were 38 healthy volunteers in the Hacettepe University, Faculty of Health Sciences, Physiotherapy and Rehabilitation Department. Pain thresholds in the right and left cervical paravertebral regions of participants were assessed with a digital algometer (Wagner Instruments, Greenwich, USA). The JPS of the cervical region was assessed with the Cervical Range of Motion 3 (CROM 3) device. While the pain thresholds in the left and right cervical paravertebral regions increased, the JPS error levels in the cervical region of the extension direction decreased (right and left cervical paravertebral region p = 0.003 and r = -0.475, p = 0.020 and r = -0.377, respectively). At the end of this study, the position sense error was higher in the participants with a low pain threshold. In participants in which the pain threshold is lower, prematurely stimulated pain receptors can decrease JPS by causing suppression of proprioceptive receptors. JPS should be assessed in individuals who define pain in the neck region. According to the result of this study, it is necessary to improve JPS in patients with neck pain, or healthy individuals who have lower pain threshold may be able to avoid neck pain when they receive appropriate proprioceptive training to improve their JPS. In conclusion, when healthy individuals were included in proprioceptive training, it was observed that neck pain could be prevented in the early period. Keywords: Joint position sense, pain threshold, cervical region

Introduction Individuals develop a variety of strategies to protect themselves from trauma coming from their surroundings. An internal pain that gives a warning to the individual and the postural awareness that the individual possesses are of crucial importance for use of these strategies [1,2]. Pain is defined by the International Association for the Study of Pain as “an unpleasant sensory and emotional feeling which starts from any part of body, originates from an organic or nonorganic cause and is associated with the past experiences of the person”. Pain has also been defined as the unconscious awareness of tissue damage. It has also been shown that pain causes panic and avoidance behaviors in the person. Many studies have emphasized that the proprioceptive system deteriorated with the emergence

*Coresponding Author: Ceyhun Turkmen , Hacettepe University, Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation, Ankara, Turkey E-mail: ztceyhunturkmen@gmail.com

of pain. As a result of reduced proprioception, deteriorations may occur in the reaction time, postural control and stability of the person. However, the reasons for this situation have not been fully explained [3-5]. Since proprioception regulates joint position, motion perception and the sensitivity of the force exerted by muscles, it is an important part of neural control [6]. Emphasizing the importance of neural control strategies in preventing injuries, Quint et al [7] reinforced the presence of an association between proprioception and injuries. Pain is always subjective, it varies according to the person’s perception and it is expressed in parallel to the extent of the pain threshold. Pain threshold is defined as the minimum stimulus value that produces the pain sensation. The past experiences, socio-cultural status and gender of the person may influence pain threshold. While causes such as central and peripheral dysfunctions, inflammatory changes, loss of descending inhibitory system and central sensitization in the pain transmission pathways decrease pain threshold value, nonsteroidal anti-inflammatory 97

doi: 10.5455/medscience.2018.07.8918

drug and opioid analgesic use, electric stimulation, and local physical therapy methods such as warm and cold application may temporarily increase the pain threshold [8]. Pain threshold measurement is an objective pain level assessment method which indicates the moment of pain emergence and which is measured by applying stimulus via algometers [9]. For painful stimulation, the methods of heat, pressure, electrostimulation and creating muscle ischemia may be used [8]. In individuals with low pain thresholds, the pain sensation activated early may depress the proprioceptive system and the individual may become vulnerable to injury. On the other hand, because pain is a perceptual sensation, it may occur earlier in individuals with proprioceptive disorders [9]. There are studies which examine the relationship between pain and proprioception in the literature. Gill et al compared proprioception sensation between individuals with and without lumbar pain. At the end of their studies, it was indicated that proprioception was low in the individuals with lumbar pain and this was considered to be caused by degenerative changes in the muscle and joints of the individuals with lumbar pain [10]. Oâ&#x20AC;&#x2122;Sullivan et al found that the proprioceptive sensation of patients with lumbar pain was less than that of normal individuals and they reported that this may occur through a positive feedback mechanism between inappropriate posture and decreased proprioception [11]. Reid et al demonstrated that proprioceptive sensation was lower in patients with neck pain compared to asymptomatic individuals, but they did not provide any clarification related to the cause [12]. These studies attempted to define the association between pain and proprioception by expressing decreased proprioceptive sensation in the presence of pain. These studies are valuable with respect to the idea that pain may cause decreased proprioceptive sensation. Although there are studies regarding the association between pain severity and proprioception in the literature, to the best of our knowledge no study has been conducted on the association between pain threshold and proprioception. The present study examines the perception of pain that individuals may experience at an early stage with impaired proprioceptive sense. If individuals face pain at an earlier stage as a consequence of low pain thresholds, functional disorders occur earlier due to proprioceptive disorders. Material and Methods Study Design Fifty-two male individuals who had not suffered from neck pain for the previous six months [those who marked a point of less than 10 mm on the Visual Analogue Scale (VAS)] and who were aged 18-30 years (mean age 22 Âą 2 years) were contacted about participation in the study between December 2015 and September 2016. Ethical approval of the work was obtained by Hacettepe University NonInterventional Ethics Committee on November 18, 2015 (Decision NO:GO 15/716-04). As a result of the assessments, nine participants were not eligible to participate in the study. Five of the participants were excluded due to various reasons during the evaluation phase. Thus, a total of 38 participants were included in the study (Figure 1). The study was conducted in the Hacettepe University, Faculty of Health Sciences, Physiotherapy and Rehabilitation Department. The demographic characteristics of the individuals were collected by using a questionnaire. The individuals were asked whether they had hypertension, diabetes, or a rheumatologic disease diagnose

Med Science 2019;8(1):97-101

previously. Their family history, medications and educational status were noted. Individuals who have had neck pain, sensory perception, or rheumatologic problems in the past, or who have received analgesic medication within the past ten days were not included in the study. Furthermore, informed consent form was signed before the start of the study by the voluntary participants. The participants underwent two assessments. In the first assessment, pain threshold was measured with a digital algometer, while in the second, the joint position sense (JPS) of the cervical region was measured with the Cervical Range of Motion 3 (CROM 3) device.

Figure 1. Flow chart of participants

Assessments Pressure Pain Threshold Pain threshold was measured bilaterally with a digital algometer (JTech Medical Industries, ZEVEX Company) in the healthy individuals. The reliability of the digital algometer was confirmed by Chung et al. The tip of the device was placed vertically in the paravertebral muscles at the level of seventh cervical (C7) vertebra. The applied pressure was 0.5 kg/cm2 for per second. The mean value of three measurements taken at 30-second intervals was calculated and recorded [13]. Joint Position Sense Error Clinical assessment of proprioception should employ tests for measuring JPS, kinesthesia, or force sense [6]. The researchers have used the CROM 3 device to measure cervical active JPS and found it as a reliable and valid method [14,15]. Errors greater than 4.5 are considered to indicate abnormal cervical active JPS. The error of the cervical regionâ&#x20AC;&#x2122;s JPS was evaluated in the directions of flexion, extension, right and left lateral flexion and 98

doi: 10.5455/medscience.2018.07.8918

right and left rotation. The JPS measurements were performed by using the CROM 3 device. When the participant started to the test, he was asked to look across while sitting upright in a relaxed position with his arms at his sides. The head of the participant was brought up slowly and passively to the target point (determined previously by the physiotherapist], which was up to 65 percent of the maximum joint range of motion. The aim of moving the head slowly was to minimize the effects of varying vestibular functions with age in individuals. The participant was told to keep his head in a passive position and to feel his position. Afterwards, the head of the participant was brought back to the neutral position. Then the participant was asked to recall it and bring his head to the point that it had been brought to passively. The error degree between the point reached by the participant using the joint position feeling and the predetermined reference point was recorded. This process was repeated three times and the mean value was calculated [14, 16] (Figure 2).

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respectively), while the negative correlation in other positions was weak (Table 2) Table 1. Pain threshold and joint position sense error Mean Value ± Standard Deviation Movement

(degree)

Flexion

3.72 ±1.53

Extension

3.90 ± 1.66

Lateral Flexion Right

3.16 ± 1.36

Left

2.90 ± 1.21

Rotation Right

4.00 ± 1.38

Left

3.91 ± 1.57

Pain Threshold

(kg/cm2)

C7 Paravertebral Muscle Right

2.66 ± 0.86

Left

2.62 ± 0.79

Table 2. Relationship between pain threshold and joint position sense error levels in the neck region of individuals n=38

Right Region PT

Left Region PT

Movement

ICC

Flexion

-0.362

0.025*

-0.296

0.071

Extension

-0.475

0.003*

-0.377

0.020*

Right

-0.367

0.024*

-0.188

0.258

Left

-0.336

0.036*

-0.366

0.024*

Right

-0.201

0.227

-0.010

0.953

Left

-0.201

0.137

-0.050

0.763

Lateral Flexion

Figure 2. Determination of cervical region joint position sense error

Statistical Analysis Statistical analysis was performed by using SPSS 18.0. Whether the data were normally distributed or not was measured by the Kolmogorov-Smirnov test. Since the data are not normally distributed, Spearman’s correlation test that was used to identify the correlation between two parameters. The statistical significance value was set at 0.05 with 95% confidence interval and the result was considered significant when the p-value was less than 0.05 (p<0,05). Results At the end of the study, it was determined that the movement with the largest JPS error was right rotation, while that with the smallest error was left lateral flexion. The error values of JPS were measured in flexion, extension, right lateral flexion, left lateral flexion right rotation and left rotation directions. The participants’ pain threshold was measured in the paravertebral muscles at the C7 vertebral level (Table 1). Correlation analysis showed there was a weak or moderate correlation between JPS error and pain threshold in all measured directions and the pain threshold was lower if the JPS error was greater. The negative correlation detected between the direction of extension and right / left paravertebral cervical muscles was moderate (p=0.003 and r=-0.475, p=0.020 and r=-0.377,

Rotation

ICC: Intraclass Correlation Coefficient, p: Spearman rank correlation PT: Pain Threshold *p<0.05

Discussion The aim of this study was to determine whether there is a relationship between pain thresholds and proprioception senses in individuals who have not yet had neck pain and to emphasize that proprioceptive training applied to healthy individuals may prevent neck problems in individuals when there is a relationship between these two senses. At the end of this study, a weak or moderate correlation was seen between JPS error and pain threshold and the pain threshold was lower when the JPS error was higher. The pain threshold levels of the male subjects with a mean age of 22 ± 2 years were approximately 2.6 kg/cm2. This result was similar to those of other studies in healthy young individuals that were used to measure the pain threshold of the neck region. Sacramento et al [2] found a mean pain threshold of 2.1 kg/cm2 in individuals with a mean age of 23 years. It was reported to be 2.1 kg/cm2 in individuals with a mean age of 21 years by Fernandez-de-las-Penas et al [17], 2.7 kg/cm2 in individuals with a mean age of 20 years by Oliviera99

doi: 10.5455/medscience.2018.07.8918

Campelo et al [18] and 2.3 kg/cm2 in individuals with a mean age of 32 years by de Camargo et al [19]. According to these results, the level of pain threshold in our study is slightly higher compared to that in many studies. Previous studies indicated that females had a pain threshold 1.2 kg/cm2 lower than that in males [20, 21]. This difference between the studies may be regarded as normal since the data of our study were obtained exclusively from male individuals. In our study, when the JPS error size in individuals was higher, the pain threshold was lower. There has been no study in the literature examining the relationship between pain threshold and JPS, there are studies describing the relationship between pain and JPS. JPS error was higher in individuals who were suffering from neck pain as a result of whiplash injury according to Loudon et al [22] and this contributed to the decreased kinesthetic awareness secondary to muscle injury and the pain which developed due to the whiplash injury. Revel et al [23] found that JPS error was significantly higher in individuals with neck pain compared to healthy individuals, and suggested that this was due to functional changes in muscle proprioceptors due to nociceptive pain impulses. In our study, the level of JPS error decreased in individuals with a high pain threshold and thus JPS was also high. The possible inhibition mechanisms that cause this result may be explained by the gate control theory [24]. According to this theory, the stimulation of a low-threshold, large-diameter mechanoreceptor which is responsible for position sense suppresses the pain fibres in that region and may increase the pain threshold in this way [25]. Based on the results, the JPS error levels were 3-4 degrees. According to Wibault et al, in healthy individuals with a mean age of 25 years, the average JPS error was 2 degrees for individuals with a Neck Disability Index score of 20 or less [14]. Reddy et al reported that JPS errors were 3-4 degrees in healthy individuals between 18 and 30 years of age [16], while Asha et al reported JPS errors of 3-12 degrees in healthy individuals between 20 and 40 years of age [26]. Wibault et al [14] found a JPS error lower of than that of our study. This may have been because they selected healthy individuals by a more discriminative method using the Neck Disability Index assessment, which evaluates neck symptoms in a more detailed way and which is a reliable method for differentiating healthy individuals. VAS assessment is a more practical but superficial method than assessing Neck Disability Index to evaluate pain. The mean JPS errors in the study by Asha et al [26] were higher compared to those in our study, especially in the rotation components. The reason for this difference may be that the universal goniometer is inadequate, especially in evaluating the rotational components, compared to the CROM 3 device. Based on our results, the correlation coefficient in the direction of cervical extension was higher than in the other directions. The reason for this may be that the suboccipital muscles are in the direction of the extension, which is the area of the proprioceptors concentrated most [27, 28]. All of these studies in the literature have identified the relationship between pain and JPS in the post-pain phase. However, unlike other studies, it was concluded that individuals without neck pain but with lower joint positions may experience neck pain earlier than individuals with higher joint positions, although they are still

Med Science 2019;8(1):97-101

healthy. This result suggests that healthy individuals who do not have neck pain but who experience any loss of proprioceptive may encounter neck pain earlier, which is a very important finding for preventive rehabilitation approaches. In this study, it was observed that healthy individuals without neck pain could experience pain at an earlier stage due to impaired proprioceptive sensations. Including only male individuals to study can be considered as a limitation because this results do not cover the entire population. In addition, a relatively small number of cases included in the study were considered another limitation of study because negatively impacted the power of the study. Conclusion In conclusion, when healthy individuals were included in proprioceptive evaluation and training, it was observed that neck pain could be prevented in the early period. In individuals with neck pain, the development of proprioception sense may increase pain thresholds and thus may prevent neck pain. More detailed work on these issues will bring new perspectives to both the treatment of patients and the studies to be done to protect public health. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Before the study, permissions were obtained from local ethical committee. Ceyhun Turkmen ORCID: 0000-0002-3125-4113 Nezire Kose ORCID: 0000-0001-8342-7293 Hatice Cetin ORCID: 0000-0001-8488-5763 Esra Dulger ORCID: 0000-0002-0488-0127 Sevil Bilgin ORCID: 0000-0003-1597-1312

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Brumagne S, Cordo P, Lysens R, et al. The role of paraspinal muscle spindles in lumbosacral position sense in individuals with and without low back pain. Spine. 2000;25:989-94.

Sacramento LS, Camargo PR, Siqueira-JĂşnior AL, et al. Presence of latent myofascial trigger points and determination of pressure pain thresholds of the shoulder girdle in healthy children and young adults: a cross-sectional study. J Manipulative Physiol Ther.2017;40:31-40.

Luoto S, Aalto H, Taimela S, et al. One-footed and externally disturbed twofooted postural control in patients with chronic low back pain and healthy control subjects: a controlled study with follow-up. Spine. 1998;23:2081-9.

Luoto S, Taimela S, Hurri H, et al. Psychomotor Speed and Postural Control in Chronic Low Back Pain Patients: A Controlled Follow-Up Study. Spine. 1996;21:2621-7.

Mannion AF, Dolan P. Electromyographic median frequency changes during isometric contraction of the back extensors to fatigue. Spine. 1994;19:1223-9.

RĂśijezon U, Clark NC, Treleaven J. Proprioception in musculoskeletal rehabilitation. Part 1: Basic science and principles of assessment and clinical interventions. Manual therapy. 2015;20:368-77.

Quint U, Wilke H-J, Shirazi-Adl A, et al. Importance of the intersegmental trunk muscles for the stability of the lumbar spine: a biomechanical study in vitro. Spine. 1998;23:1937-45.

Guldogus F, Kelsaka E, Ozturk B. The effect of gender and working conditions on pain threshold in healthy volunteers/Saglikli gonullulerde cinsiyet ve calisma sartlarinin agri esik degeri uzerine etkisi. Agri. 2013;25:64-9.

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Walton DM, Levesque L, Payne M, Schick J. Clinical pressure pain threshold testing in neck pain: comparing protocols, responsiveness, and association with psychological variables. Physical therapy. 2014;94:827.

10. Gill KP, Callaghan MJ. The measurement of lumbar proprioception in individuals with and without low back pain. Spine. 1998;23:371-7. 11. O’Sullivan P, Waller R, Wright A, et al. Sensory characteristics of chronic non-specific low back pain: a subgroup investigation. Manual therapy. 2014;19:311-8. 12. Reid S, Portelli A. Cervical proprioception in young adults with and without neck pain, who spend prolonged time on mobile devices: An observational study. Manual Therapy. 2016;25:e86-e7. 13. Celenay ST, Kaya DO, Akbayrak T. Cervical and scapulothoracic stabilization exercises with and without connective tissue massage for chronic mechanical neck pain: A prospective, randomised controlled trial. Manual therapy. 2016;21:144-50. 14. Wibault J, Vaillant J, Vuillerme N, Dedering Å, Peolsson A. Using the cervical range of motion (CROM) device to assess head repositioning accuracy in individuals with cervical radiculopathy in comparison to neckhealthy individuals. Manual therapy. 2013;18:403-9. 15. Treleaven J, Jull G, Sterling M. Dizziness and unsteadiness following whiplash injury: characteristic features and relationship with cervical joint position error. Journal of Rehabilitation Medicine. 2003;35:36-43. 16. Reddy RS, Maiya AG, Rao SK. Effect of dorsal neck muscle fatigue on cervicocephalic kinaesthetic sensibility. Hong Kong Physiotherapy J. 2012;30:105-9. 17. Fernández-De-Las-Peñas C, Pérez-De-Heredia M, Brea-Rivero M, et al. Immediate effects on pressure pain threshold following a single cervical spine manipulation in healthy subjects. J Orthop Sports Phys Ther. 2007;37:325-9. 18. Oliveira-Campelo NM, Rubens-Rebelatto J, MartÍn-Vallejo FJ, et al. The immediate effects of atlanto-occipital joint manipulation and suboccipital muscle inhibition technique on active mouth opening and pressure pain

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sensitivity over latent myofascial trigger points in the masticatory muscles. J Orthop Sports Phys Ther. 2010;40:310-7. 19. de Camargo VM, Alburquerque-Sendín F, Bérzin F, et al. Immediate effects on electromyographic activity and pressure pain thresholds after a cervical manipulation in mechanical neck pain: a randomized controlled trial. J Manipulative Physiol Ther. 2011;34:211-20. 20. Hogeweg J, Langereis M, Bernards A, Faber J, et al. Measuring pain threshold, method and characteristics in healthy subjects. Scand J Rehabil Med. 1991;24:99-103. 21. Petersen KL, Brennum J, Olesen J. Evaluation of pericranial myofascial nociception by pressure algometry. Reproducibility and factors of variation. Cephalalgia. 1992;12:33-7. 22. Loudon JK, Ruhl M, Field E. Ability to reproduce head position after whiplash injury. Spine. 1997;22:865-8. 23. Revel M, Andre-Deshays C, Minguet M. Cervicocephalic kinesthetic sensibility in patients with cervical pain. Arch Phys Med Rehabil. 1991;72:288-91. 24. Melzack R, Wall PD. Pain mechanisms: a new theory. Survey Anesthesiol. 1967;11:89-90. 25. Zusman M. Spinal manipulative therapy: review of some proposed mechanisms, and a new hypothesis. Aust J Physiother. 1986;32:89-99. 26. Asha SE, Pryor R. Validation of a method to assess range of motion of the cervical spine using a tape measure. J Manipulative Physiol Ther. 2013;36:538-45. 27. Peck D, Buxton D, Nitz A. A comparison of spindle concentrations in large and small muscles acting in parallel combinations. J Morphol. 1984;180:24352. 28. Kulkarni V, Chandy M, Babu K. Quantitative study of muscle spindles in suboccipital muscles of human foetuses. Neurol India. 2001;49:355-9.

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Available online at www.medicinescience.org

ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):102-5

The relationship between obesity and restless legs syndrome Fatma Ebru Algul1, Ayse Cikim Sertkaya2, Sibel Altinayar3 1 Malatya Educational and Research Hospital, Clinic of Neurology, Malatya, Turkey Sisli Memorial Hospital, Endocrinology and Metabolism Disorders, Istanbul, Turkey 3 Inonu University Faculty of Medicine Department of Neurology, Malatya, Turkey

Received 02 August 2018; Accepted 07 September 2018 Available online 16.12.2018 with doi:10.5455/medscience.2018.07.8940 Copyright ÂŠ 2019 by authors and Medicine Science Publishing Inc. Abstract Restless legs syndrome (RLS) has been shown to be more common in obese than in non-obese people in many studies. The aim of this study was to investigate passible relationship between obesity and seconder RLS prevalence and severity in the Turkish population. Method: A total of 70 volunteers were included in the study. Of these 44 were obese (BMIâ&#x2030;Ľ30 kg/m2) and 26 were non obese(BMI <30 kg/m2. The International RLS Study Group (International Restless Legs Study Group, IRLSS) diagnosis criteria were used for the RLS diagnosis and International RLS criteria to determine the severity. 17 subjects had RLS and of these 13 were in the obese group and 4 in the non-obese group. No significant difference was found between obese and non-obese groups in terms of RLS prevalence (p:0.165) and RLS severity (p:0.918). Our study on a small sample from the Turkish population showed no significant relationship between obesity and RLS presence and severity. The reason may be the small numbers of obese and control group subjects in our study. Keywords: Restless legs syndrome, obesity, pathology

Introduction Restless legs syndrome (RLS) is a common movement and sleep disorder characterized by the unpreventable urge to move, along with a marked and disturbing abnormal sensation, especially in the lower extremities [1]. It affects the sleep, daily activity and quality of life in 5-20% of the adults [2]. The diagnostic criteria were updated in 2002 by the International Restless Leg Syndrome Study Group and reviewed in 2012 [3]. RLS is classified as primary and secondary. The primary form has a genetic basis. It is estimated to be inherited in 50-80% of the cases [4]. The secondary form is associated with iron deficiency, magnesium deficiency, vitamin B12 deficiency, folate deficiency, uremia, end stage renal disease, pregnancy, polyneuropathy, rheumatoid arthritis, hypo-hyperthyroidism, myelitis, smoking, diabetes, tricyclic antidepressant use, selective serotonin reuptake inhibitors, lithium and dopamine antagonist use [5,6].

Dopaminergic hypofunction in the central nervous system (CNS) is thought to play a critical role in the pathophysiology of the disease [7]. Some environmental factors may play a role in the development of RLS by affecting dopamine levels and dopamine metabolism in the CNS. A decrease in the accessibility of dopamine D2 receptors in the brain and an increased risk of RLS formation occurs in obese people [8]. The body mass index (BMI) of the patients with restless leg syndrome has been found to be significantly higher than those without RLS [9]. A direct relationship is present between obesity and obstructive sleep apnea syndrome and insomnia [10]. RLS is also a sleep disorder and has been shown to be related to obesity in many studies [9]. We aimed to investigate the relationship between BMI, fat mass, fat-free body mass (FFM), body water percentage (TBW) and duration of obesity and the seconder RLS presence and severity in this study. Material and Methods

*Coresponding Author: Fatma Ebru Algul, Malatya Educational and Research Hospital, Clinic of Neurology, Malatya, Turkey E-mail: guzinbilgin@hotmail.com

The necessary explanations were provided to the volunteers included in the study and their consent was obtained. Subjects with anemia, slipped disc, rheumatoid arthritis, kidney failure, liver 102

doi: 10.5455/medscience.2018.07.8940

failure, thyroid disease, hypercholesterolemia, diabetes, and those using antipsychotics, antidepressant drugs or alcohol, in addition to pregnant women were excluded from the study. Of the 70 volunteers, 44 with BMI>30 were included in the obese group and 26 with BMI<30 were included in the non-obese group. Face-toface interviews were conducted with all subjects. The International Restless Leg Study Group (IRLSS) diagnostic criteria were used for the RLS diagnosis and the International RLS Study Group (Table 2) criteria for the severity. A score of 1-10 was considered mild, 11-20 moderate, 21-30 severe and 31- 40 very severe. Height, weight, waist circumference and hip circumference were measured and BMI calculated using the kilograms (kg)/height (m2) formula in all subjects. Those with abnormal hemoglobin, hematocrit, fasting blood sugar, HbA1c, iron, iron binding capacity, insulin, total cholesterol, LDL, HDL, triglyceride, BUN, creatinine, AST, ALT, magnesium, calcium, phosphorus or thyroid function test results were excluded from the study. Table 1. Restless Legs Syndrome Diagnostic Criteria 1.

An urge to move the legs usually but not always accompanied by or felt to be caused by uncomfortable and unpleasant sensations in the legs

The urge to move the legs and any accompanying unpleasant sensations begin or worsen during periods of rest or inactivity such as lying down or sitting.

The urge to move the legs and any accompanying unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues.

The urge to move the legs and any accompanying unpleasant sensations during rest or inactivity only occur or are worse in the evening or night than during the day.

Table 2. IRLSS criteria 1.

Overall, how would you rate the RLS discomfort in you legs or arms? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None

Overall, how would you rate the need to move around because of your RLS symptoms? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None

Overall, how much relief of your RLS arm or leg discomfort do you get from moving around? (4) No relief (3) Slight relief (2) Moderate relief (1) Either complete or almost complete relief (0) No RLS symptoms and therefore question does not apply

Overall, how severe is your sleep disturbance from your RLS symptoms? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None

How severe is your tiredness or sleepiness from your RLS symptoms? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None

Overall, how severe is your RLS as a whole? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None

. How often did you have RLS symptoms? (4) Very often; six to seven days (3)often; four to five days (2) sometimes; two to three days (1) occasionally; one day or less (0) never

When you have RLS symptoms, how severe are they on an average day? (4) Very severe (This means 8 hours per 24 hour day or more.) (3) Severe (This means 3 to 8 hours per 24 hour day.) (2) Moderate (This means 1 to 3 hours per 24 hour day.) (1) Mild (This means less than 1 hour per 24 hour day.) (0) None

Overall, how severe is the impact of your RLS symptoms on your ability to carry out your daily affairs, for example carrying out a satisfactory family, home, social, school, or work life? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None

How severe is your mood disturbance from your RLS symptoms–for example angry, depressed, sad, anxious, or irritable? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None

Med Science 2019;8(1):102-5

Statistical analysis The SPSS 22 software program was used for the analysis of the data and the Kolmogorov-Smirnov test was used to determine the compliance of the quantitative data with a normal distribution. Student’s t test was used for the data compliant with a normal distribution and the Mann-Whitney U test for the other data. The chi-square test was used for quantitative data. p < 0.05 was accepted as significant for all analyses. Results A total of 70 subjects consisting of 45 males and 25 females were included in our study. There were 8 smokers and 62 nonsmokers. The mean age was 34.53±10.9 (17-61), the mean weight 95.33±17.7 kg (75-135) and the mean height 165.4±8.6 cm (148187). The BMI range was 26 kg/m2 to 41 kg/m2 and the mean BMI was 33.33±5.6 kg/m2. Mean waist circumference value was 102.34±16.2 cm, and mean hip circumference 116.36±11.8 cm. The mean value for fat mass was 31.8±12.8 (7.1-62.5), fat-free mass (FFM) 56.3±11.3 kg (39.30-95.90), body water percentage (TBW) 41.2±8.3% (28.80-70.9%) and obesity duration 7.3±5.3 years (1-25) (Table 3). Table 3. Variable Values Mean Value

Min-Max

Age

34.53±10.9

17-61

Weight (kg)

95.33±17.7

75-135

Height

165.4±8.6

148-187

BMI

33.33±5.6

26-41

Waist circumference

102.34±16.2

67-144

Hip circumference

116.36±11.8

83-144

Fat Mass

31.8±12.8

7.1-62.5

FFM

56.3±11.3

39.3-96.9

TBW

41.2±8.3

28.8-70.9

Obesity duration

7.3 ±5.3

1-25

RLS was found in 17 subjects in our study with 13 of these in the obese group and 4 in the non-obese group. No statistically significant difference was found between the obese and non-obese groups in terms of RLS incidence (p:0.165) and RLS severity (p:0.918). There was also no significant relationship between hip circumference and the RLS presence (p:0.22) and severity (p:0.948), and also between waist circumference and the RLS presence (p:0.206) and severity (p:0.810). Again, no significant relationship was found between fat mass and the RLS presence (p;0.102) and severity (p:0.548); FFM and the RLS presence (p:0.698) and severity (p:0.980); and between TBW and RLS presence (p:0.565) RLS severity (p:0.978). The obesity duration did not create a significant change in the RLS presence (p:0.197) and severity (p:0.703) (Table 4). There was also no gender difference in RLS incidence in the population included in our study (p:0.926). 103

doi: 10.5455/medscience.2018.07.8940 Table 4. Statistical Relationship Results RLS presence

RLS severity

Hip circumference

0.220 (p)

0.948 (p)

Waist circumference

0.206 (p)

0.810 (p)

Fat Mass

0.102 (p)

0.548 (p)

FFM

0.698 (p)

0.980 (p)

TBW

0.565 (p)

0.978 (p)

Obesity duration

0.197 (p)

0.703 (p)

Discussion Obesity is now considered one of the most important preventable causes of disability in the world [11]. Increased BMI has also been found to increase the risk of developing RLS in a study conducted by Batool-Anwar et al. [12]. Similarly, obesity has been shown to progressively increase the frequency of RLS by Gao et al. [13]. Subjects diagnosed with RLS were found to have higher BMI measurements in a study conducted by Elwood et al. in 2006 [9]. Inadequate dopamine metabolism, sympathetic hyperactivity and chronic inflammation in the brain have been used in an attempt to explain the relationship between obesity and RLS [5,12]. The hypothalamic-pituitary-adrenal (HPA) system activation and inflammation usually caused by metabolic syndromes is one of underlying mechanisms of obesity increasing the risk of RLS development. Increased overnight HPA system activation was found in RLS patients in a study conducted in Germany. The physiological cortisol level was also found to be at its minimum when the RLS symptoms were maximally experienced [14]. It is therefore possible that the sleep disorder developing due to RLS may trigger HPA system activation and the RLS symptoms could also trigger HPA activation as a response to stress [15,16]. The best-proven biological abnormality in the pathophysiology of RLS is cerebral iron deficiency as shown in the cerebrospinal fluid and with magnetic resonance imaging methods and autopsy results [17]. Various studies have shown that serum iron levels were not significantly different between RLS patients and the control group, although CNS iron was lower in RLS patients. This is thought to be due to differences in iron absorption, transport of the iron from the blood-brain barrier, and intracellular iron regulation between the groups [18]. Systemic iron deficiency has been shown to cause a decrease in brain iron transport and consequently hypoxia and myelin loss [19], and obesity has been proven to cause a significant increase in the risk of systemic iron deficiency development [20]. Striatal dopamine D2 receptors have been shown to be lower in number in obese patients than in controls. Wang GJ et al. had documented a reduction in dopamine D2 receptors in morbidly obese subjects. PET was used for assess dopamine D2 receptor availability in striatum with brain glucose metabolism in ten morbidly obese subjects (BMI>40 kg/m2) and compared it to that in twelve non-obese controls. In obese subjects striatal D2 receptor availability was lower than controls and was positively correlated with metabolism in dorsolateral prefrontal, medial orbitofrontal, anterior cingulate gyrus and somatosensory cortices [21]. Iron serves as a cofactor of tyrosine hydroxylase which is a rate

Med Science 2019;8(1):102-5

determinant in dopamine synthesis. Tyrosine hydroxylase function increases with iron deficiency and extracellular dopamine increases with an increase in tyrosine hydroxylase function, resulting in a decrease in the dopamine transporter and in the number of D2 receptors on the cell surface [22]. An increase in substantia nigra tyrosine hydroxylase and a decrease in the putamen D2 receptor level have been found in autopsy studies conducted on RLS patients [23]. A significant relationship was found between BMI and RLS in another conducted in the Korean population. This positive correlation was compliant with other studies and statistically significant in females but not in males [24]. Obesity and high cholesterol levels were found to significantly increase the risk for developing RLS in both genders after excluding age, ethnic origin, physical activity, smoking, alcohol use, antidepressant use, and a history of stroke-myocardial infarction or menopause, in a large-scale, prospective study conducted by De Vito et al. [25]. A total of 197,204 subjects were analyzed in 15 studies in a metaanalysis conducted by Song Lin et al. in 2018 and a significant relationship was found between obesity (BMI>30 kg/m2) and RLS (p<0.001) while being overweight (BMI 25-30 kg/m2) was found to increase RLS risk (p<0.001) [26]. RLS was shown to be more common in obese people but the result was not statistically significant in a study on 143 obese and 94 control subjects conducted by YÄąldÄąz D et al. in the Turkish population [27]. The RLS incidence was found to be high in the diabetic group in a study on 939 subjects from Iceland and another study on 998 subjects from a Swedish population in 2010 but no significant difference was present in the group with metabolic problems such as obesity, hypertension and cardiovascular disease and RLS was found to be 2 times more common in women from Iceland than in those from Sweden in this study [28]. No significant difference was found between obese and non-obese groups in terms of RLS incidence in our study, similar to the Iceland and Sweden population (p:0.165). Besides, unlike other studies in the literature, no gender difference was seen in the RLS incidence in both the obese (p:0.783) and non-obese groups (p:1.00). Increasing waist circumference measurements were found to increase the RLS incidence progressively in a study conducted by Gao et al. [13]. Abdominal obesity was again found to increase risk of RLS incidence by 40-70% in a large-scale prospective study conducted by De Vito et al. [25]. However, no significant relationship was found between RLS incidence and waist circumference measurements (p:0.206) and obesity (p:0.16) in our study. Although our study produced results that were similar to those from the populations from Iceland and Sweden, a large number of studies and meta-analyses have shown RLS incidence to increase in obesity. Our results may have been influenced by our small numbers of obese and control subjects. 104

doi: 10.5455/medscience.2018.07.8940

Conclusion The fact that obesity is a modifiable risk factor for RLS, which is a common movement disorder that decreases quality of life, is important in terms of preventive medicine. Although there are several views regarding the underlying mechanisms, the etiopathogenesis has not yet been elucidated. Further studies on a larger number of subjects may explain the relationship between obesity and RLS together with the etiopathogenesis. Competing interests The authors declare that they have no competing interest Financial Disclosure The authors declared that this study has received no financial support

Med Science 2019;8(1):102-5

11. Wang Y, Beydoun MA. The obesity epidemic in the United States-gender, age, socioeconomic, racial/ethnic and geographic characteristics: a systematic review and meta-regression analysis. Epidemiol Rev. 2007;29:6-28. 12. Batool-Anwar S, Li Y, De Vito K, et al. Lifestyle factors and risk of restless legs syndrome: prospective cohort Study. J Clin Sleep Med. 12,187-94. 13. Gao X, Micheal A, Schwarzschild MD, et al. Obesity and restless legs syndrome in men and women. Neurology. 2009:72;1255-61. 14. Schilling C, Schredl M, Strobl P, et al. Restless legs syndrome: evidence for nocturnal hypothalamic-pituitary-adrenal system activaton. Mov Disord. 2010;25:1047-52. 15. Spath-Schwalbe E, Gofferje M, Kern W, et al. Sleep disruption alters nocturnal ACTH and cortisol secretory patterns. Biol Psychiatry. 1991;29:575-84.

Ethical approval The Ethics Committee of Inonu University approved this study

16. Högl B. Circadian rhythms in restless legs syndrome. Sleep Med. 2006:7;20910.

Fatma Ebru Algul ORCID:0000-0003-0318-7571 Ayse Cikim Sertkaya ORCID:0000-0002-6068-8834 Sibel Altinayar ORCID:0000-0002-1126-0532

17. Early CJ, B Barker P, Horská A, et al. MRI-determined regional brain iron concentrations in early and late-onset restless legs syndrome. Sleep Med. 2006;7:458.

References

18. Allen R, Early C. Defining the phenotype of the restless legs syndrome using age-of-symptom-onset. Sleep Med. 2000;1:11-9.

Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special considerations and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4:101-19.

Garcia-Borreguero D, Odin P, Schwarz C. Restless legs syndrome: an overview of the current understanding and management. Acta Neurol Scand. 2004;109:303-17.

International Restless Legs Syndrome Study Group 2012. Revised diagnostic criteria. Available from http://irlssg.org/diagnostic -criteria/

Allen RP, Walters AS, Montplaisir J, et al. Restless legs syndrome (RLS) prevalence and impact: REST (RLS epidemiology, symptoms and treatment) general population study. Arch Intern Med. 2005;165:1286-92.

Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome. Sleep Med. 2004;5:385-91.

Takaki J, Nishi T, Nangaku M, et al. Clinical and psychological aspects of restless legs syndrome in uremic patients on hemodialysis. Am J Kidney Dis. 2003;41:833-9.

Allen RP. Controversies and challenges in defining the etiology and pathophysiology of restless legs syndrome. Am J Med. 2007;120:13-21.

Wang GJ, Volkow ND, Logan J, et al. Brain dopamine and obesity. Lancet. 2001;357:354-7.

Elwood P, Hack M, Pickering J, et al. Sleep Disturbance, stroke and heart disease events: evidence from the Caerphilly cohort. J Epidemiol. Community Health. 2006;60:69-73.

10. Hargens TA, Kaleth AS, Edwards ES, et al. Assosiation between sleep disorders, obesity and exercise: a review. Nat Sci Sleep. 2013;5:27-35.

19. Allen RP. Restless leg syndrome / Willis-Ekbom disease pathophysiology. Sleep Med Clin. 2015;10:207-14. 20. Zhao L, Zhang X, Shen Y, et al. Obesity and iron deficiency: a quantitative meta-analysis. Obes Rev. 2016:16;1081-93. 21. Wang GJ, Volkow ND, Logan J et al. Brain dopamine and obesity. Lancet. 2001;357:354-7. 22. Salas RE, Gamaldo CE, Allen RP. Update in restless legs syndrome. Curr Opin Neurol. 2010;23:401-6. 23. Concor JR, Wang XS, Allen RP, et al. Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Brain 2009;132:2403-12. 24. Kim J, Choi C, Shin K, et al. Prevalence of restless legs syndrome and associated factors in the Korean adult population: the Korean Health and Genome Study. Psychiatry Clin Neurosciç 2005;59:350-3. 25. De Vito K, Yanping L, Batool-Anwar S, et al. Prospective study of obesity, hypertension, high cholesterol and risk of restless legs syndrome. Mov Disord. 2014:29;1044-52. 26. Lin S, Zhang H, Gao T, et al. The assosiation between obesity and restless legs syndrome: A systemic review and meta-analysis of observational studies. J Affect Disord. 2018;235:384-91. 27. Yıldız D, Buyukkoyuncu N, Kilic A, et al. Obesity: a possible risk factor for restless legs syndrome. Neurol Res. 2017;39:1044-8. 28. Benediktsdottir B, Janson C, Lindberg E, et al. Prevalence of restless legs syndrome among adults in Iceland and Sweden: Lung function, comorbidity, ferritin, biomarkers and quality of life. Sleep Med. 2010;11:1043-8.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):106-8

Can number of platelets, blood red cell distribution, volume of neutrophil/lymphocyte ratio and mean platelet volume in patients with systemic lupus erythematosus and sjögren be used as an inflammation marker? Arif Gulkesen1, Nevzat Gozel2 Firat University, Faculty of Medicine, Department of Physical Medicine and Rehabilitation, Medical Faculty of Elazıg, Turkey 2 Firat University, Faculty of Medicine, Department of Internal Medicine, Medical Faculty of Elazıg, Turkey

Received 31 July 2018; Accepted 07 September 2018 Available online 09.10.2018 with doi:10.5455/medscience.2018.07.8902 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Sjögren’s syndrome (SS) and systemic lupus erythematosus (SLE) are autoimmune rheumatic diseases that can cause significant organ involvements. Hematological indices such as Platelet Count (PLT), Blood Red Cell Distribution Volume (RDW), Neutrophil/Lymphocyte Ratio (NLR), and Mean Platelet Volume (MPV) can be assessed by a simple haemogram test. These parameters may be related to the activity of the patient’s other diseases, such as cardiovascular diseases and inflammatory diseases. Our aim in this study is to demonstrate the possible association of hematologic markers such as PLT, RDW, NLR, MPV with the disease activity. 40 patients diagnosed with SS and 40 patients diagnosed with SLE followed in the physical medicine and rehabilitation and internal medicine rheumatology polyclinics and 40 healthy volunteers were included in the study. Laboratory findings were obtained from routine polyclinic controls. RDW, MPV, NLR ratios and platelet counts were calculated from the results of whole blood counts (CBC). RDW, MPV, NLR, and PLT were expressed as medians (minimum-maximum). Epidemiological data and RDW, MPV, NLR, PLT values of the cases included in the study were compared. Among the patients with SS and SLE, RDW, NLR and MPV values were higher than in the healthy control group. However, the elevation in the RDW was statistically significant while the height in the MPV and NLR was not statistically significant. Although studies with further patient participation are necessary, hematologic markers can be used in the diagnosis and follow-up of rheumatic diseases as they are both inexpensive and can be utilized extensively. Keywords: Sjögren’s syndrome, systemic lupus erythematosus, hematological indices

Introduction Systemic lupus erythematosus (SLE) is a connective tissue illness which afflicts many organs and systems with autoimmune features, along with chronic, unexplained, immunologic disorders [1]. The disease was diagnosed with findings from fever, swelling in joints, erythematous skin rashes to dysfunction in kidneys, central nervous system, lungs and other organs and systems. It is thought that the frequency of SLE is 15-40 / 100.000, depending on the specifications of the research group (age, sex, etc.) and duration of study-dependent changes [1]. Sjögren’s syndrome (SS) is an integral chronic disease defined by lymphocytic pervades in exocrine organs. The disease generally afflicts females and the average age at starting period is 50-60. Many people with Sjögren’s disorder also have the symptoms of sicca, for example xerophthalmia, xerostomia and parotid gland enlargement [2]. *Coresponding Author: Arif Gulkesen, Firat University, Faculty of Medicine, Department of Physical Medicine and Rehabilitation, Medical Faculty of Elazıg, Turkey E-mail: agulkesen@hotmail.com

Irregular immune arrangement and insistent inflammation, the certain features of chronic inflammatory disorders, have negative outcomes on hematopoietic system. Variations in peripheral blood cell elements are used to determine illness activity and to diagnose some collagen tissue illnesses for instance rheumatoid arthritis (RA) [3-5]. Rheumatic inflammatory illnesses afflict usually more than one cellular pathways of hematological system, and therefore, such common hematologic findings as anemia, neutropenia, thrombocytopenia and hematological malignancies are seen in such disorders. Those hematological abnormalities are because of many immunological and non-immune mediated systems. The reasons of hematologic abnormalities are overproduction of cytokines, antibodies, immune problems, growth factor defects, expansion of peripheral accumulation, low life span, declined neutrophil function, gastrointestinal troubles, drug-related toxicity [3-8]. SLE [6,7] and other inflammatory diseases [3,5,8-11] affect the amount, rate and volume of peripheral blood cells. Mean platelet volume (MPV) is a whole blood cell count (CBC) parameter. It shows the functionality and activity of platelets and is studied in a lot of inflammatory, cardiovascular, and cerebrovascular illnesses 106

doi: 10.5455/medscience.2018.07.8902

[3,6,8,10,12]. More granules exist in large platelets than small ones. These discharge prothrombotic components like thromboxane A2, serotonin, β-thromboglobulin and adenosine triphosphate, and influence inflammatory and endothelial functionalities. It involves the explanation of adhesion components like P-selectin and glycoprotein IIb / IIIa and rises vasoconstriction as well [10]. New studies have demonstrated that amount and rates of subgroups of the blood cell change in inflammatory rheumatic illnesses [5,6,11]. But, the affiliation between hematological indices and rheumatologic illnesses is still controversial [3-6,12-14]. We therefore aimed to investigate the possible association of changes in platelet (PLT) count, blood red cell distribution volume (RDV), Neutrophil / Lymphocyte ratio (NLR) and mean platelet volume (MPV) in people with SLE and SS with these two rheumatic inflammatory diseases. Material and Methods Forty SS, 40 SLE patients and 40 healthy volunteers who applied to the rheumatology polyclinic of Physical Medicine and Rehabilitation and Internal Medicine were included in the study [14-18]. Exclusion criteria of the study; Patients under 18 and over 80 years, patients with inflectional diseases, pregnancy, antiplatelet drugs like aspirin and clopidogrel, atherosclerotic diseases, dyslipidemia, diabetes mellitus and hypertension. This present research was accepted by local ethics committee and informed consent forms and permits were obtained from all participants before joining the study. Epidemiological data such as detailed stories, age, sex, and laboratory values of whole participants were routinely obtained from desired medical reports during the control. The numbers of RDW, MPV, NLR and PLT were calculated from full blood count results. Statistical analyzes were performed using the SPSS 22 program (SPSS, Chicago, Ill., USA). The results are shown as mean ±

Med Science 2019;8(1):106-8

standard deviation. Variables’ normal distribution was assessed by the Kolmogorov-Smirnov test and the crossover distributions (RDW, MPV, NLR and PLT number) were explained as median (minimum-maximum). Statistical differentiates between the groups were analyzed by one-way variance analysis (ANOVA) followed by Tukey’s post hoc test for parametric data, Kruskal-Wallis and post hoc Mann-Whitney U tests were valued as nonparametric. A χ2 test was used to compare categorical changes. Correlation analysis was done by using the Pearson correlation coefficient. P value <0.05 was granted significant. Results The demographic, laboratory and clinical findings of the participant groups included in the study are summarized in table 1. Of the total 120 individuals studied, 40 were healthy control groups, 40 were SS and 40 were SLE patients. Of the patients with SS diagnosis, 37 were female, 3 were male, 34 of SLE patients were female, 6 were male and 21 of the control group were women and 19 were men. Mean age of groups, SS, SLE and control groups were; 49.33±12.96; 40.65±10.23; 35.75±11.72 years. The disease duration of the patient groups was 8.5±5.8 for SS and SLE, respectively; 4.6±5.2 years. Body mass index (BMI) of SS, SLE and control groups were respectively; 25.4±5; 25.1±8.1; 27.4±4.8 kg/m2. RDW, MPV, NLR and PLT numbers were as follows. The results of RDW, MPV, NLR and PLT of patients with SS were 14.83±2%; 8.64±1.14; 2.3±0.83 and 269950.00±72527.60 /μL; The results of RDW, MPV, NLR and PLT in patients with SLE were 15.1±2.4%; 8.67±1.12; 2.72±1.49 and 268275.00±89160.18 /μL, while the results of RDW, MPV, NLR and PLT of the healthy control group were 13.59±0.95%, respectively; 8.28±0.74 μL; 2.28±1.6 and 272900.00±64202.32 /μL. The erythrocyte sedimentation rates (ESR) of Sjögren, SLE and control groups were 21, 38 and 15 mm/h; C reactive protein (CRP) values were respectively 0.40; 0,10; 0.30 mg/dl.

Table 1. Clinical and laboratory data in the study groups * CONTROL ( n = 40)

SJÖGREN ( n = 40)

SLE ( n = 40)

21/19

37/3c

34/6a

Age

35.75 ± 11.72

49.33 ± 12.96c

40.65 ± 10.23a,d

RDW, %

13.59 ± 0.95

14.83 ± 2b

15.1 ± 2.4c

MPV, fl

8.28 ± 0.74

8.64 ± 1.14

8.67 ± 1.12

NLR

2.28 ± 1.6

2.3 ± 0.83

2.72 ± 1.49

272900.00± 64.202.32

269950.00± 72527.60

268275.00± 89160.18

Sex (n)( Female/Male )

PLT, 103 / µL

RDW: Red blood cell distribution width, MPV: Mean platelet volume, NLR: Neutrophil/lymphocyte ratio, PLT: Platelet. * Values are given as mean±standard deviation. When compared with the control group: ap<0.05, bp<0.01, cp<0.001 When compared with the Sjögren group: dp<0.001

Discussion The proportion of women and men in the groups of SS and SLE patients that were taken into the study was much higher for women. This was due to the fact that both diseases were seen more in women. Mean age of healthy control group was close to patient groups’ mean age. The association of hematological markers with various diseases has been shown previously with different studies [19,20]. In a study by Zhi-De Hu and colleagues in patients diagnosed

with Primer Sjögren, RDW and NLR values were significantly higher than in the healthy control group [19]. It was also found that these elevations in the same study were related to disease activity [19]. In this study, RDW, NLR and MPV values were also higher in patients with both Sjögren and SLE in comparison with the healthy control group. However, the elevation in the RDW was statistically significant while the height in the MPV and NLR was not statistically significant. Besides, the number of PLTs in our patients with SLE and Sjögren is lower than in the healthy control 107

doi: 10.5455/medscience.2018.07.8902

group. This decrease was not statistically significant. These data were consistent with previous studies [19]. Our current findings suggest that MPV, RDW, PLT numbers and NLR may be used as an inflammatory marker. In another study conducted by Demircan et al., RDW and NLR values of patients with major depression were found to be inevitably higher than the healthy control group [20]. It is the opinion that hematological markers present in the light of these data can be used not only as an inflammatory marker but also in the diagnosis and follow-up of various diseases. In a study by Sun-Yi Chen et al., Patients who were followed-up with SLE diagnosis were split into active and inactive groups, and their hematological indices were compared [21]. In this study, the platelet count of those with active disease was found to be lower than statistically meaningful (p = 0.003). However, when MPV values were examined, there was no statistical significance between active groups and inactive ones (p = 0.21). In this present study, also, the PLT counts of the patient groups were lower than those of the healthy control group. However, these decreases were not statistically significant. A statistically significant correlation also couldn’t be found between the ESR and CRP values of this present study and the hematological markers. These findings indicate that hematological markers can be used not only in diagnosis of the illness but also in the tracing of their activities. One of the limitations of the study is that the markers studied on are not correlated with disease activity scores. Another limitation is that the patient numbers are low. Conclusion As a result; in this present study, it is found that in groups with SS and SLE, RDW, MPV and NLR values were lower than those of healthy control group. The data that have been obtained through the study suggest that hematological markers which are inexpensive in the health centers and which can be taken care of in almost every health center can be used for diagnosis and follow-up of many diseases, especially inflammatory diseases. On the other hand, this study needs to be supported by studies in which larger patient groups are involved. Limitations There are some limitations in our study. The fact that the markers we work with are not correlated with disease activity scores, it is a cross-sectional research and the count of the patient group is small. The number of women in the SS and SLE patient groups we included in the study was higher than the number of men. The reason for this is that the patients we follow are predominantly female and that SLE and SS are more common in females than males. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves.

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Saunders Company. 1997;1015-56. 2.

Rischmuller M, Tieu J, Lester S. Primary Sjögren’s Syndrome. Best Pract Res Clin Rheumatol. 2016;30:189-220.

Kısacık B, Tufan A, Kalyoncu U, et al. Mean platelet volume (MPV) as an inflammatory marker in ankylosing spondylitis and rheumatoid arthritis. Joint Bone Spine. 2008;75:291-4.

Yazıcı S, Yazıcı M, Erer B, et al. The platelet indices in patients with rheumatoid arthritis: mean platelet volume reflects disease activity. Platelets. 2010;21:122-5.

Mercan R, Bitik B, Tufan A, et al. The association between neutrophil/ lymphocyte ratio and disease activity in rheumatoid arthritis and ankylosing spondylitis. J Clin Lab Anal.

2016;30(5):597-601

Şafak S, Uslu AU, Serdal K, et al. Association between mean platelet volume levels and inflammation in SLE patients presented with arthritis. Afr Health Sci. 2014;14:919-4.

Qin B, Ma N, Tang Q, et al: Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) were useful markers in assessment of inflammatory response and disease activity in SLE patients. Mod Rheumatol. 2016;26:372-6.

Soydinç S, Türkbeyler IH, Pehlivan Y, et al. Mean platelet volume seems to be a valuable marker in patients with systemic sclerosis. Inflammation. 2014;37:100-6.

10. Canpolat F, Akpınar H, Eskioğlu F. Mean platelet volume in psoriasis and psoriatic arthritis. Clin Rheumatol. 2010;29:325-8. 11. Açikgöz N, Karıncaoğlu Y, Ermiş N, et al. Increased mean platelet volume in Behcet’s disease with thrombotic tendency. Tohoku J Exp Med. 2010;221:119-23. 12. Rifaioğlu EN, Bülbül Şen B, Ekiz O, et al. Neutrophil to lymphocyte ratio in Behcet’s disease as a marker of disease activity. Acta Dermatovenerol Alp Pannonica Adriat. 2014;23:65-7. 13. Azab B, Torbey E, Singh J, et al: Mean platelet volume/platelet count ratio as a predictor of long-term mortality after non-ST-elevation myocardial infarction. Platelets. 2011;22:557-66. 14. Oehadian A, Suryadinata H, Dewi S, et al. The role of neutrophyl lymphocyte count ratio as an inflammatory marker in systemic lupus erythematosus. Acta Med Indones. 2013;45:170-4. 15. Yazıcı S, Yazıcı M, Erer B, et al. The platelet functions in patients with ankylosing spondylitis: anti-TNF-α therapy decreases the mean platelet volume and platelet mass. Platelets. 2010;21:126-31. 16. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40:17-25. 17. Masi AT. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum. 1980;23:581-90. 18. Weichsler B, Davatchi F, Mizushima Y, et al. Criteria for diagnosis of Behcet’s disease. Lancet. 1990;335:1078-80. 19. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69:1580-8.

Ethical approval This present research was accepted by local ethics committee and informed consent forms and permits were obtained from all participants before joining the study.

20. Zhi-De Hu, Yi Sun, Jie Guo, et al. Red blood cell distribution width and neutrophil/lymphocyte ratio are positively correlated with disease activity in primary Sjögren’s syndrome. Clinical Biochemistry. 2014;47:287-90.

Arif Gulkesen ORCID: 0000-0002-3008-7333 Nevzat Gozel ORCID: 0000-0001-7326-6860

21. F. Demircan F, Gözel N, Kılınç F, et al. The impact of red blood cell distribution width and neutrophil/lymphocyte ratio on the diagnosis of major depressive disorder. Neurol Ther. 2015;5:27-33.

Reference 1.

Hahn B H. Systemic lupus erythematosus and related syndromes. In: Kelly WN, Harris ED, Ruddy S, Sledge CB, eds, Text-book of Rheumatology: WB

22. Sun-Yi Chen, Juan Du, Xiao-Nian Lu, et al. Platelet distribution width as a novel indicator of disease activity in systemic lupus erythematosus. J Res Med Sci. 2018;23:48.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):109-12

Assessment of vitamin D level in Hashimoto thyroiditis in Turkish population Banu Sarer Yurekli1, Ezgi Bellikci Koyu2, Hatice Ozisik1, Dilek Ongan2, Gokhan Ozgen1 1

Ege University Faculty of Medicine, Deaprtment of Endcorinology, Izmir, Turkey 2 Katip Celebi University, Department of Nutrition and Dietetics, Izmir, Turkey Received 03 September 2018; Accepted 09 September 2018 Available online 28.09.2018 with doi:10.5455/medscience.2018.07.8883 Copyright © 2019 by authors and Medicine Science Publishing Inc.

Abstract The aim of this study was to assess vitamin D serum levels in autoimmune thyroid disease, Hashimato thyroiditis in the Turkish population. The subjects with Hashimato thyroiditis (HT, n=67, mean age 45.1±10.9,F/M-61/6), control subjects (mean age 42.1±15.7, n=29, F/M-26/3) were recruited for the study. Thyroid function tests, thyroid antibodies (AntiTg, AntiTPO, TSHRAb), ultrasound features, demographic and antropometric variables were recorded. Vitamin D level was not different between the HT and the control groups (53.1±24.7 nmol/L and 54.1±19.8 nmol/L, as mean, respectively, p = 0.482) In the HT group, 35.8% of subjects had vitamin D insufficiency, only 16.4% of subjects with HT were vitamin D sufficient. There was no significant difference between the HT and the control groups according to the vitamin D classification status (p = 0.666). Vitamin D levels were significantly higher in the subjects who were taking replacement compared to subjects who were not (58.7 ± 26.0 vs. 46.0 ± 23.3, as mean, respectively, p = 0.033). There was no significant correlation between vitamin D levels and TgAb and TPOAb levels in HT group (p = 0.754 r = -0.039, p = 0.134 r = -0.290, respectively). In both HT and control groups, vitamin D levels were significantly correlated only with the fT4 levels (p <0.001 r = 0485, p =0.02 r = 0.428, respectively). Vitamin D level was not different significantly between HT and control groups. Further studies are needed to enlighten the relationship between HT and vitamin D. Keywords: Vitamin D, Hashimoto thyroiditis, Thyroid function tests

Introduction Vitamin D is a pro-hormone which is converted to 25-hydroxy vitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D). It functions by binding to vitamin D receptors (VDRs). Vitamin D produced in the skin has also non-skelatal effects on autoimmune diseases, cardiovascular diseases, infectious diseases, cancers beside skelatal effects [1-3]. Epidemiological studies showed association between vitamin D deficiency and some autoimmune diseases like type 1 diabetes, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erthymatosus [3]. Pathogenesis of Hashimoto thyroiditis (HT) is multi-factorial in which there are genetic, environmental and immune factors. In recent years, vitamin D was thought as a contributing factor for autoimmune thyroid disease development. In HT, there is a shift in the balance between type 1 T helper (Th1) and type 2 T helper (Th2) immune response in favor of Th1-cell-mediated autoimmune *Coresponding Author: Banu Sarer Yurekli, Ege University Faculty of Medicine, Deaprtment of Endcorinology, Izmir, Turkey E-mail: bsareryurekli@yahoo.com

reaction resulting in thyrocyte destruction [4]. 1.25(OH)2D vitamin inhibits Th1 cell proliferation [5].While some studies in the literature have shown the association between vitamin D deficiency and thyroid autoimmunity [6-10], several other studies have not shown this association [5,10]. So, literature data has conflicting results about the association between vitamin D deficiency and HT. Our aim was to investigate vitamin D levels in patients with HT in Turkish population and correlation of vitamin D levels with thyroid function and thyroid autoantibodies. Material and Methods The subjects with HT(n=67, mean age 45.1±10.9, F/M=61/6) and control subjects matched with age and sex (mean age 42.1±15.7, n=29, F/M=26/3) were recruited for the study during OctoberNovember 2016. Local ethical approval was obtained from Ege University Ethics Committee. All subjects had given oral and written informed consent for the study. The subjects whose ages were between 18-75 were taken for the study. Hashimoto thyroidits (HT) was diagnosed according to the presence of antibody positivity for thyroglobulin antibody (TgAb) and/or for thyroid-peroxidase antibody (TPOAb) or both of them. 109

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The control group consisted of the subjects who didn’t have HT and were negative for TgAb and TPOAb. All subjects have normal thyroid function tests. Besides thyroid antibodies (TgAb, TPOAb) and thyroid function tests, ultrasound features, thyroid volume, anthropometric variables were also recorded. Thyrotropin stimulation hormone (TSH) was accepted as normal for the reference range of 0.35-5.5 µIU/mL. TgAb was positive above 60 IU/mL, TPOAb was positive above 60 IU/mL. The reference range for free thyroxine (fT4) was 0.89-1.76 ng/dL and for free triiodotyronine (fT3) was 2.3-4.2 pg/mL. Thyroid function and thyroid autoantibodies were evaluated with chemiluminescence immunoassays. Exclusion criteria were as follows: any malabsorptive disease causing vitamin D deficiency, chronic renal failure, chronic hepatic failure, usage of oral contraceptives and antiepileptic medications, vitamin D replacement. The serum 25(OH)D concentration was determined by using commercial chemiluminescence immunoassays (Roche diagnositcs). Vitamin D was accepted as sufficient if the vitamin D level was ≥ 75 nmol/L. Vitamin D deficiency was defined as vitamin D ≤ 50 nmol/L, insufficiency was defined if vitamin D level was between 51-74 nmol/L. Statistical analysis was performed by using IBM Statistical Package of Social Science (SPSS Inc, USA) version 21.0 for Mac. Shapiro-Wilk test was used to check the normality assumption of the continuous variables. Student’s t test or Mann-Whitney U test was used for comparison of two independent groups. Categorical variables were compared by the Chi-square test. Correlation analyses were performed using Spearman’s correlation coefficient. A p-value of less than 0.05 was accepted as statistically significant. Results Vitamin D level was not different between the HT and the control groups as shown in Table 1 (53.1±24.7 nmol/L and 54.1±19.8 nmol/L, as mean, respectively, p=0.482) The groups were not different regarding fT3 and fT4 levels (p = 0.133 and p = 0.410, respectively). TSH level was significantly higher in the HT group compared to the control group (2.5 ± 1.7 vs. 1.6 ± 1.0, as mean, respectively, p = 0.024). TgAb and TPOAb levels were significantly higher in the HT group (73 IU/mL and 339 IU/mL, as median, respectively) (Table 1). In the HT group, 35.8% of subjects had vitamin D insufficiency, 47.8% of subjects had vitamin D deficiency. Only 16.4% of subjects with HT were vitamin D sufficient. In the control group, 20.7% of subjects were vitamin D sufficient, 41.4% of subjects had vitamin D insufficiency, 37.9% of the subjects had vitamin D deficiency. There was no significant difference between the HT and the control groups according to the vitamin D classification status (p = 0.666). Significant difference was also not observed between the HT and the control groups regarding vitamin D classification status according to gender (p = 0.269) (Table 2). When all the subjects in the study group were categorized according to vitamin D levels as vitamin D level≤50 nmol/L and >50 nmol/L, fT4 level was significantly higher in the subjects whose vitamin D level was >50 nmol/L compared to subjects whose vitamin D level was ≤50 nmol/L (Table 3). TgAb and TPOAb levels were

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higher in the subjects with vitamin D level ≤50 nmol/L although this difference didn’t reach statistical significance (p = 0.050 and p = 0.325, respectively). When the subjects with HT were grouped according to the levothyroxine replacement status as shown in Table 4, vitamin D levels were significantly higher in the subjects taking replacement compared to subjects not taking (58.7 ± 26.0 vs. 46.0 ± 23.3, as mean, respectively, p = 0.033). There was no significant correlation between vitamin D levels and TgAb and TPOAb levels in HT group (p = 0.754 r = -0.039, p = 0.134 r = -0.290, respectively). No correlation between vitamin D and either TgAb or TPOAb levels was observed in the control group (Table 5). In both HT and control groups, vitamin D levels were significantly correlated only with the fT4 levels (p<0.001 r = 0485, p=0.02 r = 0.428, respectively). Table 1. Demographic and laboratory varaibles in the Hashimoto thyroiditis and the control groups Variables Age Gender (F/M) BMI (kg/m2) fT3 (pg/mL) fT4 (ng/dL) TSH (µIU/mL) TgAb (IU/mL) TPOAb (IU/mL) Vitamin D (nmol/L)

HT 45.1 ± 10.9 61/6 29.7 ± 6.4 2.9 ± 0.3 1.1 ± 0.1 2.5 ± 1.7 73 (14-501) 339 (27-1301) 53.1 ± 24.7

Control 42.1 ±15.7 26/3 29.2 ± 5.1 3.1 ± .0.4 1.1 ± 0.2 1.6 ± 1.0 14(14-20.6) 49 (27-59) 54.1 ± 19.8

p value* 0.322 0.830 0.702 0.133 0.410 0.024* 0.000* 0.000* 0.482

BMI,body mass index; fT3, free triiodothyronine; fT4, free thyroxine; TSH, thyrotroph stimulating hormone; TgAb, thyroglobulin antibody; TPOAb, thyroidperoxidase antibody. Table 2. Percent frequencies of vitamin D classification in the Hashimoto thyroiditis and the control groups according to the gender Vitamin D classification Sufficient ( Vitamin D ≥75 nmol/L) Insufficient (Vitamin D 51-74 mol/L) Total p value p value total HT, Hashimoto thyroiditis

Female

9 14.8% 31 50.8% 100%

Male 2 33.3% 1 16.7% 100%

0.240

0.269

Control Female Male 5 1 19.2% 33.3% 10 1 38.5% 33.3% 100% 100% 0.848

Table 3. Demographic and laboratory variables in subjects with vitamin D ≤50 nmol/L anvitamin D >50 nmol/L Variables Age BMI (kg/m2) fT3 (pg/mL) fT4 (ng/dL) TSH (µIU/mL) TgAb (IU/mL) TPOAb (IU/mL) Thyroid volume HT (%) Vitamin D (nmol/L)

Vitamin D ≤50 nmol/L n=42 41.8 ± 11.9 30.6± 6.4 3.05± 0.46 1.04± 0.19 2.29± 1.56 40.9 (14-501) 114.6 (27-1301) 11.5± 10.4 74.4 31.2± 8.7

Vitamin D >50 nmol/L n=54 46.0 ±12.7 28.8± 5.6 3.03± .0.38 1.19± 0.17 1.99± 1.56 17.0 (14-501) 59.4 (27-1301) 11.0± 8.4 66.0 71.2± 18.9

p value* 0.102 0.236 0.757 <0.001* 0.296 0.050 0.325 0.756 0.374 <0.001*

BMI, body mass index; fT3, free tririodothyronine; fT4, free thyroxine; TgAb, thyroglobulin antibody; TPOAb, thyroid peroxidase antibody; HT, Hashimoto thyroiditis. p<0.05 was accepted as statistically significant

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doi: 10.5455/medscience.2018.07.8883 Table 4. Demographic and laboratory variables in subjects with Hashimoto thyroiditis according to levothyroxine replacement status Variables Age BMI (kg/m2) fT3 (pg/mL) fT4 (ng/dL) TSH (µIU/mL) TgAb (IU/mL) TPOAb (IU/mL) Thyroid volume Vitamin D (nmol/L)

HT Levothyroxine replacement present

HT Levothyroxine replacement absent

47.4± 9.7 29.6± 6.2 2.87± 0.33 1.17± 0.17 2.49± 1.88 90.8 (14-501)

42.5 ±11.6 29.9± 6.7 3.14± .0.43 1.10± 0.17 2.23± 1.52 20.7 (14-501)

0.066 0.370 0.010* 0.078 0.807 0.020*

631.4 (27-1301)

112.4 (27-1301)

0.090

8.2± 3.6 58.7± 26.0

13.7± 11.9 46.0± 23.3

0.065 0.033*

p value*

BMI, body mass index; fT3, free tririodothyronine; fT4, free thyroxine; TgAb, thyroglobulin antibody; TPOAb, thyroid peroxidase antibody. p<0.05 was accepted as statistically significant Table 5. Spearman correlation analysis for vitamin D in the Hashimoto thyroiditis and the control groups Independent variables

HT group

Control group r p

Age

0.205

0.096

0.212

0.270

BMI fT3 fT4 TSH TgAb TPOAb

-0.197 0.089 0.485 0.021 -0.039 -0.033

0.110 0.471 <0.001* 0.866 0.754 0.789

0.096 -0.156 0.428 -0.270 -0.290 -0.123

0.621 0.448 0.020* 0.156 0.134 0.534

Thyroid volume

0.025

0.844

0.199

0.309

Spearman correlation analysis was used. r stands for correlation coefficient. * p <0.05 was considered significant. HT, Hashimoto thyroiditis; BMI, body mass index; fT3, free tririodothyronine; fT4, free thyroxine; TgAb, thyroglobulin antibody; TPOAb, thyroid peroxidase antibody.

Discussion Our study showed that vitamin D levels were not significantly different in HT group compared to the control group. There was no correlation between vitamin D levels and antithyroid antibodies. Vitamin D levels were significantly higher in the HT subjects taking levothyroxine replacement compared to HT subjects who are not taking. Kivity et al. [6] showed that vitamin D deficiency was higher in autoimmune thyroid patients (both HT and Graves’ disease) and association between vitamin D deficiency and antithyroid antibodies and thyroid function tests. Bozkurt et al. [7]. figured out that vitamin D levels were lower in chronic HT patients taking thyroxine replacement than newly diagnosed HT patients without thyroxine replacement and than the control subjects. They showed that vitamin D levels were positively correlated with thyroid volume and negatively correlated with TPOAb and TgAb levels. Female subjects with HT had lower vitamin D levels compared to the male HT patients in the study of Bozkurt et al. [7]. We have not found any significant difference between the HT and the control groups as far as vitamin D levels are concerned. Moreover, vitamin D levels were not different between the HT and the control groups regarding the gender in our study. Bozkurt et al. [7] hypothesized that levothyroxine may change the metabolism of vitamin D based on the finding referring to low vitamin D levels in HT subjects who

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were taking levothyroxine compared to the new onset HT subjects without levothyroxine replacement. On the other hand, we showed that vitamin D levels were higher in HT subjects who were taking levothyroxine replacement compared to HT subjects who were not. Besides, fT4 levels were significantly higher in the subjects who had vitamin D levels greater than 50 nmol/l compared to ones with vitamin D levels with ≤50 nmol/L. In opposition to the suggestion of Bozkurt et al. [7], we may speculate that serum T4 may be influencing the absorption of vitamin D level in a positive way. Vitamin D deficiency may be occurring as a consequence of the disease process. Another study showing association between vitamin D deficiency and HT by Kim et al. [11] depicted that HT subjects with overt hypothyroidism had a significantly higher rate of vitamin D insufficiency compared with euthyroid and subclinically hypothyroid and the control subjects who had no autoimmune thyroid disease. They suggested the association between vitamin D deficiency and thyrocyte damage leading to thyroxine replacement. On the contrary to those studies, Yasmeh et al. [12] showed that vitamin D levels were not different in the HT group compared to control group. They observed that female subjects with HT had a higher rate of vitamin D sufficiency and lower rate of vitamin D insufficiency compared to the control female subjects as opposed to the other studies carried out in Hungary and Turkey [6,7,9]. In the study of Yasmeh [12], vitamin D levels didn’t differ between male HT and male control subjects. According to those results, sex could be a confounding factor affecting vitamin D levels in HT but in our study vitamin D insufficiency and deficiency didn’t differ between the HT and the control groups when sex was taken into statistical analysis. In the study of Tamer et al. [9], 92% of the HT cases had vitamin D insufficiency, while the control group had 63% vitamin D insufficiency which was statistically significant. In the HT group, there was no significant difference regarding to vitamin D levels in HT subjects with overt hypothyroidism, subclinical hypothyroidism and euthyrodism. Yasmeh et al. [12] mentioned that vitamin D sufficiency rate was high in their HT group. In the other studies showing association between vitamin D deficiency and HT, the rate of vitamin D deficiency was higher. Yasmeh et al. [12] suggested that having higher rate of vitamin D sufficiency in their study may be leading to more accurate statistical results. Another study from Turkey showed that vitamin D levels were 19.4 ng/mL in the HT group and were 22.5. ng/mL in the control group pointing to the significant difference [13]. Unal et al. [13] also figured out that vitamin D levels were inversely correlated with TgAb and TPOAb levels. Small number of subjects and being cross-sectional study were limitations of our study. Since we recruited the study subjects in the October and November, it could be thought that seasonal variation had been ruled out. Conclusion To the best of our knowledge, our study was the first one in the literature regarding to Turkish population showing that HT was not associated with vitamin D deficiency. There was no significant difference for vitamin D levels between the HT and the control group. There was no correlation of vitamin D levels with thyroid antibodies. It is not clear whether there is association with vitamin 111

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D insufficiency and HT. Since vitamin D deficiency is common for most of the countries, findings regarding the association could be just a coincidence. Further studies are needed to clarify the relationship of vitamin D with the development of HT.

Med Science 2019;8(1):109-12

in autoimmune thyroid diseases. Neuroimmunomodulation. 2008;15:68-75. 5.

D’Aurizio F, Villalta D, Metus P, et al. Is vitamin D a player or not in the pathophysiology of autoimmune thyroid diseases? Autoimmun Rev. 2015;14:363-9

Competing interests The authors declare that they have no competing interest

Kivity S, Agmon-Levin N, Zisappl M, et al. Vitamin D and autoimmune thyroid diseases. Cell Mol Immunol. 2011;8:243-7.

Financial Disclosure The financial support for this study was provided by the investigators themselves.

Ethical approval Before the study, permissions were obtained from local ethical committee.

Bozkurt NC, Karbek B, Ucan B, et al. The association between severity of vitamin D deficiency and Hashimoto’s thyroiditis. Endocr Pract. 2013;19:47984.

Banu Sarer Yurekli ORCID: 0000-0003-1809-2655 Ezgi Bellikci Koyu ORCID: 0000-0001-5279-2394 Hatice Ozisik ORCID: 0000-0003-0533-3100 Dilek Ongan ORCID: 0000-0003-0531-1230 Gokhan Ozgen ORCID: 0000-0003-0533-3122

Shin DY, Kim KJ, Kim D, et al. Low serum vitamin D is associated with anti-thyroid peroxidase antibody in autoimmune thyroiditis. Yonsei Med J. 2014;55:476-81.

Tamer G, Arik S, Tamer I, et al. Relative vitamin D insufficiency in Hashimoto’s thyroiditis. Thyroid. 2011;21:891-6.

References 1.

Makariou S, Liberopoulos EN, Elisaf M, et al. Novel roles of vitamin D in disease: What is new in 2011? Eur J Intern Med. 2011;22:355-62.

Plum LA, DeLuca HF. Vitamin D, disease and therapeutic opportunities. Nat Rev Drug Discov. 2010;9:941-55.

Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-81.

Klecha AJ, Barreiro Arcos ML, Frick L, et al. Immune-endocrine interactions

10. Mazokopakis EE, Kotsiris DA. Hashimoto’s autoimmune thyroiditis and vitamin D deficiency. Current aspects. Hell J Nucl Med. 2014;17:37-40. 11. Kim D. Low vitamin D status is associated with hypothyroid Hashimoto’s thyroiditis. Hormones (Athens). 2016;15:385-93. 12. Yasmeh J, Farpour F, Rizzo V, et al. Hashimoto thyroiditis not associated with vitamın D deficiency. Endocr Pract. 2016;22:809-13. 13. Unal AD, Tarcin O, Parildar H, et al. Vitamin D deficiency is related to thyroid antibodies in autoimmune thyroiditis. Cent Eur J Immunol. 2014;39:493-7.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):113-6

Factors affecting selection of anesthesia type in elective cesarean operations and pregnant preferences for anesthesia outcome Baris Arslan, Nilgun Kavrut Ozturk, Zinet Asuman Arslan Onuk, Bilge Karsli Antalya Training and Research Hospital, Department of Anesthesia and Intensive Care, Antalya, Turkey Received 19 July 2018; Accepted 10 September2018 Available online 08.11.2018 with doi:10.5455/medscience.2018.07.8924 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The aim of study is to determine the factors having an effect on the selections of anesthesia type for the pregnant. The research was performed on 274 female patients, who applied to Antalya Research Training and Research Hospital within a 2-months period. Firstly, the pregnants were asked for their sociodemographic attributes, obstetric histories, fears and anesthesia preferences in the survey. Secondarly, the outcomes that they desire to avoid was evaluated by describing the most frequently seen nine outcomes related to anesthesia. The rate of selecting general anesthesia was 64.2% while the regional anesthesia rate was 35.8%. An increase in the choice of regional anesthesia was observed as the level of education and income increased. Anesthetist and gynecologist have shown favorable contributions to the selection of regional techniques of pregnants. In our study, the cognitive dysfunction was the least desired outcome. The physicians’ recommendations were seen as the most important factor of directing the patients to select the regional anesthesia. Keywords: Cesarean, patient prefrence, cognitive dysfunction

Introduction The most important intervention is cesarean in the obstetric surgery and has an increasing incidence. While the cesarean rate identified by the World Health Organization (WHO) were minimum 5% and maximum 15%; this rate was 27.3% in America, 41% in India, 22.8% in Nigeria and 37% in Turkey in 2002 [1,2]. The regional anesthesia methods used for the cesarean operation differ according to the institutions as mentioned in the studies performed in our country. Tore et al. determined that the regional anesthesia rates increased from 15.3% in 1998 to 36.1% in 2005 when they reviewed the anesthesia applications for their studies containing 51 hospitals [3]. While rate incrases are drawn attention to the regional anesthesia preferences, there are also differences in private hospitals, university hospitals and state hospitals [3]. Despite the low rate in Turkey, this ratio is 84 % in the UK and % 95-97 in the USA [4]. Development of the obstetric anesthesia as a fellowship and establishment of epidural services significantly decrease the maternal mortality related to anesthesia. The obstetric anesthesia’s *Coresponding Author: Zinet Asuman Arslan Onuk, Antalya Training and Research Hospital, Department of Anesthesia and Intensive Care, Antalya, Turkey E-mail: asumanonuk@hotmail.com

reliability increased by the development of the epidural anesthesia application services and increment of the regional applications, and maintaining the prevalence of these services is suggested [4]. The factors being effective should be firstly determined in the selection of patients’ anesthesia preferences to increase the regional anesthesia rates used in the cesarean operations in our country. We investigated factors affecting the selection of anesthesia type for cesarean delivery. As a secondary aim, we tried to find out that the pregnant women want to avoid the most common outcome associated with the anesthesia. Also, whether anesthesia related outcome pregnants wanted to avoid were an effect on the choice of anesthesia type were also examined. Material and Methods After the ethics committee approval number:54, from the beginning of October to the end of November 2012 within 2 months interval, 274 women undergoing elective cesarean surgery who agreed to participate in the study were included in the study. Due to the ethical values, patients who have stillbirth or abortion history and need the emergent operations were excluded from the study.

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doi: 10.5455/medscience.2018.07.8924

Formation of Survey The survey consists of 4 sections. 1st Section: It contains the socio-demographic characteristics and medical history. The patients’ name, surname, age, education status, income level, previous pregnancy number, smoking, operation history, previous anesthesia experience and anesthesia related outcomes were asked. 2nd Section: The patients were asked for what anesthesia method they preferred. The effect of healthcare personnel, anesthetist, gynecologist, relative, TV, radio, Internet and book was asked for their anesthesia type choice. 3rd Section: The patients anesthesia related phobias were asked; hearing the surgical noises and seeing something during the surgery, headache anxiety, low back pain anxiety, fear of paralysis. 4th Section: Outcomes. It is necessary here to clarify exactly what is meant by anesthesia outcome; anesthesia related unexpected death or complication during surgery or after the surgery [5]. 10 most common anesthesia related outcome were explained and defined to the pregnants. Each outcome was given together with their explanations constituted in such a way that the patients could easily understand them and occurred by 10 to 25 words with the survey form. Firstly, the patients were asked to order 10 outcomes backwards by giving number from 10 to 1 they wanted to avoid from the most to least. Thus, ranking value of each outcome was formed. Then, the patients were asked to imagine they had 100 TL (Turkish Lira) only they could spend to avoid outcome. Patients were asked to spend all their money imagining that the outcome they were spending more money was less likely to be encountered. 4 outcomes of general anesthesia and 4 outcomes of regional anesthesia were formed as follows. Pubmed, Google Academic, Turkish Anesthesiology and Reanimation Journal Archive were searched with. The words of “outcome, adverse, side effect and complication’’ were searched with‘’general anesthesia and regional anesthesia’’ in Pubmed, Google Academic, Turkish Anesthesiology and Reanimation Journal Archive. 23 of 122 articles were accepted for evulation. Some of them were mentioned in the references section. The most common anesthesia related outcomes were determined by using 23 articles for each anesthesia type. The most encountered outcomes with the regional anesthesia were headache, low back pain, nausea-vomiting, itching and urinary retention. The most encountered outcomes with the general anesthesia were throat ache, nausea, vomiting, sleepiness and shivering. Although all the side effects could be seen both in two anesthesia types, while the most frequent four side effects seen during the regional anesthesia included in the regional group, the most frequent four side effects seen during the general anesthesia were taken into the general group. The nausea and vomiting were included in the general anesthesia group, as they were in the highest position in the general anesthesia group. The cognitive dysfunction was added to these 8 possible side effects due to experiencing the similar incidences of the general and regional anesthesia. Statistical Analysis The SPSS 16 program was used in the statistical analysis. The data

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was stated as the mean±standard deviation. While T-test was used in the data suitable for the normal distribution when comparing the mean values, the Mann Whitney U test and Kruskal-Wallis H tests were used for the others. The monetary and ranking values were evaluated by the Pearson correlation. The Chi-square and Fishers Exact tests were used while comparing the percentages. The p values less than 0.05 were considered statistically significant. The income level was categorized based on the data onto the Confederation of Workers’ Trade Unions. It was accepted that the lowest income level was as the hunger threshold, the middleincome level was as the poverty threshold and higher income level was as those having an income over the poverty level. Results During 2 months period , 274 patients were studied and their reponses were analyzed. The sociodemographic deatails were shown in Table 1. The participants’ mean age was 28.12 ± 5.5. After one patient who did not remember the previous anesthesia type was dropped; 23.1% of the pregnant (n=63) did not have any anesthesia experience previously, Whereas 5.5% of them (n=15) experienced both type anesthesia experience. Only one type of anesthesia experience was found as 71.4% (n=195). However, 64.2% of the pregnant (n=176) had a cesarean operation before. Table 1. Socioeconomic characteristics of the pregnants Age (years) Monthly income in local currency

28.12± 5.5 ( TL† /month )

1398.8±953.7

< 960TL

29.6

960-3124TL

65.7

> 3124TL

5.5

(years)

7.9± 4.0

< 9yıl

61.3

9-10-11yıl

> 12yıl

14.6

Education Level

† Turkhish Lira

While 64.2% of the pregnant (n=176) preferred the general anesthesia for the operation, 35.8% of them (n=98) preferred one of the regional anesthesia methods. While 68.7% of the pregnant (n=138, p=0.011) having the general anesthesia experience preferred the general anesthesia again, selecting one of the regional anesthesia methods of 76% of them (n=19, p=0.000) having the regional anesthesia experience were statistically found significant. When considered the pregnant experienced both the anesthesia methods previously, the selection rate of regional anesthesia method was observed higher (66.7% against 33.3%, p= 0.011). The rise of regional anesthesia preference rates was statistically found significant with increasing the income level (p=0.06). Preferring the regional anesthesia technique much more was statistically found significant with increasing the education level (p=0.003). Compared to media (TV, radio, newspaper, internet), anesthetists and gynecologists has a higher effect on the pregnant’ prefrence of regional anesthesia (p=0.001). The other physicians, spouse, friend, relative, auxiliary healthcare personnel, midwife and nurse did not have a statistically significant effect in the anesthesia type 114

doi: 10.5455/medscience.2018.07.8924

preference. Fear of seeing and hearing something, fear of being paralyzed, loss of control and pain during needle at the back were the fears that lead patients to choose more general anesthesia (p < 0.05). 76.6% of the patients (n=203) participating in the survey think that the anesthesia type they selected was more healthy. 89.4% of the patients (n=84) selecting the regional anesthesia type think that the regional anesthesia type they selected was more healthy rather than the general anesthesia. The efficacy of outcome in choosing the type of anesthesia of the patients was statistically insignificant. However, the most scarring outcomes of patients participating in our survey were the cognitive dysfunction, nausea-vomiting and urinary retention; the cognitive dysfunction, low back pain and headache were the outcome that they want to avoid by spending more money. A positive correlation was found between the monetary values and ranking values of all the outcomes (Table 2). Table 2. The amount of money to be paid to avoid outcome Ranking Value (median)

Monetary Value (mean)

Pearson coefficient

No side effect

0.4± 1.9

0.098

0.108

Throat ache

5.6± 12.56

0.588

0.000*

Sleepiness

6.12± 14.90

0.472

0.000*

Itching

4.28± 7.93

0.489

0.000*

Shivering

4.60± 8.74

0.567

0.000*

Backache

17.96± 22.06

0.625

0.000*

Headeche

15.90± 21.15

0.586

0.000*

Urinary retention

10.01± 15.57

0.526

0.000*

Nausea and vomiting

13.9± 17.85

0.567

0.000*

Cognitive dysfunctions

20.81± 31.25

0.667

0.000*

Outcome

*p < 0.05

Discussion The results of this study indicate that anesthesiologist, gynecologist, increased education level and income level are the main factors that affect the choice of regional anesthesia. The findings of the current study are consistent with those of Idil (2005) showed that the gynecologist and anesthetist were effective in selecting the regional anesthesia methods in their retrospective studies [6]. In our study, the rate of preferring the regional anesthesia methods was 35.2%. When considering the literature, while the regional anesthesia preference rates showed a parallelism as 36.1% being turkey average. it was still under the regional anesthesia selection rates that developed countries had as 84% to 97% [3,4]. Mitchell at al reported that, the rate of regional anesthesia selection increases as education level increases [7]. Factors found to be influencing patients’ regional anesthesia prefrence have been explored in several studies [7,8] The level of knowledge about

Med Science 2019;8(1):113-6

anesthesia with preference of neuroaxial techniques increase as education level increases. Knowing anesthetist as a doctor from the developing countries to the developed countries is increased in terms of higher education levels [9]. In a study, the lower regional anesthesia selection rate was found in housewives [10]. An unexplained issue in the previous studies is about the anesthesia experience on preference of anesthesia type [7,10,11] . Ideally, previous anesthesia and surgery experience should have increased the patients’ knowledge related anesthesia and have effect on patients to choose a safer anesthesia type. Similarly, there was no effect of previous anesthesia experience in patients’ choice of anesthesia type in our study. Previous studies have shown that the incidences of many common fears about anesthesia type selection change widely between patient populations chosen and the type of survey instrument used. In some studies indicated that pain, fear of needles, low back pain, being awake, fear of seeing and hearing something is the reason for refusing patients’ regional technique during the operation [8,10-12]. In consideration of phobias and fears, seeing and hearing something, being paralyzed, loss of control and pain during needle at the back are the reasons why pregnants chose general anesthesia in our study. In a study conducted in Pakistan, relatives and previous experiences were found to be effective in choosing regional anesthesia, whereras needle phobia , back pain and preference of unconsciousness during the procedure was the most common reasons for rejection of neuroaxial anesthesia [12]. Unlike our study, the favorable influence of relatives on preference neuroaxial anesthesia can be explained by the different cultures, knowledge and beliefs that societies possess. Contrary to expectations, this study did not find a significant difference between the choice of anesthesia and outcomes. What is surprising is that the cognitive dysfunction is the main outcome which is most wanted to be avoided when the patients are known. Although cognitive dysfunction was first described in 1955 after surgery, awareness of the cognitive effect of anaesthesia and surgery is still limited among the medical profession [13]. To our knowledge, this is the first study to show the importance of avoiding cognitive dysfunction for the patients’ preference. In previous studies vomiting and pain was the least desirable outcomes. [14-16]. It seems possible that these results are due to selection of different outcomes and methods. In our survey, selected outcomes represents both the general and regional anesthesia equally. In contrast to previous studies, pain is subdivided as throat ache, headache and backeche. There are methodological studies performed by giving the monetary value of sorting the side effects before the operation in the obstetric population [14]. In these studies, of which reliability was proven in the different patient groups, the side effects in a certain amount are determined by the literature searching [14-18]. The patients are requested to rank outcomes that they desire to encounter least by giving the highest number. Thus, the monetary value is constituted by asking them how much money they spend to avoid these outcome from the budget determined imaginary against the outcomes constituting the ranking values. In anesthesia practice to respond patients ‘ prefrences and to avoid undesirable outcomes, if possible, are very important to the physicians by considering that how the patients perceive and attach importance 115

doi: 10.5455/medscience.2018.07.8924

of outcomes. Therefore, these studies are very important, as they are used in developing the anesthesia applications providing the answers to the patient’s questions in order to give particular importance to the patient. Our study has few limitations. Fears of pain, hearing or seeing the surgery were prominent, especially among female patients. Also, the tendency to choose general anesthesia is higher in women. Thus, the results of the current study may lead to different outcomes in different patient groups .

Another important result coming into existence of our study was that least desirable outcome was the cognitive dysfunction. The cognitive dysfunction was firstly discussed in this kind of methodological study. The patients spent more money not to encounter with the cognitive dysfunction, as they showed it as least desirable outcome. As a summary; the education level increase and income level increase, effect of the anesthetist and gynecologist positively affect the patients to prefer the regional anesthesia. Another important result coming into existence of our study was that the cognitive dysfunction was one of the most important side effects in terms of the patients. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Before the study, permissions were obtained from local ethical committee. Baris Arslan ORCID: 000-0001-9386-514 Nilgun Kavrut Ozturk ORCID: 000-0002-9320-0778 Zinet Asuman Arslan Onuk ORCID: 000-0002-9189-2926 Bilge Karsli ORCID: 000-0003-4520-8844

Med Science 2019;8(1):113-6

References 1.

TNSA-2008-Hacettepe Üniversitesi Nüfus Etütleri Enstitüsü. http://www. hips.hacettepe.edu.tr/TNSA2008-AnaRapor.pdf. acces date 12.06.2015

World Health Organization. Appropriate technology for birth. Lancet. 1985;8452:436-7.

Töre G, Gurbet A, Şahin Ş, ve ark. Türkiye’de Obstetrik Anestezi Uygulamalarindaki Değişimin Değerlendirilmesi. Türk Anestezi ve Reanimasyon Dergisi. 2009;37:86-95.

The National sentinel caesarean section audit report. https://www.rcog.org. uk/globalassets/documents/guidelines/research--audit/nscs_audit.pdf acces date 13.06.2016

Laul L, Jan G, Chan TF. Preparation of patients for anaesthesia - achieving quality care. Hong Kong Med J. 2002;8:99-105.

Tekin I, LacinS, Arıcan I, ve ark. Factors influencing patients preference of anesthesia type for caesarean section. Turkiye Klinikleri J Anest Reanim. 2005;3:1-6.

Sosis MB, Parnass SM, McCarthy RJ, et al. Spinal phobia: survey results of patient attitudes and preferences regarding anesthesia. J Clin Anesth. 1995;7:389-93.

Rhee WJ, Chung C, Lim YH Lee, et al. Factors in patient dissatisfaction and refusal regarding spinal anesthesia. Korean J Anesthesiol. 2010;59:260-4.

Sagün A, Birbiçer H, Yapici G. Patients’, who applied to the anesthesia clinic, perceptions and knowledge about anesthesia in Türkiye. Saudi J Anaesth. 2013;7:170-4.

Conclusion The regional anesthesia is accepted as more reliable rather than the general anesthesia for the cesarean. The general anesthesia causes some parts of the maternal mortality when the cesarean rates are considered as higher rather than the world average in our country, in which we know the fertility rate is high. We, as the anesthetists, incumbent upon the pregnant to tell the regional anesthesia, raise the awareness of the public and eliminate the fears and anxieties in order to decrease the maternal mortality in our country. Thus, we concluded with our study that the pregnant preferred the regional anesthesia in larger quantities, as they were affected by the anesthetists and gynecologists.

10. Salam A, Afshan G. Patient refusal for regional anesthesia in elderly orthopedic population. J Anaesth Clin Pharmacol. 2016;32:94-8. 11. Dove P, Gilmour F, Weightman WM, et al. Patient perceptions of regional anesthesia: influence of gender, recent anesthesia experience, and perioperative concerns. Reg Anesth Pain Med. 2011;36:332-5. 12. Hussain, U, Tahir A, Javaid Y, et al. Patient’s preference regarding general or regional anaesthesia for elective cesarean section. Pakistan J Med & Health Sci. 2017;11:409-10. 13. Bedford PD. Adverse cerebral effects of anaesthesia on old people. Lancet. 1955;269:259-63. 14. Brendan C, Sheila E, Cohen MB, et al. Patient preferences for anesthesia outcomes associated with cesarean delivery. Aesth Analg. 2005;101:1182-7. 15. Macario A, Weinger M, Carney S, et al. Which clinical anesthesia outcomes are important to avoid? The perspective of patients. Anesth Analg. 1999;89:652-8. 16. Gan, T J, Sloan F, de Dear L, et al. How much are patients willing to pay to avoid postoperative nausea and vomiting?. Anesthesia & Analgesia. 2001;92:393-400. 17. Jenkins K, Grady D, Wong J, et al. Post operative recovery: day surgery patients’ preferences. Br J Anaesth. 2001;86:272-4. 18. Rashiq S, Bray P. Relative value to surgical patients and anesthesia providers of selected anesthesia related outcomes. BMC Med Inform Decis Mak. 2003;3:3.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):117-22

Attitudes of health professionals working in a university hospital towards ageism Belgin Oral, Osman Gunay, Fevziye Cetinkaya Erciyes University Faculty of Medicine, Department of Public Health, Kayseri, Turkey Received 07 July 2018; Accepted 24 July 2018 Available online 13.11.2018 with doi:10.5455/medscience.2018.07.8925 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract This study was carried out to determine the attitudes of health professionals working in Erciyes University Hospitals towards ageism and the related factors. In this crosssectional study, 351 people working in Erciyes University hospitals and accepting to participate in the research were included. In the statistical analysis, unpaired t-test, one-way ANOVA test (post hoc Scheffe), covariance analysis and Pearson correlation analysis were used. Of the study group 34.8% is male, 65.2% is female and the mean age is 33.6±7.8 years. In the study group, the mean total score of the AAS was 84.5±8.2 and mean score was found to be higher in physicians than nurses and other health professionals. The effect of gender, marital status, and economic status, living with elderly individuals and the frequency of care for elderly people in their occupation on the AAS total score was not statistically significant. On the other hand, those who are 40 years of age and above, those who work more than 10 years, those who are willing to give care to elders and the physicians have a higher AAS mean total score. The ageism scores of the health professionals working in university hospital are positive but moderate. Larger studies should be carried out to evaluate the attitudes of health professionals towards elders and to improve their attitudes positively. Keywords: Health professional, elderly, attitude, ageism

Introduction As part of human life, old age is a period of change starting from the first days of life until death. The facilities that technology provides to human life, the developments in medicine, consciousness about the protection and maintaining of health, the rise in life expectancy and the proportion of the elderly population in the total population is steadily increasing [1,2]. In the majority of studies on the basis of aging, in the definition and classification of aging, the physiological dimension of aging is handled. Chronologically, aging is considered to be over 65 years old [3]. According to WHO’s 2011 Global Health and Aging Report with 8% 524 million people worldwide are over 65 years old, in 2010 [4]. WHO states that while the proportion of the population over 60 years old is 12% in 2015, in 2050 it would be 22% .It is estimated that this number will be 2 billion in 2050, one out of every five people will be over 60 years old and part of this elderly population will be in developed countries [5,6].

*Coresponding Author: Belgin Oral, Erciyes University, Faculty of Medicine, Department of Public Health, Kayseri, Turkey E-mail: belgin.zeybek@hotmail.com

Our country is among the developing countries where the aging process is fast. According to 2013 Turkey Demographic and Health Survey, in recent years while the population growth rate of the younger age groups declined, the population of older age groups has increased faster than the average of Turkey’s population [7]. Elderly population rate of approximately 8.5% in Turkey in 2017 [8]. According to projections; elderly population ratio will rise to 10.2 percent in 2023 and Turkey will be among the “very old” population countries according to the United Nations definition [9]. In addition to the physiological changes that occur with aging, various health problems arise in elderly people due to the effects of chronic diseases [10]. The coexistence of the medical and social problems of the elderly, more than one health problem and the maintenance of these problems are increasing elderly people’s need for health care. As is the case globally, the increasing population of elderly people in our country makes it necessary to plan social and health services for elderly and elderly health and to take precautions in this regard [11]. The term ‘ageism’ was first used by Butler in 1969. Butler, defined ageism as a term that can turn into action such as racial discrimination and gender discrimination towards elderly people. [12]. Ageism is also defined as a term expressing prejudice towards older people through attitudes and 117

doi: 10.5455/medscience.2018.07.8925

behaviors [13,14].

Med Science 2019;8(1):117-22

In the literature, there are also studies showing that health workers have negative attitudes [15-16] besides studies showing that they have positive attitudes towards elderly people [17-20]. In other studies about ageism on university students, it has been reported that students generally have positive attitudes [21-26].

23-115 points, restricting the life of the elderly dimension scores between 9-45, positive ageism dimension scores between 8-40, and negative ageism dimension scores between 6-30. Higher points for total AAS score and sub-dimension scores indicate that the attitude towards ageism is positive. Total AAS score and subdimension scores do not have cut off points. The AAS’s Cronbach Alpha value was found to be high at 0.80 [28].

The negative attitudes of the society towards elderly individuals and aging affect the efficiency and quality of the health services offered to these people. The negative prejudices, values, beliefs, and attitudes of related health personnel towards elderly individuals, is reflected the quality of care given to elderly people. For this reason, it is very important for health professionals to raise their awareness about aging and elderly and to make efforts their development of positive attitudes [27].

All departments of the hospital were visited by the researchers and the purpose of the study was explained to the 552 health professionals who were reached. Sociodemographic questionnaire and AAS were given to those who accepted to participate in the study and the forms were collected after filling. A total of 374 people agreed to participate in the study, 23 questionnaires were excluded because of the missing data. In this article, 351 people were evaluated.

There are not enough studies in our country about health professionals’ knowledge and attitudes about ageism. This research was carried out to evaluate the attitudes of health professionals working at Erciyes University hospitals towards ageism and related factors.

The dependent variables of the study are the total AAS score and sub-dimension scores and independent variables are gender, occupation, age, education, marital status, economic status and working status etc.

Material and Methods This cross-sectional study was carried out in Erciyes University Hospitals in first three months of 2016. Erciyes University Hospitals have a total capacity of 1300 beds and a total of 2255 health professionals are employed. Of the health professionals 593 are physicians, 899 are nurses and 763 are other health workers (technicians, medical secretaries, care workers etc.). Ethical approval from Erciyes University Ethics Committee for Clinical Investigations, administrative permission from Deanery of the Faculty and verbal approvals from participants were received. It was accepted that mean total Ageism Attitude Scale (AAS) score of the health care professionals may be approximately 80 and standard deviation 10 points [28]. Minimum sample size was calculated as 325, by taking confidence level 0.95, power 0.90 and tolerance value 2. At least 350 people were decided to include in the study. Health professionals were classified as physicians, nurses, and other health workers. The number of people who would be taken in the study from each group was calculated. The sample size is proportional to the size of the entire universe and it has been determined how many of each group should be taken. All the units in the hospital were visited and data collection was completed by accessing the person to be taken from these three working groups. A socio-demographic questionnaire and the Ageism Attitude Scale (AAS) were used as data collection tools. Socio - demographic questionnaire consisting of 26 questions was prepared by the researchers. AAS which was developed by Vefikuluçay [28] includes 23 items quintet likert types. AAS has positive and negative attitudes. All expressions are evaluated as: totally agree (5 points), agree (4 points), undecided (3 points), disagree (2 points), absolutely disagree (1 point). AAS consists of three subdimensions as; restricting the life of the elderly; (items 1, 5, 12, 14, 17, 19, 21, 22, 23), positive ageism; (items 2, 4, 6, 7, 8, 9, 13, 20), and negative ageism (items 3, 10, 11, 15, 16, 18). The responses of negative statements about ageism are reversed and total scores are calculated [28]. AAS total scores may be between

Kolmogorov–Simirnov test was used to examine whether the AAS scores fit the normal distribution. For statistical analyzes, frequency and percentage, mean value, standard deviation, highest and lowest values were used for descriptive statistics. Chi square test was used for statistical analysis of the categorical data. Unpaired t-test, one-way ANOVA test (post hoc Scheffe) and covariance analysis were used for statistical analyzes. The Pearson simple correlation coefficient was calculated to analyze the relationship between quantitative variables. Values of p<0.05 were considered statistically significant in all analyzes. Results Of the study group 34.8% is male, 65.2% female, 74.7% married and 90.3% in the nuclear family structure. The mean age of the whole group was found 33.6±7.8 years. It was determined that 27.9% of the participants were physicians, 39.9% were nurses and 32.2% were other health workers, 44.4% of respondents defined the economic status as good, while 49% mentioned as moderate. Of the participants, 15.3% have high school, 54.0% undergraduate and 30.7% graduate degree education. It was determined that 58.7% of participants are working in internal sciences and 41.3% in surgical sciences departments. Participants have mentioned themselves as 30.5% less than five years, 26.8% 5-10 years and 42.7% above ten years when they were evaluated in terms of service duration in the units they were working in. When the participants were asked what the concept of old age meant to them; 76.9% were kindliness and compassion, 51.3% were weak, 33.6% were wisdom, 59.0% were ill, 47.0% were loneliness, 35.6% were addicted, 10.5% were exclusion and 8.5% were happiness stated. While 49.3% of participants stated that they stayed with elderly people for their lifetime, it is stated that 11.1% of the participants are still living with their 65 years old and above relatives. 6% of those in the nuclear family structure and 58.8% in the extended family structure still live together with elderly individuals. When the frequency of care for elderly people in the working 118

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environment was questioned, 76.4% of the participants stated frequently. In order to express their willingness to care for elderly people, 68.1% of the participants expressed themselves as willing, 26.2% undecided and 5.7% unwilling. When willingness to care for elderly people is evaluated among the occupational groups 61.2% of the physicians, 62.9% of the nurses and 80.5% of the other healthcare workers stated that they were willing to serve elderly people. And the difference between the groups was found to be statistically significant (X2:14.721, p<0.05). While 76.1% of the participants described themselves as religious, 20.5% described less religious. AAS scores obtained from the study group are shown in Table 1. The mean of total AAS scores of participants was 84.5±8.2, As shown in Table 1, in the study group, the mean total AAS score was 84.5±8.2. Restricting the life of the elderly score was 36.34±3.75, Positive ageism score was 30.53±5.13, Negative ageism score was 18.23±3.37. Attitudes of the study group about ageism were positive, but scores were found to be moderate.

Med Science 2019;8(1):117-22

Table 1. The Scores of Health Professionals’ Ageism Attitudes Scale X̅ ±SD

Median (min-max)

Restricting the life of the elderly

36.34±3.75

36 (26-45)

Positive ageism

30.53±5.13

31 (9-40)

Negative ageism

18.23±3.37

18 (9-28)

AAS total score

84.53±8.19

84 (60-109)

AAS and sub dimensions

As the age of participants was grouped with 5 age groups, ASS scores of 40 years and over increased significantly, so the study group was divided into 2 groups as age to express this significance. It was found that AAS scores were higher among the people who are 40 years and over age, those who expressed the economic status as good and those living in the nuclear family (p<0.05). There is a positive relationship between age and total AAS scores. As age increases, AAS score also increases a positive correlation was found at 0.01, indicating a weak relationship (p<0.05). Effects of gender and the presence of elderly individuals in the family on AAS score and sub dimensions scores were not found significant, Positive ageism was found higher only in male. (p>0.05) (Table 2).

Table 2. Distribution of AAS scores according to some socio-demographic characteristics of the health professionals Characteristics

Gender

Restricting the life of the elderly

Positive ageism

Negative ageism

(X±SD)

122

35.8±4.2

30.9±5.3

18.3±3.5

85.1±8.5

229

36.6±3.5

29.5±5.0

18.2±3.3

84.3±8.0

0.069

0.013

0.696

0.380

Groups

Male Female p Age (year)

18–39

277

36.1±3.7

29.7±5.1

17.9±3.3

83.7±7.9

40 and over

37.1±3.8

30.9±5.1

19.6±3.3

87.6±8.4

0.041

0.077

<0.001

Marital status

Married

260

36.5±3.7

29.9±5.1

18.3±3.4a

84.7±8.2

Single

35.7±3.9

30.5±5.4

17.7±3.4a

83.8±8.4

Other

36.6±2.7

28.4±5.1

20.3±3.0b

85.3±7.3

0.192

0.375

0.036

0.643

Good

156

36.9±3.5a

30.4±5.1

18.3±3.4

85.6±8.3a

Moderate

172

36.1±3.7a,b

29.7±5.0

18.2±3.3

83.9±7.9a,b

Bad

34.6±3.7b

29.0±5.7

18.3±3.4

82.0±8.6b

0.009

0.256

0.963

0.051

Economic status

p Family type

Nuclear

317

36.6±3.6

29.9±5.2

18.3±3.4

84.8±8.2

Extended

34.1±4.3

30.1±4.9

17.6±3.5

81.9±7.8

<0.001

0.818

0.259

0.049

Yes

36.2±3.8

31.0±5.1

18.1±3.4

85.3±8.1

312

36.4±3.8

29.8±5.1

18.3±3.4

84.4±8.2

0.806

0.167

0.713

0.548

36.3±3.8

30.0±5.1

18.2±3.4

84.5±8.2

p Presence of elderly in the family Total

AAS total score

351

One Way ANOVA (post hoc Scheffe) a, b, c: The difference between the groups that do not carry the same letter in each column is significant (p<0.05)

AAS scores were shown in the Table 3 according to the working status of the health professionals. As seen in the table, the mean total AAS score and restricting the life of the elderly score of the physicians were higher than the nurses and the other health workers (p<0.05). After adjusting for the terms of age and gender, the difference between physicians and nurses and the other health workers was found to be significant. (By adjusting the effect of the level of education in physicians and the female gender in the nurses on the dependent variable). The effect of

the level of education on AAS score, restricting the life of the elderly score and negative ageism score were found significant, and as the level of education increase, the mean of AAS scores also increased and there is a weak correlation between the level of education and AAS scores at the 0.01 level (p<0.05). After adjusting for the terms of the level of education, there was no significant difference between the occupational groups (p> 0.05). (It is seen that the difference between the working groups is due to the education levels.) 119

doi: 10.5455/medscience.2018.07.8925

Med Science 2019;8(1):117-22

Table 2. Distribution of AAS scores according to some socio-demographic characteristics of the health professionals Variables

Occupation group

Groups

Restricting the life of the elderly X±SD

X±SD

Physicians

37.4±3.3a

31.0±4.7

18.9±2.9

87.3±7.7a

Nurses

140

36.5±3.4a

29.7±4.3

17.9±3.3

84.2±7.8b

Other

113

35.2±4.2b

29.4±6.3

18.2±3.8

82.6±8.5b

<0.001

0.064

0.062

<0.001

High school

34.7±3.2a

29.0±6.8

17.8±3.9ab

81.5±6.8a

Pre-license/Undergraduate

187

36.3±3.9b

29.8±4.9

18.0±3.3a

84.0±8.3b

Graduate

109

37.3±3.5c

30.8±4.5

18.9±3.4b

87.0±8.0c

<0.001

0.073

0.050

<0.001

Educational level

Working Unit

Frequency of elderly care

AAS total score

Less than 5 years

107

36.4±3.6

29.6±5.3b

18.0±3.3

84.0±7.9a

35.9±3.9

28.7±5.2b

17.8±3.5

82.3±7.6a

Above 10 years

150

36.6±3.8

31.0±4.7a

18.6±3.3

86.3±8.4b

0.324

0.002

0.099

0.001

Internal Sciences

206

36.2±4.0

29.8±5.2

18.5±3.4

84.6±8.9

Surgical Sciences

145

84.4±7.1

36.4±3.3

30.2±5.0

17.7±3.3

0.686

0.440

0.038

0.853

Frequent

268

36.2±3.9

29.7±5.3

18.3±3.4

84.2±8.3

Rare

36.7±3.1

30.9±4.6

18.1±3.4

85.7±7.8

0.294

0.060

0.660

0.140

Willingness of elderly care

Negative ageism

Between 5-10 years p

Working Unit

Positive ageism

Willing

239

36.4±3.8

30.3±5.2a

18.3±3.2

85.0±7.9a

Unwilling

34.7±4.0

26.0±6.2b

17.2±4.1

78.0±10.2b

Undecided

36.6±3.5

29.9±4.4a

18.2±3.6

84.8±7.8a

0.119

0.001

0.400

0.001

One Way ANOVA (post hoc Scheffe) a, b, c: The difference between the groups that do not carry the same letter in each column is significant (p<0.05)

The frequency of care to elderly people in the workplace did not have a significant effect on the AAS score and sub dimensions scores. On the other hand, those who defined themselves as unwilling to provide elderly care were found to have lower total AAS score and positive ageism score. Participants whose total working time was more than ten years have the total AAS score and the mean of positive ageism score higher than the ones who worked less than ten years (p<0.05). When working period thought above ten years of the participants the mean age was higher and the effect of AAS scores was considered, after adjusting for age; the duration of the study was not influenced by the total AAS score but the impact on positive ageism scores continued after the correcting. When the participants’ working units were examined, professionals working in the internal sciences departments were found to be higher positive ageism score than in the surgical sciences departments. Participants who defined themselves as religious were found to have a lower level of restricting the life of the elderly and negative ageism scores than the ones who described themselves as less religious. There was no difference in terms of total AAS scores between the participants who defined themselves as religious and less religious. Discussion In the study, the attitudes of the health professionals working in a university hospital to the ageism were evaluated using the AAS.

It was determined that the participants had a generally positive attitude about the ageism, but their scores were moderate. In the literature, there are also studies showing that health workers have positive attitudes [21-24,29] besides studies showing that they have negative attitudes towards elderly people [15,16,30]. In our study, the mean total AAS score was found 84.5±8.2. The mean total AAS score was found in the study by Demir et al. 79.49±9.04 among health vocational college students in Kırşehir [25]. In another study, this score was found by Çayır and Yılmaz as 86.72±7.6 among nursing students in health vocational college and 83.74±8.7 among elderly care program students in Ağrı [24]. In Yılmaz and Özkan’s study, this score was found as 100.92±5.6 among nursing students studying at Health College [23]. It can be said that the attitudes towards elderly are positive in Turkey because of the traditional structure of Turkish society; elderly have a high respect and prestige among the people. However, moderate scores also indicate that ageism may be among health professionals. The mean total AAS score and score and restricting the life of the elderly score were found to be higher in the age group of 40 and over, those who stated that the economic situation was good, those living in the nuclear families and those with the graduate education (p<0.05). In some studies, there was no significant relationship between age and AAS scores [20,22-26]. In our study, it was determined that the attitude toward the elderly changed positively as the age progressed similar to other studies [29,31]. The development of people’s ideas and attitudes towards elderly 120

doi: 10.5455/medscience.2018.07.8925

can be attributed to the recognition of the fact that aging is a physiological process, the development of empathy, the increase in the number of elderly people in their surroundings and in their relatives, and the frequent involvement of elderly individuals. The mean AAS score and restricting the life of the elderly score were found to be higher among those living in nuclear families and those who expressed economic status as good. The higher AAS scores in the group with a good economic status can be interpreted as reflecting the responsibilities and difficulties of economic troubles to the attitudes of the individuals. When some other studies were examined, there was no significant relationship between family structure and AAS scores [16,22, 23, 26]. In our study, participants living in a nuclear family were found to be higher AAS scores. This can be explained by the fact that more than half (58.8%) of the extended family members of our study lives with elderly individuals in their families. Those individuals with an extended family structure are faced with old age problems and have difficulties living with physical, social and cultural changes brought about by their aging. In the literature, there are also studies that show the gender can an influence attitude towards elderly [20,21] beside it is ineffective [22,24]. In our study, there was no significant difference between men and women in terms of AAS scores. This data shows that elderly respect is transferred to the future generations regardless of gender. In our study, it was determined that AAS score, restricting the life of the elderly score and negative ageism score increased as the level of education increased. These data are similar to some studies showing that the level of education affects the attitude towards the elderly positively [20,31]. In some studies which were conducted on the students, there was a significant difference between the upper and lower classes in terms of AAS scores [23,24,32-34]. These data shows that as the level of education increases, the increasing knowledge and experience effect positively attitudes towards elderly. In physicians, the mean AAS score and restricting the life of the elderly score were higher than the nurses and other health workers (p<0.05). However, after the correction according to the level of education, there is no difference between the occupational groups. This indicates that the difference between physicians and other occupational groups in terms of the mean AAS scores can be attributed to the level of education rather than differences among the professions. Physicians all have a post-graduate education, and the majority of nurses and other occupational groups have education at undergraduate level. In our study, the effect of care to elderly people in the workplace and the total number of AAS scores of the units that the participants worked in were not significant. Altay [32], in a study on nursing students, did not find any effect on the AAS scores of giving care to the elderly. On the other hand, another study on nursing students found that the experience of care to elderly people improved positive attitudes towards elderly [29]. While elderly care can affect the attitudes towards the elderly in the process of student life, it can be attributed to the fact that

Med Science 2019;8(1):117-22

this effect is not seen in working life more frequently than elderly individuals and attitudes and thoughts are formed with age and experience. When the study evaluated from the point of view of the working period, total AAS scores were found to be higher in the cases with more than 10 years of total working period. In a study of surgical nurses in Trabzon, there was no significant effect on the attitudes towards ageism in the study period [20]. Since our study is not targeted at the whole of the healthcare groups of similar studies, there is a source inadequacy in terms of the extent to which a variable such as the working year may affect the attitude towards elderly. In our study, higher AAS scores in the group with more than 10 years of total working time indicates that attitudes towards elderly can be improved positively by experiences gained. In our study, there was no significant difference in total AAS scores between health professionals living with elderly and not living with elderly in their families. In similar studies, there was no significant relationship between individuals living with elderly and ageism [16,32,33]. On the other hand, there was a significant difference about mean total AAS scores between the groups that defined themselves as unwilling to give care to the elderly in the various studies and the willing and undecided ones [20,32,33]. In our study, it was determined that unwillingness to give care to elderly affects attitudes towards elderly negatively. In addition, there is a significant difference between subscale dimension scores among the groups in terms of religiosity perception. There is no difference between total AAS scores because of the fact that Turkish society has generally a traditional family structure. Traditions, and religious beliefs are intertwined, and social and cultural factors are combined with the perception of religiosity. But it may be envisaged that the perception of piety can be affected by gender, age, socio-economic and cultural factors. Limitations of the Study There are two limitations of this study. The study was conducted in only one hospital and nonprobability sampling was used to create the study sample. Conclusion The ageism scores of health professionals working in the university hospital are positive but moderate; the total AAS score was found higher in those are physicians, those 40 and over age group, those expressing the economic status as good, those living in the nuclear family, those having graduate level education and those willing to give care to the elderly. There was no significant effect of gender, marital status, and the frequency of elderly care, living together with elderly individuals and religiosity on the total AAS scores. In order to improve the attitudes of health professionals towards elderly, course contents related to seniors should be added to educational programs at all levels, especially health-related programs. In addition, the same topics should be included in inservice training of health professionals. The reasons for unwillingness to serve elderly in health professionals should be investigated and efforts should be made to improve health professionalsâ&#x20AC;&#x2122; attitudes towards elderly patients. 121

doi: 10.5455/medscience.2018.07.8925

New and comprehensive social policies should be developed, taking into account the fact that the country’s elderly population is rapidly increasing and that ageism can cause serious problems. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Before the study, permissions were obtained from local ethical committee. Belgin Oral ORCID: 0000-0002-2246-4733 Osman Gunay ORCID: 0000-0001-7131-2253 Fevziye Cetinkaya ORCID: 0000-0001-5590-7011

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16. Köse, G. Ayhan H, Taştan S et al. Determination of the attitudes of students from different department in the field of health on the discrimination against the elders. Gulhane Med J. 2015;57:145-51. 17. Mc Lafferty I, Morrison F. Attitudes towards hospitalized older adults. J Adv Nurs. 2004;47:446-53. 18. Gallagher S, Bennett KM, Halford JC. A Comparison of acute and longterm health-care Personnel’s attitudes towards older adults. Int J Nurs Pract. 2006;12:273-9. 19. Kang Y, Moyle W, Venturato L. Korean nurses’ attitudes towards older people with dementia in acute care settings. Int J Older People Nurs. 2011;6:143-52. 20. Bulut E, Çilingir D. Attitudes of surgical nurses towards the elderly. Turk J Geriat. 2016;19:253-9. 21. Güve DŞ, Muz GU, Ertürk NE. The attitudes of universıty students towards elderly discrimination and the relation of these attitudes with some variables. J Anatol Nurs Health Sci. 2012;15:99-105.

Akdemir N, Çınar İF, Görgülü Ü. Perception of ageing and ageism. Turk J Geriatri. 2007;10:215-22.

Öz, F. The last stage of life: elderty the review of psychosocial dimension. J Crisis. 2002;10:17-28.

Beğer T, Yavuzer H. Ageing and ageing epidemiology. Klinik Gelişim, 2012;25:1-3.

World Health Organization, Global Health and Ageing. National Institute on Aging, National Institutes of Health NIH Publication no. 2011;11-7737 p:2.

World Health Organization, Ageing and health. access address: http:// www.who.int/news-room/fact-sheets/detail/ageing-and-health date access: 15.08.2018

25. Demir G. Attitudes of nursing students about ageism and the related factors. Intern J Caring Sci. 2016;9:900-8.

Global strategy and action plan on ageing and health . World Health Organization 2017, p:iv

26. Adıbelli D, Türkoğlu N, Kılıç D. Student nurses’ views on aging and attitudes towards aging. DEUHFED. 2013;6:2-8.

Hacettepe University, Institute of population studies. 2013 Turkey Demographic and Health Survey, Ankara, 2014, p:7.

27. Vefikuluçay YD, Terzioğlu F. Ageism and nursing: Review. Turkey Clinics J Nurs Sci. 2010;2:137-44.

Elderly Statistics, 2017 Turkish Statistical Institute, No: 27595 access address http://www.turkstat.gov.tr/PreHaberBultenleri.do?id=27595 date access:21.08.2018

28. Vefikuluçay YD, Terzioğlu F. development and psychometric evaluation of ageism attitude scale among the university students. Turk J Geriat. 2011;14:259-68.

TSI, Elderly statistics 2015, Turkish Statistical Institute, Ankara, 2016, p:1.

29. Özdemir Ö, Bilgili N. Attitudes of Turkish nursing students related to ageism. J Nurs Res. 2016;24:211-6.

10. Status of Elderly People in Turkey and National Plan of Action on Aging 2007, State Planning Organization, Ankara, 2007,2741, p:60. 11. Özdemir Ö, Bilgili N. Ageism in health care. Gulhane Med J.. 2014;56:12831. 12. Butler R. Dispelling ageism: The cross-cutting intervention. Annals of the American Academy of Political and Social Science. 1989;503:138-47. 13. Palmore EB. Ageism: Negative and Positive, In: Helvi G, Sandi B Eds. Introduction and Basic Definitions. 2nd edition. New York, USA: Springer Publishing Company, 1989, p. 3-18.

22. Soyuer F, Ünalan D, Güleser N, Elmalı F. attitudes of health vocational school students towards ageism and the relation of the attitudes with some demographical variables. Mersin Univ Saglık Bilim Derg. 2010;3:20-5. 23. Yılmaz E, Özkan S. Attitudes of nursing students towards ageism. DEUHFED. 2010;3:35-53. 24. Çayır YM, İnce FZ. Relationship between nursing and elderly care students attitudes towards ageism. Belitung Nurs J. 2017;3:281-96.

30. Rajvınder S, Griffiths A, Cox T, et al. Medical students’ and doctors’ attitudes towards older patients and their care in hospital settings: A conceptualization. Age and Ageing. 2015;44:776-83. 31. Söderhamn O, Lindencrona C, Gustavsson SM. Attitudes toward older people among nursing students and registered nurses in Sweden. Nurs Educ Today. 2001;21:225-9. 32. Altay B, Aydın T. Evaluation of the attitudes of nursing students towards ageism. J Educ & Res Nurs. 2015;12:11-8.

14. Çilingiroğlu N, Demirel S. Aging and ageism, Turk J Geriatri. 2004;7:225-30.

33. Ceylan H, Öksüz M. Analyzing attitudes of undergraduate social work students towards ageism. J Intern Social Res. 2015;8:459-66.

15. Herdman E. Challenging the discourses of nursing ageism. Int J Nurs Stud. 2002;39:105-14.

34. Usta YY, Demir Y, Yönder M, et al. Nursing students’ attitudes toward ageism in Turkey. Arch Gerontol Geriatr. 2012;54:90-3.

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Available online at www.medicinescience.org

ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):123-8

Does heparin dosage calculated with ideal body weight reduce blood product use in open heart surgery? Duygu Kara1, Cafer Mutlu Sarikas1, Asli Demir2, Mehmet Ali Kaygin3, Ertekin Utku Unal4 1 Erzurum Regional Training and Research Hospital, Department of Anesthesiology and Reanimation, Erzurum, Turkey Turkey Yuksek Ihtisas Training and Research Hospital, Department of Anesthesiology and Reanimation, Ankara, Turkey 3 Erzurum Regional Training and Research Hospital, Department of Cardiovascular Surgery, Erzurum, Turkey 4 Turkey Yuksek Ihtisas Training and Research Hospital, Department of Cardiovascular Surgery, Ankara, Turkey

Received 31 July 2018; Accepted 12 September2018 Available online 13.11.2018 with doi:10.5455/medscience.2018.07.8926 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The heparin regimen providing anticoagulation during cardiopulmonary bypass (CPB) is usually adapted to total body weight (TBW). However, this may cause redundant anticoagulation and increase perioperative bleeding, transfusion requirements and reoperation. We compared a heparin regimen based on ideal body weight (IBW) with the traditional regimen. After ethical approval, 100 adults undergoing elective cardiac surgery with CPB were recruited for the prospective, observational study in a tertiary hospital. Prior to CBP an unfractioned heparin dose was adjusted to 300 IU/kg based on TBW (Group TBW, n=50), or IBW (Group IBW, n=50). IBW was calculated using the Lorentz formula. The minimal Activated Coagulation Time (ACT) target value is 400 sec for CPB. Demographic data, cross-clamp and CPB durations, and Hb, Htc, platelet, PT, Aptt and fibrinogen values were similar between the groups (p>0.05). Heparin and total protamine doses were significantly higher in Group IBW (p<0.001). Differences were also determined in ACT-1, ACT-2, and ACT-3 (p˂0.05). Group TBW had significantly higher ACT values after initial heparin doses (p=0.02) and Group IBW after reversal with protamine (p=0.001). Amounts of blood and blood products used differed significantly (p<0.001). In terms of drainage at 6 and 24 h, blood loss was significantly higher in Group TBW (p<0.001). Postoperative erythrocyte suspension and fresh frozen plasma use were higher in Group TBW (p<0.001), and length of ICU stay was significantly longer (p<0.006). Heparin doses based on IBW provided sufficient anticoagulation. Heparin and protamine doses decreased, while postoperative bleeding, transfusion requirements and hospitalization decreased. Keywords: Ideal body weight, total body weight, heparin, protamine, cardiopulmonary bypass, blood transfusion

Introduction Contact between blood components and the cardiopulmonary bypass (CPB) circuit during cardiac surgery induces coagulation activation. Potent anticoagulation by means of unfractionated heparin (UFH) injection is therefore required to avoid thrombosis in the circuit. There is currently no consensus concerning the modalities of UFH in cardiac surgery and the optimal anticoagulation target assessed intraoperatively on the basis of activated clotting time (ACT). In a recent review, Finley et al. [1] considered an ACT target of at least 350 sec as necessary and sufficient to perform CPB under safe conditions. All situations, including heparin resistance, can be managed with a plasma heparin concentration of at least 4 IU/ml [1]. The initial heparin *Coresponding Author: Duygu Kara, Erzurum Regional Training and Research Hospital, Department of Anesthesiology and Reanimation, Erzurum, Turkey E-mail: drduygukara@yahoo.com

dose is usually calculated based on the patient’s total body weight (TBW). In the standard regimen, a dose of 300 IUUFH/kg of TBW is injected before the start of CPB. Inappropriate doses of heparin may result in intraoperative and postoperative bleeding. Heparin administration is required to prevent thromboembolism caused by blood contact with the CPB machine during cardiac surgery. However, excess heparin doses may cause bleeding, tamponade and bleeding-related reoperation in the postoperative period [2]. There are no specific standards for the clinical management of heparin administration during CPB [3]. Anticoagulation and the heparin response may be complicated in clinical practice, due to heparin insensitivity, antithrombin III deficiency, heparin binding proteins and the use of different heparin formulations [4]. No universal consensus has been achieved regarding the quantitative value of heparin and anticoagulation in CPB, in other words, the ideal ACT value for CPB. Most cardiac centers have specified a target ACT value for CPB of 400-480 sec [5,6]. and also most of the centers where CPB and open heart surgery are performed, 123

doi: 10.5455/medscience.2018.07.8926

heparin is usually administered at a dose of 300 IU / kg, which has been determined by observations and is universally agreed, although this dosage may sometimes lead to high perioperative ACT values [7]. Protamine is used for heparin neutralization at the end of CPB. Similarly to heparin, protamine also has its own particular side-effects. These include hypersensitivity, systemic hypotension, pulmonary hypertension, right ventricular failure, angioedema, bronchospasm and anticoagulation with overdoses [8]. The risk of heparin-induced bleeding and the need for protamine increases in a dose-dependent manner, and the risk of developing both complications also rises [8]. The purpose of this study was to investigate the feasibility of adequate anticoagulation with heparin doses calculated based on ideal body weight (IBW), and also to evaluate the risk of postoperative bleeding, transfusion requirements and bleeding reoperations associated with heparin overdose. Material and Methods Following ethical committee approval (No. 55, 09.06.2016), 100 ASA II-III patients scheduled for elective cardiac surgery with CPB were recruited for the study. Written informed consent was obtained from all patients before surgery. The primary objective of the study was to compare the effects of a standard heparin injection based on TBW during cardiac surgery on ACT in elective cardiac surgery patients. The secondary objectives were to evaluate the ACT in each group of patients and, at different time points during CPB, and to compare the incidence of bleeding, intraoperative blood transfusion and complications in the two patient groups. An additional objective was to calculate the optimal heparin regimen for all patients depending on their IBW, which can be easily assessed using the Lorentz formulae [9]. The patients included in the study were at least 18 years of age and were scheduled for cardiac surgery (coronary artery bypass graft or valve surgery) under CPB. Exclusion criteria included receipt of preoperative heparin therapy (UFH or low molecular weight heparin), emergency surgery, redo surgery, heart transplantation, surgery for circulatory assistance, and heparin allergy. Routine monitoring with electrocardiography, pulse oximetry and noninvasive arterial blood pressure measurement were performed in the operating room. Following the insertion of two peripheral large bore venous cannulas (18 and 16 gauge), arterial cannulation was performed via the right/left radial artery. After preoxygenation, anesthesia was induced with fentanyl 10 μg/kg and midazolam 0.15 mg/kg. Muscle relaxation was achieved with rocuronium 0.6-1 mg/kg. Patients were generally intubated with 7.5 internal diameter (ID) endotracheal tubes (ETTs) for women and 8.5 ID ETTs for men according to the physical characteristics of the patients. Following intubation, patients were mechanically ventilated with a tidal volume of 4-6 ml kg-1 depending on their IBW. Respiratory frequency was set such as to maintain an EtCO2 level of 35-40 mmHg, and anesthesia was maintained with sevoflurane 0.8-1 MAC with a 40% O2/air mixture. Central venous cannulation was performed via the internal jugular vein. Nasopharyngeal probes were used to monitor body temperature. All patients received tranexamic acid infusion in the form of an initial loading dose (10 mg/kg 30 min), resuscitation until the end of the operation (1 mg/kg per hour), and the addition of 1 mg/kg to the CPB prime solution. Patients were selected in the light of

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demographic similarities using the closed envelope method for the study and control groups. The control group (Total body weight group, TBW) was administered a standard heparin dose regimen calculated 300 IUUFH/kg according to total body weight before initiating of CPB. In group IBW (Ideal body weight group, IBW), the ideal body weight was calculated according to the Lorentz formulae [9]. and the heparin dose was calculated by multiplying the IBW weight by 300 IUUFH/kg with a target ACT value of at least 400 s. Additional boluses of UFH (50 to 100 IUUFH /kg TBW) were injected if ACT, measured every 30 min during CPB, was insufficient. Surgery was performed under normothermia or mild hypothermia. The body temperature of the patients were kept at the same standard value at different time points. At the end of CPB, the residual effects of heparin were reversed by injection of protamine, based on the total heparin dose (1:1.3). The cut-off point for transfusion was defined as a postoperative hemoglobin concentration of 10 g/dl or less. Blood samples were collected intraoperatively at the following times: T0, at the start of the operation, measurement of baseline ACT (Hemochron Signature Elite, Gamida, Paris, France); T1, 3 min after injection of UFH, measurement of ACT; and T2, at the end of cardioplegia, measurement of ACT, heparin and antithrombin concentrations. ACT measurements were then performed every 30 min during CPB, with maintenance of the target value of at least 400 sec; T3, ACT was measured 10 min after the injection of protamine. All patients were transferred to the ICU postoperatively. Multimodal analgesia was provided and adapted to each patient. The data collected for each patient included the characteristics, use, or discontinuation of antiplatelet agents; type of surgery; CPB and aortic clamping times; data concerning the heparin protocol and its monitoring; intraoperative transfusions; blood loss from chest drains at 6 h (H6) and 24 h (H24); postoperative transfusions of blood products or factor concentrates; total number of days spent in the ICU; postoperative complications; and reoperation requirements. IBW was calculated for each patient using the Lorentz formulae: IBW women= (height - 100) - ((height - 150)/2.5) IBW men= (height -100) - ((height - 150)/4) Statistical analysis Continuous variables were tested for normal distribution using the Kolmogorov-Smirnov test. Normally distributed continuous variables were expressed as mean± standard deviation (SD) or median values with the relevant interquartile range if not normally distributed. Categorical variables were expressed as numbers and percentages. Demographic characteristics, operative and postoperative variables, laboratory data, hemostatic data and amount of blood utilization were compared using the independent samples t-test or the Mann-Whitney-U test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. A p value < 0.05 was considered statistically significant. All statistical analyses were performed on SPSS statistical software (SPSS for Windows 15.0, Inc., Chicago, IL, USA). Results One hundred patients were recruited into the study. The preoperative characteristics of the two groups of patients were similar (Table 1). Comparison of groups TBW and IBW revealed no significant differences in terms of Hb, Htc, platelet, PT, Aptt or fibrinogen 124

doi: 10.5455/medscience.2018.07.8926

values (p>0.05) (Table 2). Type of surgery, CPB and aortic clamping times were also similar. Mean CPB time in Group TBW was 77.0±20.2 min, and mean cross-clamp time was 53.4±18.4

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min, while in Group IBW, mean CPB time was 83.4±31.5 min and mean cross-clamp time was 54.6±38.7 mean. The differences between the two groups were not statistically significant (Table 3).

Table 1. Preoperative characteristics of the study population Age (years) (mean±SD)

Group TBW

Group IBW

p value

59.3±11.36

59.78±10.34

0.72

24 (%48)

12 (%24)

0.07

Gender Female, n(%) Male, n(%)

26 (%52)

38 (%76)

Height (cm)

165.8±7.4

163.6±9.7

0.35

Total body weight (kg) (mean ±SD)

74.0±11.0

73.0±15.7

0.53

Ideal body weight (kg) (mean ±SD)

59.8±8.0

Diabetes n(%)

18 (%36)

1.00

Dyslipidaemia n(%)

12 (%24)

1.00

Hypertension n(%)

26 (%52)

28 (%54)

0.77

Smoker n(%)

10 (%20)

12 (%24)

0.73

COPD n(%)

10 (%20)

14 (%28)

0.50

OSAS

0 (%0)

Stroke

0 (%0)

Renal failure

0 (%0)

Heart Disease

0.64

Ischaemic

38 (%76)

40 (%80)

Valvular

8 (%16)

4 (%8)

Ischaemic,valvular

4 (%8)

6 (%12)

38 (%76)

34 (%68)

4 (%8)

14 (%28)

Warfarin

2 (%4)

0 (%0)

Clopidogrel

6 (%12)

2 (%4)

Antiplatelet agents None Acetylsalycyclic acit

SD: standart deviation, COPD: chronic obstructive pulmonary disease, OSAS: obstructive sleep apnoea syndrome

The characteristics of heparin therapy and ACT values during surgery are shown in Table 3. The initial and total doses of heparin, as well as the total dose of protamine, were significantly higher in Group TBW (p<0.001). The initial dose of heparin administered in Group IBW was 17,964.0±2400.5, compared to 21,856.0±3505.6 in Group TBW. Patients in Group TBW with ACT˂400 during pump received no additional heparin dose, while six patients in Group IBW received an additional dose of heparin, and the difference was statistically significant (p=0.02). Patients in Group TBW received a total heparin dose of 21,856.0±3505.6 IU during CPB, while those in Group IBW received 18,824.0±3527.9 IU, and the difference was again significant (p=0.004). Patients in Group TBW received 33,500.0±5199.9 IU protamine for heparin neutralization after conclusion of CPB, while those in Group IBW were administered 26,618.0±4066.7 IU, and the difference was significant (p<0.001). Significant differences were also determined between the two groups in terms of ACT-1, ACT-2, and ACT-3 values (p˂0.05). ACT values in the two groups were comparable at baseline (Group IBW 142.6±20.8 sec, Group TBW 124.3±20.5 sec, p=0.005). However, as expected, Group TBW had significantly higher ACT values after the initial dose of heparin (Group IBW 526.7±74.1

sec ±113.79, Group TBW 605.2±20.5 sec, p=0.02). The number of additional boluses of heparin required during CPB to maintain the target ACT was higher in the Group IBW (Group IBW 12%, Group TBW 0%0, p=0.02). Group IBW had significantly higher ACT values after reversal with protamine (p=0.001) (Table 3). A mean 3.96±2.23 units of blood and 2.12±1.01 units of fresh frozen plasma were used in the operative period in Group TBW patients. In Group IBW, a mean 1.48±0.51 units of blood and 1.12±0.67 units of fresh frozen plasma were used. The differences between the blood and blood products used in the two groups were statistically significant (p<0.001) (Table 3). When the two groups were compared in terms of amounts of drainage at 6 and 24 h, blood loss was significantly higher in Group TBW than in Group IBW (p<0.001). When the two groups were compared in terms of use of blood and blood products, the amounts of erythrocyte suspension and fresh frozen plasma given in the postoperative period were higher in the Group TBW patients than in those in Group IBW, and the difference was statistically significant (p<0.001). No patient in either group required bleeding control (Table 3). Length of stay in the ICU was significantly longer in Group TBW (p<0.006, Table 3). No significant difference was observed in the patients 125

doi: 10.5455/medscience.2018.07.8926

included in the study in terms of development of postoperative complications. However, length of stay in the ICU was statistically significantly shorter in Group IBW (p= 0.005) (Table 3). Mortality

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was observed in 4 patients in Group IBW and in 10 patients in Group TBW (p=0.41, Table 3).

Table 2. Laboratory data of the study population Group TBW

Group IBW

p value

Haemoglobin (gr/dL) (mean±SD)

14.2±1.6

14.9±1.3

0.07

Haematocrit (%)(mean ±SD)

42.2±6.0

45.1±4.1

0.10

Platelets (109 L-1) (mean ±SD)

239,760±67,020

265,375±63,963

0.18

Phrothrombin time (10.5-14.9 sn)( mean ±SD)

13.2±1.58

12.7±0.8

0.28

Aptt (21-35sn) (mean ±SD)

25.8±5.0

25.0±2.3

0.79

353.0±48.4

326.1±73.8

0.11

Fibrinogen (180-350 mg/dL) (mean ±SD)

SD: standart deviation, aPTT: activated partial thromboplastin time Table 3. Intra- and postoperative data of the study population Group TBW

Group IBW

Surgery type n(%) CABG

0.34 38 (%76)

40 (%80)

AVR

2 (%4)

0 (%0)

MVR

6 (%12)

2 (%4)

CABG, MVR

4 (%8)

2 (%4)

CABG, AVR

0 (%0)

2 (%4)

AVR, MVR

p value

0 (%0)

4 (%8)

CPB time (sn) (mean±SD)

77.0±20.2

83.4±31.5

0.48

Aortic clamp time (sn) (mean±SD)

53.4±18.4

54.6±38.7

0.08

RBC (units) (mean±SD)

3,96±2.23

1.48±0.51

<0.001*

2.12±1.01

1.12±0.67

<0.001*

21856.0±3505.6

17964.0±2400.5

<0.001*

Platelets (units) (mean ±SD) FFP (units) (mean ±SD) Fibrinogen (180350 mg/dL) (mean±SD) Heparin initial dose (IU) (mean ±SD) Reinjection dose n (%)

0 (%0)

6 (%12)

0.02*

Total heparin dose (IU) (mean ±SD)

21856.0±3505.6

18824.0±3527.9

0.004*

Protamin dose (IU) (mean ±SD)

33500.0±5199.9

26618.0±4066.7

<0.001*

ACT-1 (sn) (mean ±SD)

124.3±20.5

142.6±20.8

0.005*

ACT-2 (sn) (mean ±SD)

605.2±20.5

526.7±74.1

0.002*

ACT-3 (sn) (mean ±SD)

117.5±14.8

127.8±12.4

0.001*

Blood loss – H6 (mL) (mean ±SD)

548.0±108.4

403.2±101.2

<0.001*

Blood loss– H24 (mL) (mean ±SD)

770.0±170.7

596.4±149.6

<0.001*

2.3±0.9

1.56±0.5

0.001*

Post-op RBC (units) (mean ±SD) Post-op platelet (units) (mean ±SD)

Post-op FFP (units) (mean ±SD)

2.3±0.6

1.0±0.7

<0.001*

Reoperation n(%)

6 (%12)

4 (%8)

1.00

Complication

0.35

None

38 (%76)

42 (%84)

Stroke

4 (%8)

0 (0)

Sepsis

4 (%8)

2 (%4)

Acute renal failure

2 (%4)

0 (%0)

Respiratuar depression

2 (%4)

6 (%12)

3.8±1.2

3.0±0.9

0.005*

10 (%20)

4 (%8)

0.41

Length of ICU stay (days) (mean±SD) Mortality n(%)

*: statistically significant, SD: standart deviation, Values are expressed as mean_SEM, or n (%). FFPr6, fresh frozen plasma; H24, 24th hour postoperation; H6, sixth hour postoperation;

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Discussion In this study we observed that heparin doses calculated based on ideal body mass provided adequate anticoagulation in cardiac surgery patients. The total dose of heparin calculated including additional doses and the protamine dosage were lower in the IBW group. Postoperative drainage, postoperative blood and blood product transfusion requirements, and number of patients requiring protamine in the ICU were also higher in the TBW group. Highdose systemic heparin administered in CPB leads to bleeding in the postoperative period and causes non-surgical intracranial, gastrointestinal or urinary system hemorrhage, and also increases the need for postoperative blood transfusion and reoperations [5, 6]. The half-life of heparin is approximately 1-2 h in human plasma, depending on dose [10]. The half-life of protamine is shorter than that of heparin. When high doses are used, heparin binds to receptors on endothelial cells and macrophages and to plasma proteins, which leads to slower elimination through the kidneys, and a longer half-life [11]. Heparin rebound may be caused by high-dose heparin that is bound to the protein and does not form a complex with protamine sulfate, and these complexes may slowly dissociate and produce anticoagulant effects [12]. Several authors have reported a higher risk of postoperative bleeding when high heparin doses are used during CPB [13-16]. Dercksen et al. [17] showed that the use of high doses of heparin and protamine was responsible for defective postoperative coagulation. In a study comparing 1, 2, 2.5, and 3 mg/ kg heparin regimens, target ACT was achieved in 81.5% of patients. Postoperative blood loss in that study was found to be directly proportional to preoperative heparin doses, and postoperative blood loss was lower in patients receiving heparin at 2 mg/ kg [8]. In a study in which heparin doses were administered at 300 IU/kg and 145 IU/kg irrespective of body weight, less blood transfusion was required and less postoperative drainage volumes were observed in the low-dose heparin group [18]. Haas et al. [19] reported that when heparin was administered to obese patients based on IBW, both the amount of heparin used and potential complications associated with heparin use decreased. Evidence suggests that as body mass index increases, the percentage of body fat receiving less blood flow per gram increases [20,21]. In our opinion, dosages based on IBW can be used not only for obese, but also for non-obese patients. One study examining heparin pharmacokinetics during CPB reported wide individual differences in plasma heparin levels, and that peripheral compartment distribution contributed to these differences and was responsible for heparin rebound [22]. We therefore think that individualized heparin dose adjustment based on IBW represents a more correct approach than standard low dose heparin administration. It has been suggested that ACT has a nonlinear relationship with heparin concentration and that ACT tends to plateau in high-dose heparin concentrations. Moreover, the excess of heparin in that plateau phase, which is responsible for increased perioperative bleeding, cannot be accurately assessed using ACT [19]. The EACTA/EACTS 2017 guideline states that the best followup can be achieved with heparin blood levels, not with ACT [23]. Protamine administration is another important issue and is heparin dose-dependent. Since protamine may be associated with perioperative bleeding and increased transfusion requirements, a 1:1 dosage, equivalent to the initial heparin dose, should not be

Med Science 2019;8(1):123-8

exceeded [23]. It has also been suggested that high-dose heparin and protamine may result in postoperative clotting problems [17]. The protamine dosage should therefore be reduced in order to prevent serious dose-dependent side-effects, including arterial hypotension, pulmonary vasoconstriction, reduced cardiac output, platelet inhibition, and allergy [24,25]. The most common sideeffects in large-scale CPB studies are coagulation disorders and protamine reactions [26,27]. Low-dose heparin has been shown to result in a significant decrease in postoperative blood loss and lower protamine requirements [28]. In our study, reducing the heparin dosage resulted in a decrease in that of protamine, which contributed to decreased postoperative bleeding and additional protamine requirements in the postoperative intensive care unit. However, studies have also reported that low-dose heparin administration in patients undergoing off-pump CABG does not result in any difference in terms of intraoperative and postoperative bleeding, transfusion requirements, or complication rates [29,30]. However, these studies involved off-pump cases without CPB. Conditions used for on-pump CABG, such as CPB, high heparinization requirement, and hypothermia, lead to very complex and deleterious effects on the coagulation system. Offpump and on-pump surgery may therefore produce inconsistent results. Our study has a number of limitations. First, blood heparin levels according to ACT values were not determined. Second, other factors such as the surgical technique employed and the surgeonâ&#x20AC;&#x2122;s experience may influence postoperative bleeding rates, however, the operations performed by senior surgeons with extensive experience of cardiac surgery. Investigation of such factors would elicit a better understanding of the pharmacokinetics and volume of heparin in cardiac surgery patients. Conclusion In conclusion, sufficient anticoagulation was achieved with titration of heparin doses calculated based on IBW in cases of cardiac surgery using CPB, and total heparin and protamine dosages decreased, postoperative bleeding, blood and blood product transfusion, and hospital stays all decreased. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Our study was approved by the local ethics review board. Duygu Kara ORCID: 0000-0003-3325-2565 Cafer Mutlu Sarikas ORCID: 0000-0002-9342-7964 Asli Demir ORCID: 0000-0003-3053-0443 Mehmet Ali Kaygin ORCID: 0000-0003-2038-8244 Ertekin Utku Unal ORCID: 0000-0002-1144-8906

References 1.

Finley A, Greenberg C. Review article: heparin sensitivity and resistance: management during cardiopulmonary bypass. Anesth Analg. 2013;116:121022.

Jobes DR, Aitken GL, Shaffer GW. Increased accuracy and precision of heparin and protamine dosing reduces blood loss and transfusion in patients undergoing primary cardiac operations. J Thorac Cardiovasc Surg. 1995;110:36-45.

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Shuhaibar MN, Hargrove M, Millat MH, et al. How much heparin do we really need to go on pump? A rethink of current practices: European Journal of Cardio-thoracic Surgery. 2004:947-50.

Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th edition 2006 section 9-10, pp 1433-89.

Lobato RL, Despotis GJ, Levy JH, et al. Anticoagulation management during cardiopulmonary bypass: a survey of 54 North American institutions. J Thorac Cardiovasc Surg. 2010;139:1665-6.

Levy JH, Sniecinski RM. Activated clotting times, heparin responses, and antithrombin: have we been wrong all these years? Anesth Analg. 2010;111:833-5.

Doty DB, Knot HW, Hoyt JI, et al. Heparin dose for accurate anticoagulation in cardiac surgery. J Cardiovasc Surg. 1979;20:597-604.

Bull BS, Huse WM, Brauer FS, et al. Heparin therapy during extracorporeal circulation. II. The use of a dose-response curve to individualize heparin and protamine dosage. J Thorac Cardiovasc Surg. 1975;69:685-9.

Lorentz PDFH. Ein neuer Konstitutionsindex. Klin Wochenschr. 1929;8:34851.

10. Schulman S, Bijsterveld NR. Anticoagulants and their reversal. Transfus Med Rev. 2007;21:37-48. 11. Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecularweight heparin mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest J. 2001;119:64-94. 12. Teoh K, Young E, Bradley C, et al. Heparin binding proteins. Contribution to heparin rebound after cardiopulmonary bypass. Circulation. 1993;88:420-5. 13. Gravlee GP, Haddon WS, Rothberger HK, et al. Heparin dosing and monitoring for cardiopulmonary bypass. A comparison of techniques with measurement of subclinical plasma coagulation. J Thorac Cardiovasc Surg. 1990;99:518-27. 14. Babka R, Colby C, El-Etr A, et al. Monitoring of intraoperative heparinization and blood loss following cardiopulmonary bypass surgery. J Thorac Cardiovasc Surg. 1977;73:780-2. 15. Jobes DR, Aitken GL, Shaffer GW. Increased accuracy and precision of heparin and protamine dosing reduces blood loss and transfusion in patients undergoing primary cardiac operations. J Thorac Cardiovasc Surg. 1995;110:36-45. 16. Runge M, Møller CH, Steinbrüchel DA. Increased accuracy in heparin and protamine administration decreases bleeding: a pilot study. J Extra Corpor Technol. 2009;41:10-4. 17. Dercksen SJ, Linssen GH. Monitoring of blood coagulation in open heart surgery. II. Use of individualized dosages of heparin and protamine controlled

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by activated coagulation times. Acta Anaesthesiol Belg. 1980;31:121-8. 18. Fromes Y, Daghildjian K, Caumartin L, et al. A comparison of low vs conventional-dose heparin for minimalcardiopulmonary bypass in coronary artery bypass grafting surgery. Anaesthesia. 2011;66:488-92. 19. Haas E, Fischer F, Levy F, et al. Identifying optimal heparin management during cardiopulmonary bypass in obese patients: A prospective observational comparative study. Eur J Anaesthesiol. 2016;33:408-16. 20. Chemoyl G. Clinical Pharmacokinetics of drugs in obesity. An up-date. Clin Pharmacokinet. 1993;25:103-14. 21. Barras M, Legg A. Drug dosing in obese adults. Aust Prescr. 2017;40(5):18993. 22. Jia Z, Tian G, Ren Y, et al. Pharmacokinetic model of unfractionated heparin during and after cardiopulmonary bypass in cardiac surgery. J Transl Med. 2015;13:45. 23. Boer C, Meesters MI, Milojevic M, et al. 2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery. Task Force on Patient Blood Management for Adult Cardiac Surgery of the European Association for Cardio-Thoracic Surgery (EACTS) and the European Association of Cardiothoracic Anaesthesiology (EACTA) J Cardiothorac Vasc Anesth. 2017;S1053-0770(17)30552-9. 24. Pretorius M, Scholl FG, McFarlane JA, et al. A pilot study indicating that bradykinin B-2 receptor antagonism attenuates protamine-related hypotension after cardiopulmonary bypass. Clin Pharmacol Ther. 2005;78:477-85. 25. Miyashita T, Nakajima T, Hayashi Y, et al. Hemostatic effects of low-dose protamine following cardiopulmonary bypass. Am J Hematol. 2000;64:11215. 26. Mejak BL, Stammers A, Rauch E, et al. A retrospective study on perfusion incidents and safety devices. Perfusion. 2000;15:51–61. 27. Charriere JM, Pelissie J, Verd C, et al. Survey: Retrospective survey of monitoring/safety devices and incidents of cardiopulmonary bypass for cardiac surgery in France. J Extra Corpor Technol. 2007;39:142-57. 28. Babka R, Colby C, El-Etr A, et al. Monitoring of intraoperative heparinization and blood loss following cardiopulmonary bypass surgery. J Thorac Cardiovasc Surg. 1977;73:780-82. 29. Chun DH, Baik SW, Kim SY, et al. Heparin responsiveness during off‑pump coronary artery bypass graft surgery: Predictors and clinical implications. Acta Pharmacol Sin. 2011;32:133‑38. 30. Chakravarthy M, Prabhakumar D, Thimmannagowda P, et al. Comparison of Two Doses of Heparin on Outcome in Off-pump Coronary Artery Bypass Surgery Patients: A Prospective Randomized Control Study. Ann Card Anaesth. 2017;20:8-13.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):129-31

The effects of different centrifugation temperatures on blood coagulation parameters Esin Calci1, Cigdem Yucel2, Turan Turhan2 1 Usak Public Health Laboratory, Clinical Biochemistry, Usak, Turkey Ankara Numune Training and Research Hospital, Department of Biochemistry, Ankara, Turkey

Received 31 August 2018; Accepted 08 October 2018 Available online 13.11.2018 with doi:10.5455/medscience.2018.07.8929 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract In this study we aimed to detect the effect of different centrifugation temperatures on coagulation parameters in the emergency laboratory. Duplicate samples were collected into sodium citrate tubes from 45 patients and centrifuged concurrently with non-cooling (group 1) and cooling centrifuges (Group 2) in Ankara Numune Training and Research Hospital emergency laboratory. Inner temperatures of the centrifuges were recorded during the study. Afterwards, PT, aPTT, D-dimer and fibrinogen values were determined. No statistically significant difference was detected between groups for any of the parameters tested (PT, aPTT, D-dimer and fibrinogen) (p> 0,05). Results of the present study show that there is no significant effect of internal temperature of the centrifuge device used on blood coagulation parameters. Keywords: Coagulation, centrifugation, temperature, pre-analytical phase, sample handling

Introduction Bleeding or thrombosis occurs in people with coagulation disorders. Coagulation factors and activation of platelets result in hemostasis [1]. Prothrombin time, active partial thromboplastin time, D-dimer and fibrinogen tests are used routinely to evaluate the coagulation panels. It is important to give accurate and reliable results in in the laboratory. The laboratory testing is actually partitioned into three phases which are (pre)pre-analytical, analytical, and (post)postanalytical phases [2]. The type of anticoagulant used, sampling technique including fasting state, length of the venous stasis, order of draw, sampling from a catheter, centrifugation, transportation, and storage time and temperature time and temperature prior to analysis are the main preanalytical variables which can affect the results of coagulation tests [3-5]. Centrifugation of the samples is an important part of the preanalytical phase and common guidelines recommend the centrifugation of samples at room temperature [6,7].

*Coresponding Author: Esin Calci, Usak Public Health Laboratory, Clinical Biochemistry, Usak, Turkey E-mail: esn_calci@hotmail.com

In the present study we aimed to detect the effect of different centrifugation temperatures on coagulation parameters in the emergency laboratory with the use of cooling and non-cooling centrifuge devices. Material and Methods The study was performed in Ankara Numune Training and Research Hospital Emergency Biochemistry Laboratory. Duplicated blood samples from 45 patients were drawn into citrated tubes by the same phlebotomist (Becton, Dickinson and Company, Franklin Lakes, NJ) using 21 gauge needles for coagulation tests. All of the fasting blood samples were collected in the morning of the same day. The samples were centrifuged in the non-cooled (group 1) (NF 1200; Nüve, Turkey) and cooled (group 2) (NF 1200R; Nüve, Turkey) centrifuges at 1500 x g for 15 minutes at the same time. After centrifugation, plasma was immediately analyzed. All test parameters were studied in duplicates in the same run of the analyzer. Group 1 was centrifuged at room temperature as suggested [6] where as Group 2 was centrifuged with a cooled centrifuge. The inner temperatures of the centrifuges were recorded during the study (Group 1: 22,7-47,0°C) (Group 2: 4,8-9,9 °C). Hemolyzed, lipemic, clotted and icteric samples were excluded from the study. The duplicated samples were analyzed in a synchronized manner with ACL TOP 700 (Werfen, Warrington, UK) analyzer using 129

doi: 10.5455/medscience.2018.07.8929

original reagents. PT, aPTT, D-Dimer and fibrinogen tests were studied. PT and aPTT were measured with photometric method, fibrinogen levels were measured with Clauss method and D-dimer levels were measured with latex based immunassay. The study was approved by the local Ethics Committee of Ankara Numune Training and Research Hospital. The research protocol complies with the 2000 Declaration of Helsinki and written informed consent was obtained from all participants. Statistical Analysis The data were analyzed by using Statistical Package for Social Sciences (SPSS 18)(SPSS Inc., Chicago, IL, USA). The results are reported as median (min-max). Differences between groups were compared using Wilcoxon Signed Ranktest. P value less than 0.05 was considered statistically significant. Percent changes were calculated for each parameter with (Group2- Group1/ Group 1) *100 formula and the results were evaluated with acceptable

Med Science 2019;8(1):129-31

performance (AP) limits according to CLIA guidelines [8,9]. Results The results of the study are shown in Table 1. The internal temperature of the centrifuge devices were recorded during the study. The temperature of non-cooled centrifuge (group 1) was recorded as 22,7-26 °C while the temperature of cooled centrifuge (group 2) was recorded as 4,8-7,7 °C. When the centrifugation temperature was recorded in concurrent runs, it was observed that the maximum temperature reached by the noncooled centrifuge was 47,0 °C and that of the cooled centrifuge was 9,9 °C. There were no statistically significant differences for PT, aPTT, D-Dimer and fibrinogen results. The % differences were calculated and found to be within the desirable limits for bias derived from biological variation, with respect to current analytical quality specifications (Table 1) [9].

Table 1. Between group comparisons of the analytes Analyte

Group 1

Group 2

PT (sec)

11.7(10.0-33.0)

11.9(10.2-34.7)

0.174

aPTT (sec)

Difference,

Desirable

Bias, %

1.7

2.0

31.5(24.6-65.0)

31.1(25.1-53.4)

0.674

1.3

2.3

D-Dimer (ng/mL)

100(30- 591)

100(13-606)

0.940

8.82

Fibrinogen(mg/dL)

313(139- 511)

317(151-511)

0.135

1.3

4.8

Values are expressed as median (min-max), Group 1: non-cooled centrifuge, Group2: cooled centrifuge PT:Prothrombin time aPTT:activated partial thromboplastin time, p<0,05 statistically significant

Discussion

significant clinically.

Pre-analytical phase describes all the procedures before the initiation of the laboratory analysis and is responsible for the majority of laboratory errors [10-11]. Pre-analytical errors may occur throughout the testing process. For example, during test selection, patient preparation, sample collection, sample transport, centrifugation, and storage [12]. Centrifuges can have different rotor types like swing out and angle rotors. There are also centrifuge types such as cooled and non-cooled ones. Clinical & Laboratory Standards Institute (CLSI) guidelines recommend the plasma preparation by once-centrifugation of a whole blood sample in non-cooled centrifuges for processing routine coagulation assay [7].

Conclusion

Previously, Lippi et al. have evaluated the effect of different centrifugation temperatures (+4 °C, +12 °C, +25 °C) on routine coagulation test parameters and found that there was no significant effect of centrifugation temperature on PT, aPTT, D-dimer and fibrinogen parameters . Our findings are also similar to this study [6]. On the other hand, the study of Yılmaz et al. revealed that centrifugation temperature may affect some test results as ALT, TSH and FT4 [13]. Analyses at Lower temperatures are not recommended for most plasma-based coagulation assays because of possible cold activation of Factor VII, loss of von Willebrand factor, and platelet disruption [7,14]. In previous studie, PT was shown to be shortened on specimens carried on ice and this was devoted to activaiton of factor VII at cold [15]. On contrary to this, cooled centrifugation yielded prolonged PT results, although not

This manuscript was previously presented as a poster in the European Conference on Preanalytical Phase, Amsterdam 2017 congress.

In conclusion, pre-analytical factors in coagulation testing are critical as they may lead to diagnostic errors. Although results of the present study did not yield any significant differences in tested parameters at different centrifugation temperatures, it can be accepted as a pioneer one and future studies should be planned with enlarged sample size with various centrifugation temperatures among with the inclusion of other coagulation parameters such as coagulation factors. Acknowledgements The authors thank Nese Selcuk for technical assistance.

Competing interests The authors declare that they have no competing interest Financial Disclosure This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Ethical approval This study was conducted at Ankara Numune Teaching and Research Hospital with approval of the local Ethics Committee and suitable with the Declaration of Helsinki. (E-17-1293) Esin Calci ORCID:0000-0002-4941-1586 Cigdem Yucel ORCID:0000-0003-2647-440X Turan Turhan ORCID:0000-0002-7316-1273

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Imprecision, and Bias, derived from intra- and inter-individual biologic variation, Updated for 2014.

Elizabeth M, Van Cott MD, Micheal Laposata Ph.D: MD. Coagulation. In: Jacobs DS, et al., editors. The laboratory test handbook. 5th ed. Cleveland, OH: Lexi-Comp; 2001; p.327-58.

Lundberg G. Acting on significant laboratory results. JAMA 1981; 245:1762–3.

10. Valenstein PN, Sirota RL. Identification errors in pathology andlaboratory medicine. Clin Lab Med. 2004;24:979-96.

Lima-Oliveira G, Salvagno GL, Lippi G, et al. Could light meal jeopardize laboratory coagulation tests? Biochem Med. 2014;24:343–9.

11. Schiff GD, Hasan O, Kim S, et al. Diagnostic error in medicine: analysis of 583 physician-reported errors. Arch Intern Med. 2009;169:1881-7.

Koçak FE, Yöntem M, Yücel O, et al. The effects of transport by pneumatic tube system on blood cell count, erythrocyte sedimentation and coagulation tests. Biochem Med. 2013;23:206–10.

12. International Organization for Standardization (ISO). ISO 15189:2012: Medical laboratories: Particular requirements for quality and competence. Geneva, Switzerland: ISO; 2012.

Bonar R, Favaloro EJ, Adcock DM. Quality in coagulation and haemostasis testing. Biochem Med. 2010;20:184–99.

13. Yilmaz FM, Kıral S, Boğdaycıoglu N, et al. An underestimated preanalytical error source: Centrifuge temperature. Turk J Biochem. 2013; 38:356-9.

Lippi G, Salvagno GL, Poli G, et al. Influence of centrifugation temperature on routine coagulation testing. Clin Chem. 2006;52:537-538.

Clinical and Laboratory Standards Institute.Collection, transport, and processing of bloodspecimens for testing plasma-based coagulation assays and molecular hemostasis assays; approvedguideline H21-A5, 5rd ed. Wayne, PA: CLSI, 2008.

14. Van Geest-Daalderop JH, Mulder AB, Boonman-de Winter LJ, et al. Preanalytical variables and off-site blood collection: influences on the results of the prothrombin time/international normalized ratio test and implications for monitoring of oral anticoagulant therapy. Clin Chem. 2005;51:561-8.

westgard.com/biodatabasel.htm Desirable Specifications forTotal Error,

Ricos C, Alvarez V, Cava F, et al. Current databases on biologic variation: pros, cons, and progress. Scand J Clin Lab Invest. 1999;59:491-500.

15. Adcock D, Kressin D, Marlar R.A, The effect of time and temperature variables on routine coagulation tests. Blood Coagulation and fibrinolysis. 1998;9:463-70.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):132-7

Correlation of alvarado scoring system with C - Reactive protein and leukocytes in the diagnosis of acute appendicitis Burak Hasgul1, Serhat Karaman2, Murat Ayan2, Nilay Sefa Ucar3 1 Yozgat City Hospital, Emergency Service, Yozgat, Turkey Tokat Gaziosmanpasa University, Faculty of Medicine, Department of Emergency Medicine, Tokat, Turkey 3 Tokat City Hospital, General Surgery Service, Tokat, Turkey

Received 05 September 2018; Accepted 14 Octaber2018 Available online 13.11.2018 with doi:10.5455/medscience.2018.07.8930 Copyright ÂŠ 2019 by authors and Medicine Science Publishing Inc. Abstract In this study, we aimed to investigate the correlation of Alvarado scoring with C-reactive protein and leukocytes and the reliability of Alvarado scoring, and to guide clinicians for patient management. This study was planned as a prospective study. Data of the patients who presented to the emergency department with abdominal pain and diagnosed with acute appendicitis, and the control group were examined by the researchers. After a detailed physical examination, patientsâ&#x20AC;&#x2122; Alvarado scoring parameters and laboratory outcomes were recorded. Pathologic outcomes of the patients who were considered to have acute appendicitis and operated were studied. A different pathology other than appendicitis was found in 13 (15.1%) of 86 patients who were considered to have acute appendicitis and operated (negative appendectomy). According to the pathologic outcomes of the patient group, the most common cause of acute appendicitis was found to be fecalloids by 84.9%. Whereas simple appendicitis was observed in 85% of the patients, perforation was found in 8.2%. The most common finding of physical examination was right iliac fossa (95.8%), while the most common symptom was nausea / vomiting (67.1%) the in the cases of acute appendicitis. Among the Alvarado scoring parameters, fever was the least common symptom by 12.4%. In our study, we found a significant correlation between Alvarado scoring and leukocytes both in patients and control groups. Whereas there was no correlation between Alvarado scoring and C-reactive protein in the patient group, there was a correlation between these two parameters in the control group. There was a weak negative correlation between Alvarado scoring and acute appendicitis. Although Alvarado scoring has been reported to be a guiding scoring system in management of patients considered to have acute appendicitis, in our study this scoring was found to be statistically insignificant. Alvarado scoring alone is not sufficient in establishing a diagnosis, and the diagnosis should be supported by laboratory tests or imaging methods. Keywords: Alvarado, appendicitis, CRP, leukocyte

Introduction Acute appendicitis (AA) is one of the conditions that are seen as acute abdominal manifestation in all age groups, and require emergency surgery. Especially in young population, AA is more common between 10 and 30 years of age. Approximately 7% of general population is diagnosed with acute appendicitis in a certain period of life, and operated [1]. With early diagnosis, the rates of morbidity and mortality are low in AA [2]. AA may be encountered with different complaints, clinical findings, and laboratory outcomes. Complaints and finding may be confused with other diseases than can cause abdominal pain, causing difficulty in the diagnosis. This in turn may lead to delay in the *Coresponding Author: Serhat Karaman, Tokat Gaziosmanpasa University, Faculty of Medicine, Department of Emergency Medicine, Tokat, Turkey E-mail: drserhatkaraman@hotmail.com

diagnosis of AA or unnecessary negative appendectomy. Studies have shown various complications developing due to negative appendectomy [3]. Delayed diagnosis of AA increases possibility of perforation. Morbidity and mortality are more likely in the case of perforation. Therefore, many patients with suspected AA are taken to the operation without delaying. It has been reported that normal appendix vermiformis is encountered between 13% and 36% following appendectomy [4,5]. The most important cause of AA is lumen obstruction. Stool stones known as fecalith are the most common of lumen obstruction. The other causes may include tumors, vegetable and fruit stones, intestinal parasites, obstruction of the lumen by barium after barium imaging, and lymphoid tissue hypertrophy [6,7]. Fecaliths are responsible for the etiology in simple appendicitis by 40%, in non-perforated gangrenous appendicitis by 65%, and in perforated gangrenous appendicitis by 90% [7,8]. Easy to use, rapid and inexpensive methods are needed in order to establish the diagnosis, and reduce 132

doi: 10.5455/medscience.2018.07.8930

the rate of negative laparotomy, thus preventing the possible complications. In addition to the clinical findings and laboratory outcomes of the patient; scoring systems, ultrasonography (USG), computed tomography (CT), magnetic resonance imaging (MRI) and diagnostic laparoscopy are among the diagnostic methods [9]. Among the scoring systems, Alvarado scoring (AS) was described in 1986. AS is a clinical scoring system consisting of medical history, physical examination findings, and laboratory outcomes [9,10]. Patients with a total score ≤ 4 points are considered to have a low risk, patients with a score between 5 – 6 points are suggested to be followed-up and undergo further investigations, and those with a score ≥ 7 point should be evaluated for operation [11]. Some studies have reported the AS alone is an insufficient test to establish a diagnosis, but it may be a guiding scoring tests which can be used in clinical practice if AS is supported with imaging methods and other possible potential laboratory tests. Leukocyte and C-reactive protein (CRP) are the most used tests in the diagnosis of AA. Studies have been conducted to investigate leukocyte and CRP levels in the diagnosis of AA in emergency departments [12,13]. These parameters rapidly raise in the cases of acute inflammation. Leukocyte count is usually elevated in the patients diagnosed with AA, but leukocyte elevation may be found also in other inflammatory diseases imitating AA. Leukocyte is not helpful enough for the diagnosis despite its high sensitivity, because its specificity is low [14,15]. CRP is another test helpful for the diagnosis and is an acute phase reactant [3,16]. Elevation of serum CRP level is manifested 6-12 hours after initiation of the inflammatory process [17]. There are AA cases with normal CRP levels due to late elevation of this parameters, and there have been misdiagnosed patients with high level of CRP which may be raised also in the disease groups progressing with inflammatory process [12,18]. There are publications in the literature reporting 98% sensitivity for a combination of increased leukocyte and CRP, and appendicitis is less likely in case of both parameters being within normal limits [19]. There are different opinions in the literature about whether the AS alone is sufficient in AA or should be supported by alternative methods. In this study, we studied reliability of AS in patients with suspected AA and we reviewed the correlation of AS, CRP and leukocyte for the diagnosis in patients who presented to emergency department with abdominal pain, and aimed to guide clinicians for emergency patient management. Material and Methods The study was started after receiving the necessary approval from the Gaziosmanpasa University Medical School, Clinical Research Ethics Committee (14-KAEK-023). The study was designed as a prospective study. The stud y included a total of 150 patients including 130 patients who presented to the Gaziosmanpasa University Medical Faculty Hospital, Emergency Department (ED) with abdominal pain, and 20 patients who presented to Tokat Public Hospital with the same complaint and pathologically diagnosed with acute appendicitis between 15/08/2013 and 26/01/2016. Data of 73 patients with pathologic diagnosis of AA, and of the control group of 77 patients who were considered to not have AA after observation in the general surgery clinic were examined. All patients gave informed consent. Patients <18 years old and > 65 years, and pregnant were excluded from the study. After receiving informed consent from all patients, a detailed physical examination was performed from the time of admission to the ED. Patients’

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age, gender, vital findings, AS parameters, microbiological and biochemical laboratory parameters were recorded. Examination findings, symptoms, and laboratory outcomes in the scoring were evaluated and recorded. AS parameters are shown in Table-1. Patients’ outcomes in the ED were also recorded. Pathologic outcomes of the patients operated with the presumed diagnosis of AA were recorded. Patients whom pathologic outcome was not AA, and those considered to have appendicitis, hospitalized by the general surgery clinic, but not operated and discharged after followup were included in the control group. Patients in the control group who presented to the ED with abdominal pain, and were discharged upon the outcome was not AA, and those discharged by the general surgery clinic after follow-up were called by phone, and questioned about whether they have been diagnosed in a different center or the hospitals where this study was conducted in the following period. For complete blood count, among the microbiological parameters white blood cell (WBC) and neutrophil were recorded. Among the biochemical parameters CRP values were recorded. Complete blood count parameters were analyzed using sysmex Xn 1000, and CRP was measured using Cobase-501 devices. Statistical analysis of the data was performed using SPSS for Windows version 18.0. The correlations between AS and CRP, AS and WBC, AA and AS were tested using Chi-square independence test. p<0.5 values considered statistically significant. Table 1. Alvarado Scoring Parameters Parameters Symptoms

Signs

Points

Migratory pain

Anorexia

Nausea/Vomiting

Right lower quadrant tenderness

Rebaund

Fever (>37.3 )

Leukocytosis (>10000/mm3)

Laboratory

Shift to the left of neutrophils (>%75 neutrophil)

Total point

Results Epidemiological data of the 150 patients evaluated within the scope of this study are given in Table 2. Table 2. Epidemiological Distribution of the Patients Gender (Total=150)

Number

Female

51.3

Male

48.7

Mean

Min.-Max.

30.73+12.25

18-65

Age

Of the 150 patients, 73 (48.6%) were diagnosed with AA, while 77 (51.4%) were considered as the controls. Of the 73 patients evaluated in the AA group, 37 (50.6%) were female and 36 (49.4%) were male (F/M: 1.02 / 1). The mean age was found as 30.6 in general, 30.5 in male and 30.8 in female patients. Of patients in the AA group, 33 aged between 18-25, 23 aged between 26-40, and 17 aged 41 and over. Majority (45.2%) of 133

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the patients aged between 18-25 years. Evaluating AS scores of the AA group; 10.9% of the patients received 0-4 points, 35.6% received 5-6 points, and 53.5% received 7-10 points. Scoring points are given in Table 3. Table 3. Acute Appendicitis Group Alvarado Scores Points

Number of Patients

0-4

5-6

7-10

Total

When among AS parameters, clinical symptoms and vital signs of the AA group were examined; nausea was found in 67.1%, anorexia in 54.8%, and migration in 54.8% of the patients. Fever was observed in 12.4% and evaluated as the parameter with the lowest sensitivity. When among AS parameters, physical examination finding and laboratory parameters were analyzed; elevated leukocyte level was found in 79.4%, elevated neutrophil level in 75.3%, tenderness in the right iliac fossa in 95.8%, and rebound in 69.8% of the patients. Alvarado scoring outcomes of the AA group are given in Table 4. Table 4. Alvarado Scoring Outcomes of the Acute Appendicitis Group Parameter

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Table 5. Correlation between Acute Appendicitis and Alvarado Scoring OUTCOME Acute appendicitis

No appendicitis

Low (0-4)

Moderate (5-6)

High (7-10)

TOTAL

In contrary to what was expected, AS was not considered as significant in evaluation of patients who presented with abdominal pain for AA. When we examined AS points of 5 patients who we called by phone and learned that they have been diagnosed with AA in the following period; three of them were in the low risk group with 0-4 points, and two were in the high risk group with 7-10 points. When among AS parameters, clinical symptoms and vital signs of the control group were examined; nausea was found in 75.3%, anorexia in 44.1%, migration in 29.8%, and fever in 20.8% of the patients. When among AS parameters, physical examination finding and laboratory parameters were analyzed in the control group; elevated leukocyte level was found in 58.4%, elevated neutrophil level in 53.2%, tenderness in the right iliac fossa in 87%, and rebound in 36.3% of the patients. Alvarado scoring outcomes of the AA group are given in Table 6.

Number (73)

High

79.4

Normal

20.6

Parameter

High

75.3

Normal

Yes No

WBC

Table 6. Alvarado Scoring Outcomes of the Control Group Number (77)

High

58.4

24.7

Normal

41.6

95.8

High

53.2

4.2

Normal

46.8

Yes

69.8

Yes

30.2

67.1

Yes

36.3

32.9

63.7

54.8

Yes

75.3

45.2

24.7

Yes

54.8

Yes

44.1

45.2

55.9

Yes

12.4

Yes

29.8

87.6

70.2

Yes

20.8

79.2

Elevated neutrophil

Tenderness in the right iliac fossa

Rebound

Nausea Yes No Anorexia Yes No Migration

Fever

Appendicitis was found as a result of the pathological examination in 8 (23.5%) of 34 patients in AS 0-4 range, 26 (53%) of 49 patients in AS 5-6 range, and 39 (58.2) of 67 patients in AS 7-10 range. The correlation between AS and AA was studied with Chi-square test, and a weak and negative correlation was found between these two parameters (p<0.05). The results are given in Table 5.

WBC

Elevated neutrophil

Tenderness in the right iliac fossa

Rebound

Nausea

Anorexia

Migration

Fever

Considering the parameters in the AA and control groups; nausea which was the most common symptom in both groups was not statistically significant in the diagnosis of AA (p>0.05). Again, 134

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tenderness in the right iliac fossa which was the most common sign in both groups, was significantly higher in the AA group (p<0.05). When AS-CRP correlation was examined in the AA group; CRP values were high in 50%, and normal in 50% of 8 patients with AS 0-4 points, high in 73.1% and normal in 26.9% of 26 patients with AS 5-6 points, and high in 58.9% and normal in 41.1% of 39 patients with AS 7-10 points. There was no statistically significant correlation between AS scores and CRP values of the AA group (p>0.05). When AS-CRP correlation was examined in the control group; CRP values were high in 34.6%, and normal in 65.4% of 26 patients with AS 0-4 points, high in 47.8% and normal in 52.2% of 23 patients with AS 5-6 points, and high in 85.7% and normal in 14.3% of 28 patients with AS 7-10 points. There was a statistically significant correlation between Alvarado scores and CRP values in the control group (p<0.001). When AS-WBC correlation was examined in the AA group; WBC values were high in 37.5%, and normal in 62.5% of 8 patients with AS 0-4 points, high in 61.5% and normal in 38.5% of 26 patients with AS 5-6 points, and high in 100% 39 patients with AS 7-10 points. There was a statistically significant correlation between Alvarado scores and leukocyte values in the AA group (p<0.001). When AS-WBC correlation was examined in the control group; WBC values were high in 11.5%, and normal in 88.5% of 26 patients with AS 0-4 points, high in 65.2% and normal in 34.8% of 23 patients with AS 5-6 points, and high in 96.4% and normal in 3.6% of 28 patients with AS 7-10 points. There was a statistically significant correlation between Alvarado scores and leukocyte values in the group (p<0.001). Of all patients, 86 (57%) were considered to have AA and operated, 64 (43%) were not scheduled for operation, and discharged after follow up or because they were considered to not have AA. Operation status of the patients is given in Table 7. Table 7. Evaluation of Patients’ Operation Status Number Operated

Non-operated

Total

150

Pathological examination of the 86 operated patients was reported as AA in 73 (84.9%) patients, while there was a different pathology other than appendicitis in 13 (15.1%) patients (negative appendectomy). Of these 13 patients, pathological examination was reported as follicular lymphoid hyperplasia in 4 (30.7%), appendix vermiformis showing luminal obliteration in 4 (30.7%) patients. The other outcomes included duodenal perforation, inflammatory bowel disease, acute salpingitis, acute cholecystitis and fibro inflammation in the appendix in each one patient. These 13 patients were assigned to the control group. When pathology results of the AA group were examined; simple appendicitis was found in 62 (85%), and appendix perforation in 6 (8.2%) of the 73 patients. Whereas pathology result was necrotizing appendicitis in 5 (6.8%) patients. The cause of appendicitis was fecaloid in 62 (84.9%) of the 73 patients. Looking to the pathology outcomes, the most common cause of AA was fecaloid by 84.9%, while simple appendicitis was found in 85%, perforation in 8.2%, and necrotizing appendicitis in 6.8% of the patients.

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A total of 64 patients in the control group who were considered to not have AA after emergency department evaluation or follow up in the general surgery clinic were called by phone and asked if they have been operated due to AA after discharge. Of these, five (7.8%) patients verbally reported that they had been operated in outer center with the presumed diagnosis of AA and their pathological reports were compatible with acute appendicitis. When AS scores of these patients were examined; three patients were in the lower risk group with AS 0-4 points, and two patients were in the high risk group with 7-10 points. Discussion AA is a pathology that may be encountered in all age groups as an acute abdominal manifestation, and require emergency surgery. Early diagnosis is crucial to prevent the possible postoperative complications and patients’ comfort. Well received history and detailed physical examination are of paramount importance for the diagnosis of AA. Several studies have shown that AS alone is not sufficient for the diagnosis of AA and should be supported by various laboratory assays if available and with imaging methods if deemed necessary especially in patients with low and moderate risk [6,30,41]. Of the 73 patients in the AA group, 37 (50.6%) were female and 36 (49.4%) were male. It has been stated in the literature that AA is more common among women (F/M 1.2-1.3/1) [7]. We found F/M ratio as. While the mean age is 31.3 years in AA patients, the most common peak age has been reported as 22 years [16,26,29]. Studies by Shafi SM et al. and Bröker Me et al. reported the mean age of patients who underwent appendectomy due to AA between 20.3 and 27.1 years [20,21]. Sand M et al. found the mean age as 33.8 years [22], while Anielski R et al. reported the mean age as 36 years [23]. In the present study, the mean age was found as 30.6 years in study population, 30.5 years in male patients, and 30.8 years in female patients. We think the difference from the other studies might be resulted from the exclusion of patients < 18, and > 65 years old. Looking to our negative laparotomy data, a different pathology other than appendicitis was observed in 13 (15.1%) of 86 operated patients. Studies by Inan et al. and Lee SL et al. reported this rate between 13% and 36% [4,5]. In their two separate studies, Flum et al. found the rate of negative appendectomy as 15.5% and 23.2%, respectively [24,25]. Ma et al. reported this rate as 18.2% [26], and Mohebbi et al. as 18.2% [27]. In our study, this rate was lower than reported in the literature. One of the most common complications encountered due to the delays in diagnosis and treatment of AA is appendix perforation which progresses with high rate of morbidity and mortality. Studies by Körner et al. and Flum DR et al. reported the incidence of appendix perforation as 25.8% [24,28]. In their meta-analysis evaluating 24 studies, Andersson et al. reported the rate of appendix perforation as 17.4% [29]. In their prospective study, M Inan et al. reported this rate as 3.7% [4]. We found the rate of perforation as 8.2%. The major mechanism leading to AA is development of obstruction in the appendix lumen due to various reasons. The most common cause of this obstruction are fecaliths that are also known as stool stones. Turhan et al. and Birnbaum et al. reported the incidence of fecaliths between 15% and 30% [30, 31]. In the present study, we found the rate of fecaliths as 84.9% with histopathological studies. In their study, Wagner et al. 135

doi: 10.5455/medscience.2018.07.8930

reported two parameters with the highest sensitivity as tenderness in the right iliac fossa and vomiting after pain [32]. We found the rate of tenderness in the right iliac fossa as 95.8% and this was the highest-sensitivity parameter. In physical examinations, rebound was seen by 69.8%. Whereas nausea/vomiting was the most commonly observed symptom among the AS parameters in the AA group by 67.1%. Andersson et al. reviewed 24 study in 2004 and created a meta-analysis about clinical findings and laboratory outcomes in acute appendicitis [29]. In this analysis, two parameters with the highest diagnostic value were reported as rigidity in the right lower quadrant (involuntary defense) and migration. In our study, migration was the second most common symptom by 54.8% following nausea / vomiting. Fever (>37.3oC) was found only in 12.4% of our patients. Fever was more common in the control group (20.8%). We thought that this was resulted from the other inflammatory diseases leading to abdominal pain or various infectious reasons. We believe that, fever may be a leading sing rather in the complicated appendicitis cases. Turhan et al. stated that anorexia is one of the most important clinical findings, and the presumed diagnosis should be revised in the lack of anorexia in a case of suspected appendicitis [31]. Old et al. reported the most commonly observed signs during the diagnosis of AA as abdominal pain and anorexia [33]. We found the rate of anorexia as 54.8%, same with the migration. Lau et al. found the sensitivity of leukocytosis as 81% in 1032 patients who underwent appendectomy [34]. Peltola et al. investigate the place of leukocyte count in the diagnosis of AA in 162 patients, and found the sensitivity of leukocytosis as 58% in the uncomplicated patients, and 76% in the complicated patients [35]. Looking to these rates, Peltola emphasized the importance of serial leukocyte count in patients with suspected AA. In their study on the importance of laboratory tests in the diagnosis of AA, Marchand et al. reported the sensitivity as 84% in the patients with leukocyte count ≥ 10.000/mm3 [36]. In their study on 212 AA patients, Kafetzis et al. accepted a leukocyte count ≥ 10.000/mm3 as significant for leukocytosis, and found the sensitivity of leukocytosis as 87.5% [37]. In our study, we found the leukocyte count ≥ 10.000/mm3 in 58 of the 73 patients in the study group and the sensitivity was 79.4%, consistently with the literature. As seen in these analyses, we believe that despite it has a high sensitivity in the diagnosis of AA, leukocyte alone is not sufficient alone because of its low specificity, although it may be a guiding parameter. CRP which is among the reliable laboratory parameter in distinguishing acute bacterial inflammations from the other types has a non-specific and variable reliability [38,39]. CRP may be elevated due to infections and inflammatory diseases as well as because of several reasons including malignancies, trauma, autoimmune diseases, sepsis, burn, and ageing. It has a high sensitivity, but a low specificity [40]. Blood levels of CRP begin to raise 6 to 12 hours after the initiation of inflammatory process in AA, and further elevation of the control values with leukocyte count in the following hours supports the diagnosis of AA. In our study, we found no correlation between CRP values and AS scores of the 73 patients. We thought that this was resulted from the late elevation of CRP values during the inflammatory process of AA. Whereas, CRP was correlated with AS scores in 77 patients in the control group. Peltola et al. found significantly high CRP values 72% at least 12 hours after onset of the complaints in 162 patients

Med Science 2019;8(1):132-7

with AA. This rate was reported as 83% in the complicated cases. Both or one of CRP and leukocyte levels have been found to be high in 88% of all AA cases. This rate was reported as 96% in the complicated cases [35]. In their study with 212 AA patients, Kafetzis et al. reported CRP sensitivity as 46% and specificity as 90% in appendicitis cases [37]. In our study, we found elevated CRP by 60.2% in our patients with AA. Conclusion AA remains a condition with problems that maybe encountered in patients presenting to emergency departments with abdominal pain. AS may guide the diagnosis of AA. However, as seen in our study, there are patients with a high AS score (AS 7-10 points) but without appendicitis, as well as patients with a low score of AS (AS 0-4 points), but resulted in appendicitis. No statistically significant correlation was found between AS and CRP in the AA group. We found that tenderness in the right iliac fossa in the physical examination and in laboratory tests, leukocyte elevation is seen as the most guiding factor in AA evaluation findings from the AS parameters. According to our study results, AS is not a directacting scale for the diagnosis of AA but it is more appropriate to use it for guidance and diagnosis. Our results indicate that AS should be supported both with various laboratory tests and imaging methods in patients with suspected AA. Despite all these approach, if no any outcome could be achieved and suspicion of AA continues, the patient should be taken under observation and surgical consultation should be ordered. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval The study was started after receiving the necessary approval from the Gaziosmanpasa University Medical School, Clinical Research Ethics Committee (14-KAEK-023). Burak Hasgul ORCID:0000-0001-6779-4843 Serhat Karaman ORCID: 0000-0003-4554-1364 Murat Ayan ORCID: 0000-0001-5670-5745 Nilay Sefa Ucar ORCID: 0000-0002-5607-782X

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):138-42

Effects on patellar chondromalacia of the size of the infrapatellar fat pad Abuzer Uludag1, Mehmet Sirik2 Adiyaman University,Faculty of Medicine, Department of Orthopaedics and Traumatology, Adiyaman, Turkey 2 Adiyaman University,Faculty of Medicine, Department of Radiology, Adiyaman, Turkey

Received 14 JFebruary 2019; Accepted 18 JFebruary 2019 Available online 22.02.2019 with doi:10.5455/medscience.2019.08.9017 Copyright ÂŠ 2019 by authors and Medicine Science Publishing Inc. Abstract Infrapatellar fat tissue (IPFP), which is placed in the anterior compartment, has a vital role in the biomechanics of knee. It is thought that infrapatellar fat pad, which also functions as a storage for repair cells after injury, has a protective effect in mechanical and inflammatory knee pain. In this study, the relationship between patellar chondromalacia, which is among significant causes of anterior knee pain, and the sizes of IPFP was investigated. MRI images of patients over 18 years of age, who underwent MRI examination in June 2017 - December 2017, were examined retrospectively by recovering from the electronic patient registration system in the hospital. Eighty-three cases had patellar chondromalacia with normal-healthy IPFP tissue in the examination of knee MRI, and 53 cases without chondromalacia were included in the study. The average age of all evaluated 134 patients was 37.8 (22-68) years. The degree of chondromalacia patella was made according to Outerbridge classification. The height and depths of IPFP in all cases were measured from the widest site on the T1-weighted MRI images in the sagittal plane. The relationship among age, gender, the degree of patellar chondromalacia and IPFP sizes were evaluated. While the average of 51 patients without patellar chondromalacia was 29.04 (22-51) years, the average of 83 patients with chondromalacia was 43.20 (27-68) years. According to Outerbridge classification, patellar chondromalacia grade 3 in 14 patients, grade 2 in 41 patients, grade 1 in 26 patients and grade 4 in 2 patients were observed. It was not seen a significant difference between the groups in terms of gender (p = 0.78). It was seen a significant increase in between patellar chondromalacia and increasing age (p <0.001). It was observed that while IPFP height was averagely 35.33 mm and IPFP anteroposterior width was 17.29 mm in the patients with patellar chondromalacia, IPFP height was averagely 38.65 mm, and IPFP anteroposterior width was averagely 19.49 (15-37) mm in the patients without chondromalacia. It was observed a statistically significant increase in the frequency of patellar chondromalacia as the size of the IPFP tissue decreased (p<0.001). Incidence of patellar chondromalacia increases both with increasing age and a decrease in IPFP sizes. We consider that IPFP tissue has a contribution to joint cartilage in both biomechanical and physiological levels. For this reason, protection of IPFP tissue is required in both the prevention of patellofemoral joint degeneration and in the decrease of anterior knee pain during knee arthroscopy or arthroplasty interventions. Keywords: Infrapatellar fat pad, chondromalacia, effect, volume, size

Introduction IPFP (infrapatellar fat pad), which is also known as Hoffaâ&#x20AC;&#x2122;s fat pad, is an intra-capsular and extrasynovial structure filling the anterior knee compartment [1,2]. Gallagher et al.[3] stated that the anatomical border of this structure consists of the inferior pole of the patella in superior, anterior tibia, an intermeniscal ligament, meniscus horns and infrapatellar bursa in inferior, a patellar tendon in anterior, a femoral condyle and an intercondylar notch in posterior. Chondromalacia patella is a cartilage disease which is seen related to a disorder of hyaline cartilage covering the joint surface of the bone. It begins with the softening of the cartilage and then *Coresponding Author: Abuzer Uludag, Adiyaman University,Faculty of Medicine, Department of Orthopaedics and Traumatology, Adiyaman, Turkey E-mail: uludagabuzer@gmail.com

it results with tearing, fissuring and erosion. It is called patellar chondromalacia, patellofemoral syndrome or runners knee. It may lead to chondromalacia many causes including post-traumatic injuries, micro trauma, wear and tear, axial patella disorders, and iatrogenic injections. It may also be observed as immobilization and the complication of surgical procedures [4]. Patellar chondromalacia, which is seen mostly in the 2nd-3rd decades of life, is among the most common causes of mechanical anterior knee pain [5]. Women are affected more than man due to increased Q angle. It is observed in high incidence related to increased stress on patellofemoral joint due to especially repetitive jumping and knee bending movements in young adult runners and workers [4]. Magnetic resonance imaging (MRI) and knee arthroscopy are helpful in the diagnosis of patellar chondromalacia. MRI is a non-invasive and radiation-free gold standard procedure. Knee arthroscopy is an invasive technique which provides the direct view of patellar cartilage [5]. 138

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Med Science 2019;8(1):138-42

The main complaint in these patients is anterior knee pain. Other reasons of anterior knee pain are Hoffa’s disease, osteochondritis dissecans of the patellofemoral joint, patellar tendinitis, patella alta, patella baja, plica and bi-partite patella [4]. IPFP pathologies are one of the common causes of anterior knee pain. Recurrent local micro-traumas, impingement, local bleeding after surgery and inflammation are the most common causes of IPFP pain, and these may lead to various arthrofibrotic lesions. Abnormalities and edema observed in IPFP on MRI are often symptomatic, but some such types of changes can be observed in asymptomatic persons [6]. IPFP tissue of the patients with osteoarthritic knees have macrophages, lymphocytes, and granulocytes alongside adipocytes, and these may contribute to the progression of knee osteoarthritis. Furthermore, there are nociceptive nerve fibers in IPFP, which are thought as responsible for some of the anterior knee pain in patients with osteoarthritic knees. These nerve fibers secret substance P which induces immune responses and causes vasodilatation in response to inflammation. This substance P may cause extravasation of immune cells and edema in IPFP. Besides, IPFP tissue is secreted substances such as cytokines, interleukins, growth factors, and adipokines, which affect cartilage. These secreted substances regulate the production of matrix metalloproteinases (MMPs), stimulates the expression of pro-inflammatory cytokines, and inhibits the production of cartilage matrix proteins [1]. IPFP is a flexible structure which can adjust to different degrees of flexion and extension of the knee. The primary function of IPFP is reducing friction among patella, patellar tendon, and deep skeletal structures. It also prevents the impingement of the synovial membrane and facilitates the vascularization of adjacent structures [6]. It is evident that the biomechanics of this area are altered with IPFP extent. It was evaluated the relationship between patellar chondromalacia and the dimensions of the infrapatellar fat pad which is among the significant reasons for anterior knee pain in this study. Material and Methods MRI images of patients over 18 years of age, who underwent MRI examination in June 2017 - December 2017, were examined retrospectively by recovering from the electronic patient registration system in the hospital. The study protocol was established according to the principles of the Helsinki Declaration by obtaining approval from Adiyaman University Clinical Ethics Committee (2018/8-5) for this study. The patients who have edema, inflammation, scar and fibrosis in their IPFP tissue were excluded from the study. Eighty-three cases had patellar chondromalacia with normalhealthy IPFP tissue in the examination of knee MRI, and 53 cases without chondromalacia were included in the study. The degree of chondromalacia patella was made according to Outerbridge classification [7]. Infrapatellar fat pad height and depths in all cases were measured from the widest site on the T1-weighted MRI images in the sagittal plane (Figure 1). An experienced radiologist performed all measurements. The relationship among age, gender, the degree of patellar chondromalacia and IPFP sizes of cases were evaluated.

Figure 1. Measurement of the height and depth of the Infrapatellar fat pad

MRI protocol All MRI examinations were performed on a 1.5 T Achieva scanner (Philips, Best, The Netherlands). Sequences used for knee MR examination; 1- Axial, coronal and sagittal plane PD SPAIR (proton density, spectral attenuated inversion recovery), 2- sagittal T1W TSE image. SPAIR sequences; 1- Sagittal plane: Repetition Time (TR) 3034 ms, Echo Time (TE) 30 ms, 3.5 mm slice thickness, Gap 0.3 mm, 2- Coronal plane: Repetition Time (TR) 3034 ms, Echo Time (TE) 30 ms, 3.5 mm slice thickness, Gap 0.3 mm, 3Axial plane: Repetition Time (TR) 3034 ms, Echo Time (TE) 30 ms, 3.5 mm slice thickness, Gap 0.3 mm, T1W TSE(turbo spinecho) Coronal plane: Repetition Time (TR) 560 ms, Echo Time (TE) 17 ms, 3.5 mm slice thickness, Gap 0.6 mm. Statistical analysis Statistical analyses were obtained using the IBM SPSS Statistics 22 (Chicago, IL, USA) software program. A Student’s t-test was used to compare the normally distributed continuous parametric data between groups. Normally distributed continuous parametric data were shown as mean ± standard deviation. Non-parametric data were investigated using by the Mann-Whitney U, Chi-Square and Fisher’s exact tests. The p-values <0.05 were considered statistically significant. Results The average age of a total of 134 cases was 37.8 (22-68) years. The gender of the cases which were included in the study were 70 males and 74 females. The study involved 83 patients with chondromalacia patella and 51 patients without chondromalacia. The average age of 51 patients, 32 of them were females, and 29 were males, without chondromalacia was 29.04±7.5 (22-51) years. The average age of totally 83 patients, 41 of them were males, and 42 were females, with patellar chondromalacia was 43.20±9.6 (27-68) years. It was not seen a significant difference between the groups in terms of gender (p= 0.78). An increase in the rate of patellar chondromalacia was specified with increasing age. A statistically significant difference was observed between the patients with patellar chondromalacia and without patellar chondromalacia in terms of age. It was seen a significant increase in between patellar chondromalacia and increasing age (p<0.001). 139

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According to Outerbridge classification, patellar chondromalacia grade 3 in 14 patients, grade 2 in 41 patients, grade 1 in 26 patients and grade 4 in 2 patients were observed. When considering all patients, the average height of the IPFP was measured as 36.58 mm, and the anteroposterior width of the IPFP was measured as 17.69 mm. It was observed that while IPFP height was averagely 35.33±4.06 (26-48) mm in the patients with patellar chondromalacia, it was averagely 38.65±3.59 (32-48) mm in the patients without chondromalacia. It was observed that while IPFP anteroposterior width was averagely 17.29±2.76 (9-26) mm in the patients with patellar chondromalacia, it was averagely 19.49±3.32 (15-37) mm in the patients without chondromalacia. A statistically significant increase (p<0.001) was observed in the incidence of patellar chondromalacia as the sizes of IPFP tissue decreases. Discussion Knee osteoarthritis is a joint disease, which affects the individuals’ daily life activities and reducing their quality of life, with its chronic and progressive trend [8], and it is characterized by joint cartilage loss and osteophyte formation in old ages [9,10]. This event is not only limited to joint cartilage, but it is a process which also covers menisci, ligaments, subchondral bone, capsule, synovium, and periarticular muscles. Although the etiology of this disease cannot be fully defined, are known to have affected many factors such as genetically, metabolic and mechanical [9,10]. Osteoarthritis not only affects the medial and lateral compartments of the tibiofemoral joint but it is also observed in patellofemoral joint (PFJ). PFJ [8] osteoarthritis (PFJ OA) is observed as in the rate of %26 by being isolated in individuals with knee pain below 50 years of age, and as in the rate of %29 with tibiofemoral joint involvement [11]. In our study, it is seen that there is a linear relationship between the incidence of patellar chondromalacia and increasing age. There are relatively few studies investigating PFJ OA. Mainly, the source of pain in PFJ OA could not be detected entirely [12]. Cowan et al. [12] searched the relationship between IPFP volume and pain in the patients with and without PFJ OA. They reported that IPFP volume was more significant in the group with PFJ OA compared to the control group by 26% without adding variables and 19.6% after the variables were added. They also stated that there is a correlation between pain and volume size in patients with PFJ OA. They indicated that large-volume IPFP has a role in the development of PFJ OA. They also expressed that this coincidental relationship between PFJ changes and IPFP should be supported with further studies. IPFP protects joint against mechanical damage by its shock absorption effect [13]. Pan et al. [14] reported that every 1cm2 increase in IPFP, which is over 2.6 years, decreases total knee pain score in 0.86 in women. When the cartilage volume was considered in female patients, they informed that there was a positive correlation between the medial and lateral condyle cartilage thickness and the size of IPFP except for patella. They stated that this clinical finding indicated that the IPFP site showed a protective effect on mechanical and inflammatory knee pain. They also urged that the decrease of IPFP during knee surgery may cause an increase in knee pain in women and for this reason, it should be protected during knee surgery. However, in another study, it was reported that resection of IPFP did not affect knee

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pain and its function during total knee replacement. This situation should be interpreted with caution as there are limited studies. It was indicated that IPFP tissue has both protective and diseaseenhancing effect in OA [15]. It is thought that IPFP tissue plays a role in the biomechanics of knee or functions as a storage for repair cells after injury. Various arthrofibrotic lesions such as Hoffa’s disease, infrapatellar contracture syndrome, anterior interval scarring can be observed in IPFP due to inflammation and fibrosis. It was expressed that while positive results were obtained with arthroscopic partial resection in IPFP impingement and Hoffa’s disease, concurrent total excision with arthroplasty caused terrible results compared to partial excision [2]. Han et al. [16] reported that the IPFP site is averagely 7.59 cm2 (range 4.56 to 12.14), and less OA is seen radiographically in those with large IPFP site. They stated that there was only a correlation between osteophyte and IPFP, but there was no statistical significance. They also indicated that the knee is protective in terms of OA. Therefore the resection of normal IPFP should be avoided in knee surgeries, and special attention should be paid to IPFP in clinical events. It is observed that there are different evaluations in the abovementioned studies. In our study, it was observed that there was a decrease in the frequency of patellar chondromalacia as IPFP sizes increased. We think that IPFP tissue with its large volume in normal (healthy) structure has an especially protective effect in terms of patellar chondromalacia, and for this reason, IPFP tissue should be protected not only in arthroscopic interventions but also during arthroplasty. IPFP has long been thought of as a structural fat tissue having minimal or no metabolic response. However, it is estimated that it contributes to the expansion of the synovial space when considering its anatomical structure, and for this reason, it may increase the distribution of lubrication of the knee joint [17]. In the metaanalysis, Clockaerts et al. [1] reported that infrapatellar adipose tissue has the capacity to modify inflammatory and destructive responses in knee osteoarthritis due to its metabolic properties, containing nerve fibers, adipocytes and immune cell combinations. Furthermore, they also informed that it contributes to the disease process with the production and release of inflammatory mediators. IPFP with large-volume may cause pathological results by changing the release of cytokines from adipocytes and other potential proarthritic mediators or distribution and size of PFJ forces. On the contrary, it may also lead to the extension of IPFP by causing the change of environment with osteoarthritis molecular and local mechanical effect which first developed in PFJ. Although the cause and effect relationship between PFJ OA and IPFP volume is not entirely known, it was shown that there was a linear relationship between volume size and pain scores [12]. Gallagher et al. [3] stated in the cadaver study between 80-95 years of age that the volume of IFP is averagely 24 ml (12-36), there may be averagely 4ml difference between the right and left knees. Culvenor et al. [18] reported that IPFP volume is quite significant in the patients with chronic patellar tendinitis compared to a healthy control group. Although a whole relationship between IPFP diseases and cartilage problems is not known, it was indicated that hypertrophy and fibrosis of IPFP induce degeneration by causing an increase in cartilage contact pressure [19]. 140

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The potential role of IPFP on the development of osteoarthritis (OA) originates from the local production of adipocytokines [20]. Inflammatory adipokines, including high levels of interleukin 6, adipsin, adiponectin and visfatin, and cytokines are secreted from adipose tissue in IPFP in patients with OA [21]. Meanwhile, lipid mediators such as multiple oxylipins may play a role in the pathogenesis of OA by being secreted [22]. Favero et al. [20] reported that they observed inflammatory infiltration, vascularization, increase in interlobular septa thickness, fibrosis, and hyperplasia in the content of IPFP tissue in the patients with OA compared to control group. They indicated that they observed VEGF, MCP-1 and IL-6 proteins as higher in the content of IPFP in patients with osteoarthritis compared to the control group. They urged that while VEGF protein levels are correlated with increased vascularity, MCP-1 and IL-6 protein levels are correlated with excessive inflammatory infiltration. There is a direct relationship between anterior knee pain and IPFP. IPFP has rich vascularization and nerve innervation. The degree of nerve stimulation in inflammatory pathologies, the ratio of fibrils containing substance-P and its relationship with posterior synovial sheath affects infrapatellar knee pain [2]. Bennell et al. [23] reported that they created anterior knee pain with nociceptive stimulation in the study in which they performed hypertonic saline solution injection to demonstrate the presence and sensitivity of sensory fibers in IPFP. Pressure changes due to anterior interval volume are observed throughout the movement of the knee joint. The presence of edema in IPFP causes irritation of the adjacent tissues and an increase in pressure [2]. Ballegaard et al. [24] indicated that the amount of inflammation observed in IPFP tissue in the examination of MRI in osteoarthritic knees and perfusion changes are correlated with pain level. No relationship was found between the volume of IPFP and BMI, and total body fat [24]. Adipose tissue produces cytokines, interleukins, and growth factors through paracrine, endocrine and autocrine mechanisms. IPFP plays a role in the beginning and progression of osteoarthritis linked to its role in the release and activation of pro-inflammatory mediators. Degenerative joint disease is considered as an inflammatory process. The relationship between obesity and joint degeneration is not only correlated with the biomechanical disorder but also adipose tissue with the ability to activate the inflammatory process. It has a direct effect on the composition of synovial fluid due to IPFP localization, and it is thought that it has also effect on other elements of joint. Pro-inflammatory cytokines activate the substance P fibers that stimulate anterior knee pain. They have a direct effect in the formation of chemokines, cytokines and growth factors together with fat tissue, immune and nervous system in IPFP. All of these effects influence the metabolism and function of the synovial membrane and articular cartilage. They stated that it is essential to investigate the complex relationship among nervous system, immune system and adipose tissue in the light of this information [25]. Evaluating the role of IPFP in the knee joint involves difficulties for several reasons. When it is intended to be evaluated through arthroscopy, access to information related to pathology, physiology, and composition of pathological changes in this tissue will be restricted. Information regarding IPFP can be achieved through examining the

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specimen which was excised during knee replacement or obtained from cadaver studies. Other information is often obtained from non-invasive techniques such as ultrasound and MRI, and these examinations may specify inflammatory changes in tissue other than the information related to molecular and cellular mechanisms [15]. Sagittal MRI is the most common imaging technique to evaluate IPFP pathologies which include mass-like lesions, edema, inflammation, and fibrosis [2]. IPFP tissue is observed as predominantly hyper intense in T1-and T2-weighted MRI images, and it is structurally similar to subcutaneous fat tissue [6]. Signal changes in IPFP may be observed in noncontrast-enhanced MRI [15]. As seen in the studies reported above, PFJ arthrosis or anterior knee pain is observed in patients with large-volume IPFP tissue, who were observed with inflammation infiltration, edema, and vascularity increase. This may be explained with the process caused by mediators released from IPFP tissue. However, all patient groups had healthy IPFP tissue in our study. In this manner, we consider that healthy IPFP tissue contributes positively both to lubrication and shock absorption of the knee. This study shows the relationship only between patellar chondromalacia and IPFP sizes in the patients with healthy IPFP tissue in MRI examination. Therefore, the effect of IPFP tissue on chondromalacia or joint degeneration should be analyzed in radiological, histopathological and biochemical respects. Although there are some studies concerning the volume of IPFP tissue in the literature, as far as we know there is no study evaluating the relationship between its sizes and chondromalacia. However, this study has many potential restrictions such as its being a retrospective study, the absence of different parameter measurements such as extremity axis measurements in the knee, the lack of clinical history and examination information of patients. Conclusions Consequently, an increase in the risk of patellar chondromalacia and decrease in IPFP sizes are observed with increasing age. We can state that there is a linear relationship between the reduction of IPFP volume and chondromalacia. Therefore, we consider that IPFP tissue should be protected in both the prevention of patellofemoral joint degeneration and reduction of anterior knee pain during the interventions of knee arthroscopy or arthroplasty. Acknowledgments: The author would like to thank for data collection to Assoc. Prof. Dr. H. Bayram Tosun. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support. Ethical approval The study protocol was established according to the principles of the Helsinki Declaration by obtaining approval from Adiyaman University Clinical Ethics Committee (2018/8-5) for this study. Abuzer Uludag ORCID: 0000-0003-3556-4327 Mehmet Sirik ORCID: 0000-0002-5543-3634

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Clockaerts S, Bastiaansen-Jenniskens YM, Runhaar J, et al. The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: a narrative review. Osteoarthritis Cartilage. 2010;18:876-82.

Dragoo JL, Johnson C, McConnell J. Evaluation and treatment of disorders of the infrapatellar fat pad. Sports Med. 2012;42:51-67.

Gallagher J, Tierney P, Murray P, et al. The infrapatellar fat pad : anatomy and clinical correlations. Knee Surg Sports Traumatol Arthrosc. 2005;13:268-72

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Salehi-Abari I, Khazaeli S, Niksirat A. Chondromalacia patella and new diagnostic criteria. Open Sci J Clin Med. 2015;3:126-8.

Draghi F, Ferrozzi G, Urciuoli L, et al. Hoffa’s fat pad abnormalities, knee pain and magnetic resonance imaging in daily practice. Insights Imaging. 2016;7:373-83.

Outerbridge RE. The etiology of chondromalacia patellae. 1961.Clin Orthop Relat Res. 2001;389:5-8.

Hinman RS, Crossley KM. Patellofemoral joint osteoarthritis: an important subgroup of knee osteoarthritis. Rheumatology (Oxford). 2007;46:1057-62.

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10. Hunter DJ, Spector TD. The role of bone metabolism in osteoarthritis. Curr Rheumatol Rep. 2003;5:15-9. 11. Hinman RS, Lentzos J, Vicenzino B, et al. Is patellofemoral osteoarthritis common in middle-aged people with chronic patellofemoral pain? Arthritis Care Res. 2014;66:1252-7. 12. Cowan SM, Hart HF, Warden SJ, et al. Infrapatellar fat pad volume is greater in individuals with patellofemoral joint osteoarthritis and associated with pain. Rheumatol Int. 2015;35:1439-42. 13. Kohn D, Deiler S, Rudert M. Arteria blond supply of the infrapatellar fat pad. Anatomy and clinical consequences. Arch Orthop Trauma Surg. 1995;114:725. 14. Pan F, Han W, Wang X, et al. A longitudinal study of the association between infrapatellar fat pad maximal area and changes in knee symptoms and

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structure in older adults. Ann Rheum Dis. 2015;74:1818-24. 15. Ioan-Facsinay A, Kloppenburg M. An emerging player in knee osteoarthritis: the infrapatellar fat pad. Arthritis Res Ther. 2013;15:225. 16. Han W, Cai S, Liu Z, Jin X, Wang X, Antony B, et al. Infrapatellar fat pad in the knee: is local fat good or bad for knee osteoarthritis? Arthritis Res Ther. 2014;16:145. 17. Saddık D, McNally EG, Richardson M. MRI of Hoffa’s fat pad. Skeletal Radiol. 2004;33:433-44. 18. Culvenor AG, Cook JL, Warden SJ, Crossley KM. Infrapatellar fat pad size, but not patellar alignment, is associated with patellar tendinopathy. Scand J Med Sci Sports. 2011;21:405-11. 19. Kumar D, Alvand A, Beacon JP. Impingement of infrapatellar fat pad (Hoffa’s disease): results of high-portal arthroscopic resection. Arthroscopy. 2007;23:1180,1186.e1 20. Favero M, El-Hadi H, Belluzzi E, Granzotto M, Porzionato A, Sarasin G, et al. Infrapatellar fat pad features in osteoarthritis: a histopathological and molecular study. Rheumatology (Oxford). 2017;56:1784-93. 21. Klein-Wieringa IR, Kloppenburg M, Bastiaansen-Jenniskens YM, Yusuf E, Kwekkeboom JC, El-Bannoudi H, et al. The infrapatellar fat pad of patients with osteoarthritis has an inflammatory phenotype. Ann Rheum Dis. 2011;70:851-70. 22. Gierman LM, Wopereis S, van El B, Verheij ER, Werff-van der Vat BJ, Bastiaansen-Jenniskens YM, Metabolic profiling reveals differences in concentrations of oxylipins and fatty acids secreted by the infrapatellar fat pad of end-stage osteoarthritis and normal donors. Arthritis Rheum. 2013;65:2606-14. 23. Bennell K, Hodges P, Mellor R, Bexander C, Souvlis T. The nature of anterior knee pain following injection of hypertonic saline into the infrapatellar fat pad. J Orthop Res. 2004;22:116-21. 24. Ballegaard C, Riis RG, Bliddal H, Christensen R, Henriksen M, Bartels EM, et al. Knee pain and inflammation in the infrapatellar fat pad estimated by conventional and dynamic contrast-enhanced magnetic resonance imaging in obese patients with osteoarthritis: a cross-sectional study. Osteoarthritis Cartilage. 2014;22:933-40. 25. Paduszyński W, Jeśkiewicz M, Uchański P, Gackowski S, Radkowski M, Demkow U. Hoffa’s Fat Pad Abnormality in the Development of Knee Osteoarthritis. Adv Exp Med Biol. 2018;1039:95-102.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):143-7

Association between heart rate turbulence and anxiety symptom levels Bugra Ozkan, Ozcan Orscelik, Cevahir Ozkan, Mert Koray Ozcan, Ayca Arslan, Ahmet Celik, Ismail Turkay Ozcan Mersin University Faculty of Medicine.Department of Cardiology, Mersin, Turkey Received 06 August 2018; Accepted 18 October 2018 Available online 16.11.2018 with doi:10.5455/medscience.2018.07.8931 Copyright ÂŠ 2019 by authors and Medicine Science Publishing Inc. Abstract General anxiety disorder (GAD) is a condition characterized by extreme, persistent, and uncontrollable worry lasting for more than six months. In addition to cognitive and behavioral symptoms, individuals with GAD also commonly exhibit physical signs and autonomic nervous system symptoms. Heart rate turbulence (HRT) is the assessment of sinus rhythm cycle fluctuation occurring in the presence of ventricular premature contraction (VPC), and is a parameter used to show autonomic dysfunction. There are no studies in the literature investigating the association between GAD and HRT. The aim of the present study was to determine the association between HRT and anxiety symptom levels. The study included 72 consecutive patients. The patients were fitted with Holter devices for 24-hr rhythm monitoring and asked to complete the Hospital Anxiety and Depression Scale (HADS) to assess their anxiety symptom levels. The study participants were grouped based on the severity of their anxiety symptoms as low (group 1) and high (group 2). Of the 72 participants, 26 had high anxiety levels and 46 had low anxiety levels. There was a significant difference between the two groups in HRT parameters. Patients in the high-anxiety group had significantly higher turbulence onset (TO) and significantly lower turbulence slope (TS) when compared with the low-anxiety group. Anxiety score was positively correlated with TO (r=0.296, p=0.01) and negatively correlated with TS (r=-0.304, p=0.009). In the present study, we found that patients with high anxiety levels showed greater abnormality in HRT parameters, indicating autonomic dysfunction. Keywords: Heart rate turbulence, anxiety, autonomic dysfunction

Introduction General anxiety disorder (GAD) is a condition characterized by extreme, persistent, and uncontrollable worry lasting longer than 6 months. A review of epidemiologic studies conducted in Europe reported that GAD has a prevalence of 4.3-5.9% and is seen more frequently in women and the elderly.1,2 In addition to cognitive and behavioral symptoms, individuals with GAD also commonly exhibit physical signs such as fatigue and myalgia. They often exhibit symptoms related to the autonomic nervous system such as palpitations, sweating, shivering, and hot flashes [3,4]. Ventricular premature contractions (VPC) are extra beats triggered by the myocardium in various conditions. They may occur in *Coresponding Author: Bugra Ozkan, Mersin University Faculty of Medicine. Department of Cardiology, Mersin, Turkey E-mail: bugraozkan@yahoo.com

individuals with no heart disease, and are seen in various heart conditions, independent of disease severity. The prevalence of VPC is up to 80% in 24-hr rhythm Holter recordings in the general population and increases with advancing age [5]. Heart rate turbulence (HRT) is the assessment of sinus rhythm cycle fluctuation occurring in the presence of VPC and is a parameter used to show autonomic dysfunction [6]. HRT comprises two parameters, turbulence onset (TO) and turbulence slope (TS), which are calculated from VPCs on rhythm Holter recordings. HRT measurement can be done in individuals showing at least 5 VPCs during 24-hr rhythm Holter monitoring. Heart rate variability (HRV), defined as cyclic changes in sinus speed over time, provides information about sympathetic/ parasympathetic balance and is thus evaluated as a measure of cardiac autonomic tone and as a cardiorespiratory system indicator. Previous studies have shown that HRT is a stronger and more independent predictor of mortality than HRV [7]. Although 143

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HRV has been used to demonstrate autonomic dysfunction in GAD patients, there are no studies in the literature investigating the association between GAD and HRT [8]. The aim of the present study was to evaluate the relationship between anxiety levels and HRT parameters as indicators of autonomic dysfunction. Material and Methods Participants The study included 72 consecutive patients between 18-80 years of age who presented to the cardiology outpatient clinic with complaints of palpitations and showed at least 5 VPCs during 24hr rhythm Holter monitoring. Patients who were unable to sign the informed consent form, those with thyroid dysfunction, coronary artery disease, or heart failure, and those using beta blockers and antiarrhythmic drugs that may affect VPC were excluded. Other exclusion criteria were: chronic systemic disease, congenital heart disease, significant valvular heart disease, hypertrophic cardiomyopathy and cor-pulmonale [9]. The patients’ demographic data, left ventricular ejection fraction measured from transthoracic echocardiographs, and blood test results were recorded. This study was approved by the local clinical research ethics committee (2017/146). Sample size The number of patients to include in the study was determined by power analysis. A total of 44 patients (22 patients in each group) are needed to achieve 80% power at two-sided 5% significance level (MedCalc 9.2.0.1). Biomedical data Venous blood samples were taken in the morning between 8:00-8:30 after a 12-hr fast. Height (cm) and weight (kg) were recorded and used to calculate body mass index (BMI). Patients’ 24-hr rhythm Holter recordings were analyzed using the Cardio Track Holter Analysis System (Hangzhou, China). TO evaluates the presence of tachycardia by comparing the average interval between two normal beats before and after a VPC. A lack of this response (TO ≥0) is a sign of insufficient autonomic adaptation. TO reflects vagal break ability, which is necessary to compensate for acute cardiac output loss due to VPC. TS measures the degree of heart rate deceleration (bradycardia, tachycardia, return to baseline level) after a VPC. TS <2.5 is a strong indicator of autonomic dysfunction of the cardiovascular system [10]. Previous studies have shown that abnormal HRT is an indicator of cardiac autonomic dysfunction and leads to higher mortality [11-13]. TO and TS were calculated automatically by the software (Cardio Track Holter System Premier version 1.4.1.5). Psychometric measurements The patients were fitted with 24-hr rhythm Holter devices and asked to complete the Hospital Anxiety and Depression Scale (HADS) to assess their anxiety symptom levels. The HADS is one of the most widely used tools in the assessment and management of anxiety and depression symptoms. The HADS has separate scales for anxiety and depression. The HADS consists of two factors: the first is anxiety symptoms and the second is depression symptoms. Using receiver operating characteristic curve analysis, cut-off points for the Turkish version of the HADS were determined as 10 points for the anxiety subscale and 7 points for the depression subscale

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[14]. This scale was originally designed to detect symptoms of depression and anxiety in patients attending medical outpatient clinics [14]. Although the scale uses the word “hospital”, it can also be used in every health establishment including outpatient polyclinics. Both the original HADS and the Turkish version have been shown to be valid and reliable in the assessment of outpatients [15,16]. A cardiology specialist measured the physiological parameters and a psychiatrist administered the HADS. After the patients in our study were fitted with 24-hr Holter monitors, they were given the HADS questionnaire form and asked to fill it in while the Holter monitor was recording. The HADS form was given after the patient was fitted with a 24-hour rhythm holter and was asked to fill out the form themselves during recording. The patients returned the HADS forms together with their Holter monitors when they returned to the outpatient clinic 24 hours later. The patients’ responses were recorded by two separate psychiatric specialists who had no knowledge of the study and their anxiety and depression scores were calculated. The study participants were separated into groups based on the severity of their anxiety symptoms as low (group 1) and high (group 2). Patients without anxiety symptoms also were included in the low anxiety level group. Statistical analysis Statistical analyses were done using SPSS version 21.0 (SPSS Inc., Chicago, IL, USA) software package. The data were evaluated for normal distribution using the Kolmogorov-Smirnov test. Categorical variables were expressed as percentage; numerical variables showing normal distribution (parametric) were expressed as mean ± standard deviation and those not normally distributed (non-parametric) were expressed as median and interquartile range. Student’s t-test or Mann-Whitney U test was used to analyze numerical variables; chi-square (χ2) test was used for categorical variables. Correlation analysis was done with Pearson rank test for parametric variables and Spearman test for non-parametric variables. P values less than 0.05 were accepted as statistically significant. Results Seventy-two participants were included in the study, 26 with high anxiety levels (group 1; 18 females, mean age 45.6±16.1 years) and 46 with low anxiety levels (group 2; 27 females, mean age 47.5±16.9 years). The study participants’ demographic and clinical characteristics are presented in Table I. There were no significant differences between the groups with respect to diabetes mellitus, hypertension, cigarette use, body mass index, or biochemical and hematologic parameters. Patients in the high-anxiety group had significantly higher TO (0.6 vs. -2.2, p<0.001) and significantly lower TS (1.8 vs. 3.5, p<0.001) when compared with the lowanxiety group (Table I). When TO and TS values were classified as normal and abnormal, patients with high anxiety scores had higher rates of abnormal TO (65.3% and 19.7% respectively in the high and low anxiety groups, p<0.001) and TS (80.7% and 34.7% respectively, p<0.001) (Table II). Anxiety score was positively correlated with TO (r=0.296, p=0.01) (Figure 1) and negatively correlated with TS (r=-0.304, p=0.009) (Figure 2). 144

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Table 1. Demographic, echocardiographic and clinical features of patients according to anxiety level.

Variable

Low anxiety level Group (n=46)

High anxiety level Group (n=26)

Age, year

45.6 ± 16.1

47.5 ± 16.9

0.64

Gender, male (n,%)

19, %41.3

8, %30.7

0.37

DM, present (n,%)

10, %21.7

7, %26.9

0.61

HT, present (n,%)

12, %26

7, %26.9

0.91

Creatinine, mg/dl

0.9 ±1.0

0.77±0.2

0.4

119.4±39.3

96.5±34.3

0.62

Active Smoking, (n,%)

12, %26

6, %23

0.77

TSH (µıu/mL)

1.9±1.4

1.8±0.8

0.08

Body mass index(kg/m2)

26.5±2.6

27.1±2.5

0.16

-2.23±3.2

0.66±3.3

<0.001

3.57±3.3

1.86±2.2

<0.001

LDL Cholesterol, mg/dL

DM; diabetes mellitus, HT; hypertension, LDL; low density lipoprotein, TSH; Thyroid stimulating hormone, TO; turbulence onset, TS; turbulence slope p value below 0.05 was considered significant and significant parameters were shown by bold type

Table 2. The relationship with anxiety levels and abnormal heart rate turbulence. Low anxiety level group n=46

High anxiety level group n=26

Abnormal TO

9, %19.5

17, %65.3

<0.005

Abnormal TS

16, %34.7

21, %80.7

<0.005

TO; turbulence onset, TS; turbulence slope, HRT; heart rate turbulence, Abnornmal TO; TO≥0, Abnormal TS; TS≤2.5 p value below 0.05 was considered significant and significant parameters were shown by bold type

Figure 2. Correlation between turbulence slope and anxiety level (scatter dot). TS; turbulence slope

Discussion The effect of anxiety disorder on autonomic dysfunction was previously demonstrated in a study using HRV.8 The present study is the first in the literature to investigate the effect of anxiety level on HRT. In the present study, we found that patients with high anxiety levels showed greater abnormality in HRT parameters indicating autonomic dysfunction, and the degree of abnormality correlated with anxiety scores.

Figure 1. Correlation between turbulence onset and anxiety level (scatter dot). TO; turbulence onset

Certain psychiatric diseases have been shown to cause dysregulation of the autonomic nervous system. Kop et al. found that cardiovascular mortality was higher in patients with autonomic nervous system dysfunction detected by HRT [17]. Carney et al. 145

doi: 10.5455/medscience.2018.07.8931

reported that patients with depression following acute myocardial infarction had a higher incidence of abnormal HRT measurement and higher mortality rate [18]. Although autonomic dysfunction has been shown in depressed patients using the HRT method, our study is the first to use HRT to demonstrate autonomic impairment in patients with GAD. GAD and depression are distinct psychiatric disorders. Depression is described as having feelings of anguish or despair and no longer deriving pleasure from activities once enjoyed. GAD is a common condition characterized by uncontrollable, extreme agitation and anxiety. Anxiety disorders have been shown to increase the risk of cardiovascular disease by 3-4 fold, and approximately double the risk of cardiac mortality [19,20]. In previous studies, GAD was found to cause disruption between the cortical and subcortical networks [21]. This connection is believed to be an important component of the central autonomic network [22]. There are studies in the literature demonstrating autonomic dysfunction in individuals with anxiety disorder. Furthermore, meta-analyses have revealed that this autonomic disruption is independent of medication use and medical comorbidities [23]. Kim et al observed that GAD patients not under medical treatment showed greater abnormality in HRV parameters when compared with healthy individuals [24]. Abnormal HRV due to psychological stress is thought to develop secondary to reduced parasympathetic tone [25]. GAD compounded by major depression was found to have a stronger negative effect on HRV compared to GAD alone [14]. In the present study, patients presenting to a cardiology outpatient clinic with complaints of palpitations were asked to complete the HADS in order to determine their anxiety symptom levels. Zigmond and Snaith developed and demonstrated the validity and reliability of the HADS in 1983 [15]. A VPC is followed by a temporary drop in blood pressure. This results in decreased baroreceptor activity and reduced vagal stimulation, which in turn causes the heart rate to increase. Following increased myocardial contractility and blood pressure after a VPC, sinus node activity declines due to a counter effect, creating a biphasic HRT curve with increases and decreases. Abnormal HRT is a sign of autonomic dysfunction or impaired baroreflex sensitivity and increases the risk of mortality and sudden death [26]. Previous studies have reported abnormal HRT in conditions such as coronary artery disease [27], heart failure [28], metabolic syndrome [29], and polycystic ovary syndrome. Furthermore, Baydar et al showed that abnormal HRT was correlated with coronary artery disease severity [30]. There are no other studies in the literature that evaluate the relationship between anxiety level and HRT. Limitations of Study One of the limitations of this study is the relatively limited number of patients and correlation analysis revealing weak correlations. Groups are also heterogeneous. We believe that a thorough assessment of HRT parameters following psychiatric therapy in patients with high anxiety levels will better elucidate the relationship between anxiety and HRT. Conclusion Disrupted HRT function is an important indicator of autonomic dysfunction and is associated with increased mortality. HRV has

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been used to demonstrate the negative effects of anxiety disorders on autonomous function. In the present study, we found that patients with high anxiety levels showed greater abnormality in HRT parameters indicating autonomic dysfunction. Anxiety levels were positively correlated with TO and negatively correlated with TS. Results from this study suggest that the long-term adverse cardiovascular consequences of anxiety may be partially explained by autonomic dysfunction. Treatment of patients with anxiety by either pharmacological or psychological interventions may lead to improved long-term cardiovascular outcomes. The manuscript was presented as a poster in the 33th. Turkish Cardiology Congress with International Participation. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Before the study, permissions were obtained from local ethical committee. Bugra Ozkan ORCID:0000-0002-0603-4370 Ozcan Orscelik ORCID:0000-0003-4349-9852 Cevahir Ozkan ORCID:0000-0001-8805-9944 Mert Koray Ozcan ORCID:0000-0001-6075-753 Ayca Arslan ORCID:0000-0002-9152-1199 Ahmet Celik ORCID:0000-0002-9417-7610 Ismail Turkay Ozcan ORCID:0000-0001-6607-8474

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Miloyan B, Pachana NA. Clinical significance of worry and physical symptoms in late-life generalized anxiety disorder. Int J Geriatr Psychiatry. 2015;30:1186â&#x20AC;&#x201C;94.

Tully PJ, Cosh SM, Baune BT. A review of the affects of worry and generalized anxiety disorder upon cardiovascular health and coronary heart disease. Psychol Health Med. 2013;18:627-44.

Lichstein E, Morganroth J, Harrist R, et al. Effect of propranolol on ventricular arrhythmia. The beta-blocker heart attack trial experience. Circulation. 1983;67:15.

Watanabe MA, Schmidt G. Heart rate turbulence: a 5-year review. Heart rhythm. 2004;1:732-8.

Francis J, Watanabe MA, Schmidt G. Heart rate turbulence: a new predictor for risk of sudden cardiac death. Ann Noninvasive Electrocardiol. 2005;10:1029.

Lyonfields JD, Borkovec TD, Thayer JF. Vagal tone in generalized anxiety disorder and the effects of a versiveimagery and worri some thinking. Behav Ther. 1995;26:457-66.

Soylu MO, Altun I, Basaran O, et al. Impact of QRS morphology on heart rate turbulence and heart rate variability after cardiac resynchronization therapy in patients with heart failure. Eur Rev Med Pharmacol Sci. 2016;20:317-22.

10. Bauer A, Malik M, Schmidt G, et al. Heart rate turbulence: standards of measurement, physiological interpretation, and clinical use: International Society for Holter and Noninvasive Electrophysiology Consensus. J Am Coll Cardiol. 2008;52:1353-65. 11. Davies LC, Francis DP, Ponikowski Pet al. Relation of heart rate and blood pressure turbulence following premature ventricular complexes to baroreflex

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doi: 10.5455/medscience.2018.07.8931 sensitivity in chronic congestive heart failure. Am J Cardiol. 2001;87:737-42. 12. Mrowka R, Persson PB, Theres H, et al. Blunted arterial baroreflex causes “pathological” heart rate turbulence. Am J Physiol Regul Integr Comp Physiol. 2000;279:1171-5. 13. Ghuran A, Reid F, La Rovere MT, et al. Heart rate turbulence-based predictors of fatal and nonfatal cardiac arrest (The Autonomic Tone and Reflexes After Myocardial Infarction substudy). Am J Cardiol. 2002;89:184-90. 14. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67:361-370. 15. Aydemir O, Guvenir T, Kuey L, ve ark. Hastane anksiyete ve depresyon ölçeği Türkçe formunun geçerlilik ve güvenilirlik çalışması. Türk psikiyatri dergisi. 1997;8:280-7. 16. Härter MC, Conway KP, Merikangas KR. Associations between anxiety disorders and physical illness. Eur Arch Psychiatry Clin Neurosci. 2003;253:313-20. 17. Kop WJ, Stein PK, Tracy RP, et al. Autonomic nervous system dysfunction and inflammation contribute to the increased cardiovascular mortality risk associated with depression. Psychosom Med. 2010;72:626-35.

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understanding of pathological anxiety: the dorsal medial prefrontal-amygdala ‘aversive amplification’ circuit in unmedicated generalized and social anxiety disorders. Lancet Psychiatry. 2014;1:294-302. 22. Thayer JF, Friedman BH, Borkovec TD. Autonomic characteristics of generalized anxiety disorder and worry. Biol Psychiatry. 1996;39:255-66. 23. Kim K, Lee S, Kim JH. Diminished autonomic neurocardiac function in patients with generalized anxiety disorder. Neuropsychiatr Dis Treat. 2016;12:3111-8. 24. Berntson GG, Cacioppo JT, Quigley KS. Respiratory sinus arrhythmia: autonomic origins, physiological mechanisms, and psychophysiological implications. Psychophysiology. 1993;30:183-96. 25. Porges SW. Cardiac vagal tone: a physiological index of stress. Neurosci Biobehav Rev. 1995;19:225-33. 26. Lin LY, Lai LP, Lin JL, et al. Tight mechanism correlation between heart rate turbulence and baroreflex sensitivity: sequential autonomic blockade analysis. J Cardiovasc Electrophysiol. 2002;13:427-31. 27. Barthel P, Schneider R, Bauer A, et al. Risk stratification after acute myocardial infarction by heart rate turbulence. Circulation. 2003;108:1221-6.

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28. Koyoma J, Watanabe J, Yamada A, et al. Evaluation of heart rate turbulence as a new prognostic maker in patients with chronic heart failure. Circ J. 2002;66:902-7.

19. Vogelzangs N, Seldenrijk A, Beekman AT, et al. Cardiovascular disease in persons with depressive and anxiety disorders. J Affect Disord. 2010;125:241-8.

29. Erdem A, Uenishi A, Küçükdurmaz Z, et al. The effect of metabolic syndrome on heart rate turbulence in non-diabetic patients. Cardiol J. 2012;5:507-12.

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30. Baydar O, Oktay V, Sinan ÜY, et al. Heart rate turbulence in patients with stable coronary artery disease and its relationship with the severity of the disease. Turk Kardiyol Dern Ars. 2015;43:594-8. .

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Available online at www.medicinescience.org

ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):148-53

A study examining women’s sexual function in twelve months postpartum Eda Sahin1, Ayten Senturk Erenel2 Giresun University Health Science Faculty, Department of Obstetric and Gynecologic Nursing, Giresun, Turkey 2 Gazi University Health Science Faculty, Department of Obstetric and Gynecologic Nursing, Ankara, Turkey

Received 08 October 2018; Accepted 19 October 2018 Available online 28.12.2018 with doi:10.5455/medscience.2018.07.8953 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The postpartum period has physical, psychological, and social effects on women’s health, two of which include sexual function and dysfunction. The aim of this study was to identify women’s sexual function in twelve months postpartum. This descriptive study was conducted between January and May 2018 at the Well-Child Outpatient Service at Giresun University’s Women’s Obstetrics and Gynaecology Training and Research Hospital. The sample of the study consisted of all women who applied to the clinic and who met the inclusion criteria. The research population consisted of 236 women with 0 to 12 month-old children. The ‘Identification Features Specification Form’ and ‘Turkish Version of the Sexual Distress Scale-Revised (Tr-FSDS-R)’ were used in order to collect data. The Mann Whitney U and Kruskal-Wallis tests, as well as Spearman correlation analysis were used in the analyses because the data did not show any normal distribution features. The age average of the participants was 28.68 ± 5.43. The mean Tr-FSDS-R score was determined as 7.50 ± 9.45 (min0- max52). SD was found in 24.6% (n:59) of women when the cut point of the scale (>11.5) was taken into consideration. A positive weak correlation was seen between the mean Tr-FSDS-R score of women and the average of marital year points. The mean Tr-FSDS-R score significantly differed depending on the time of sexual intercourse (z: -2.61, p:0.009), the use of contraception (z:-2.20, p:0.028), and current sexual activeness (x2:64.798, p:0.000) (p<0.05). In conclusion, a significant proportion of women experience sexual problems during the postpartum period. Keywords: Nursing, sexual distress, postpartum period, postpartum sexuality

Introduction The World Health Organization (WHO) defines sexual health as a state of physical, mental, and social wellbeing in relation to sexuality [1]. Various elements such as anatomical, physiological, psychological, and socio-cultural factors, as well as educational level, age, illness, and life stages all affect sexuality. Sexual function is influenced by the structure and function of the tissues and organs that play a role in sexual function, mental state; societal customs and traditions, beliefs, values, law pertaining to sexuality, and forms of sexual behaviour [1]. Therefore, apart from affecting sexual function and sexual health, sexual dysfunction is seen as a multidimensional health problem. Several studies suggest that female sexual function also may be affected factors such as chronic diseases (e.g. diabetes and hypertension), neurological and hormonal imbalances, depression, age, education level, income, body mass index, emotional and social status, socioeconomic and environmental factors, *Coresponding Author: Eda Sahin, Giresun University Health Science Faculty, Department of Obstetric and Gynecologic Nursing, Giresun, Turkey E-mail: edabasustaoglu@gmail.com

menopause, general health, family planning (including methods used, information, and attitudes towards sexuality), drugs used, physical, and mental health [2,3]. The postpartum period affects female sexual function. Factors such as hormonal, physical and psychological changes during this period, parenting roles, infant care, breastfeeding, fatigue, insomnia, customs, beliefs, and traditions influence all female sexual function [4,5]. It is also known that the number of children a woman has given birth to, her age, and the number of her births that have been intervened upon (e.g. episiotomy, vacuum, forceps) can negative effect sexual function after birth [6]. The sexual problems women faced during this period primarily relate to sexual drive, arousal, orgasmic disorders, dyspareunia, and vaginismus [7]. Many studies have reported that women receiving episiotomy experience dyspareunia during the postpartum period [6-8]. Upon examining the literature, one observes that studies probing women’s health during the postpartum period generally take a look at psychological and physiological issues. Moreover, in Turkey, there is a limited number of studies related to sexual health in relation to women and family health. Sexual life and function are considered taboo in conservative societies, which thus poses a 148

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hindrance towards health workers, women, and couples access to sexual health care services. Nurses have important responsibilities in the protection and development of health. Hence, nurses ought to provide women with opportunities to express, identify, and resolve their sexual problems, which in turn would better contribute to enhancing women’s and families’ health and quality of life, as well as in order to achieve occupational satisfaction by providing holistic and professional care. Therefore, it is believed that examine women’s sexual function during the postpartum period will contribute to the literature as well as raise awareness about the issue of sexual health in every environment where nursing services are provided. Aim The aim of our research was to identify women’s sexual function over twelve months postpartum. Material and Methods This descriptive study was conducted between January and May 2018 at the Well-Child Outpatient Service at Giresun University’s Women’s Obstetrics and Gynaecology Training and Research Hospital. The sample of the study consisted of all women who applied to the clinic and who met the inclusion criteria (have children between the ages of 0 to 12 month old children, able to read and write in Turkish and willing to participate in the study) between the dates the study took place. We calculated the sample size using Power and Sample Size Programme. In 2017, the number of women admitted to the outpatient clinic was 1840. We calculated that a sample size of 236 women, within a confidence interval of 90% and a power of 80%. The ‘Identification Features Specification Form’ and ‘Turkish Sexual Distress Scale-Revised’ (Tr-FSDS-R) were used in order to collect data. The ‘Identification Features Specification Form’ consists of 19 questions related to women’s and their spouses’ socio-demographic characteristics (e.g. age, place of birth, education level), as well as women’s obstetric characteristics and their current sexual lives [24,6,7]. The Tr-FSDS-R Scale is a patient-reported outcome measure consisting of 13 items assessing different aspects of sexual activityrelated distress in women. It is a self-report scale developed by DeRogatis in the United States [3]. The reliability and validity of the Turkish version of the scale was determined by Kitis (2016) [9]. The intra-class correlation coefficient of the scale was identified as being 0.74, and the Cronbach alpha coefficient determined as being 0.86 [9]. 13 items are scored on a five-point Likert-type scale: never (0), rarely (1), occasionally (2), frequently (3), or always (4). A total score ranging from 0 to 52 can be computed by adding the score of all 13 items. Higher scores indicate higher levels of sexual distress. The score of > 11.5 was proposed as being a cutoff to detect the presence of sexually related personal distress in Turkish women suffering from sexual dysfunction. In our study, the Cronbach alpha value of the scale was found to be 0.92. Within the frame of this study, the data was collected through face-to-face interviews. Prior to data collection, the researchers introduced themselves and informed women about the research. The women included in the sample were told that the results would only be used in research, that their names would be kept confidential,

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and that they were free to stop filling out questionnaires any time. The participants’ written consents were obtained. Data collection forms were filled out within 5 to 20 minutes. The Ethical Dimension of the Study In order to be able to carry out the research, the approval of Giresun University’s ethics committee alongside institutional approval of the hospital where the research was to be conducted were both obtained. Principles of the Declaration of Helsinki were followed at all stages of the study. Analysis of Data SPSS 21.0 package software was used for the analysis of the data. Descriptive statistics were presented as numbers, percentages, and mean ± standard deviation (SD). The Kolmogorov Smirnov test was employed in order examine whether or not the data distribution was normal. Statistical analysis was performed using Mann Whitney U and Kruskal-Wallis tests as well as using Spearman Correlation Analysis due to the fact that data did not ultimately fit normal distribution. Spearman Correlation Analysis was used to examine the correlation between the mean age of women and their spouses, the age of their babies (months) and the age of marriage. Kruskal-Wallis test was used to look at the difference between the mean Tr-FSDS-R scores and their educational status, the number of living children, the type of contraceptive method used and the current sexual experience. The Mann Whitney U test was used to look at the difference between the mean Tr-FSDS-R scores and the type of delivery, the method used, the status of breastfeeding, the time of initiation of sexual intercourse, the use of a contraceptive method. Statistical significance level was determined as being p <0.05. Limitations of the Research Given that the sample of the research include women applying to the well-child outpatient service of a maternity hospital in Giresun, Turkey, the results obtained are specific to this group and cannot be transposed to the entire Turkish population. Results Table 1 presents the socio-demographic characteristics of the participants and their spouses. The average age of the women is 28.68 ± 5.43, and the average age of their spouses is 33.04 ± 6.16. The average number of years women have been married is 6.87 ± 6.21. The birth place of 77.5% of women and 85.2% of their spouses is Giresun, Turkey. 30.9% of the women and 3.9% of their spouses are high school graduates. The number of living children of 39.8% of the women is one 58.9% of participants had cesarean sections during their last delivery; 12.3% of whose children are 4 months old. 93.3% of women re-entered sexual forty day following birth. It has been determined that 77.5% of women use contraception, including the withdrawal method (41.5%). 73.3% of the women are satisfied with the method they used. It was determined that 21.2% of women who use no contraception method whats over stated that they did so because they were breastfeeding their babies. When women’s breastfeeding status was evaluated, it was observed that 75.4% of them continued to breastfeed their babies. 14.4% of those who were not breastfeed their child claimed that they lacked milk. When the general health status of women was evaluated, it has been found that 89.8% of the participants have no 149

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chronic disease, and that 92.4% have never undergone any surgical procedure beforehand. When women were asked to compare their

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current sexual life with that of their prenatal sexual state, 72% of the women had indicated that there was no difference (Table 1).

Table 1. Sociodemographic Characteristics of Women and Their Spouses X ± SS The Average Age- Year Womens

28.68±5.43

Husbands

33.04±6.16

The Average Marriage- Year

6.87±6.21 N

Not literate

1.3

Primary school

22.9

Middle school

28.0

High school

30.9

University

16.9

Women's Education

Husbands's Education Not literate

0.4

Primary school

21.6

Middle school

20.8

High school

36.9

University

20.3

39.8

34.7

16.5

4 and over

9.0

Vaginal

41.1

Cesarean

139

58.9

Number of Living Children

Type of Delivery

Time to Start Sexual Relationship 40 days before

6.7

After 40 days

220

93.3

Using Contraceptive Methods Yes

183

Contraceptive Method Type (n:183) Withdrawal

41.5

Condom

16.9

Tubal ligation

9.3

12.0

Intrauterine device

5.1

Pill

4.2

Injection

0.4

Yes

173

3.3

4.2

Still breastfeeding

178

75.4

Not breastfeeding

24.6

There is no difference

170

72.0

Better

6.4

Worse

21.6

Method Satisfaction (n:183)

Breastfeeding Situation

Opinion about Current Sexual Life According to Pregnancy

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The mean Tr-FSDS-R scores of the women are given in Table 2. The mean Tr-FSDS-R score for women was determined as being 7.50 ± 9.45 (min 0- max 52) (Table 2). Considering that the cut point of the scale was > 11.5, it was determined that there was sexual function distress in 24.6% of the participants (n: 59) A weak positive correlation was found between women’s TrFSDS-R averages and average number of years married, whereby it was determined that as the marriage year increased, the scale point average increased had respectively as well (r: 0.150; p: 0.022). On the other hand, there was no statistically significant correlation

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between the average age of the women and their spouses, the age of the infants (months), or the Tr-FSDS-R scores (p> 0.05). The mean Tr-FSDS-R scores did not reveal any significant difference according to level of educational of women or their spouses, their number of living children, the type of delivery, the type of contraception method used, the satisfaction with the method used, and the mother’s breastfeeding status (p> 0.05) (Table 3). The mean Tr-FSDS-R scores were found to differ significantly according to the time of sexual intercourse (z: -2.61, p:0.009), using contraception (z: -2.20, p: 0.028), and current sexual activity (x2: 64.798, p:0.000) (Table 3).

Table 2. Women’s ‘Turkish Version of The Female Sexual Distress Scale-Revised (Tr-FSDS-R)’ Score Averages Tr-FSDS-R

X ± SS 7.50 ± 9.45

Minimum 0

Maximum 52

Table 3. Examination of Women’s Mean Tr-FSDS-R Scores According to Some Characteristics of Them and Their Spouses Tr-FSDS-R Score X ± SS Women's Education Not literate Primary school Middle school High school University Husbands's Education Not literate Primary school Middle school High school University Number of Living Children 1 2 3 4 and over Type of Delivery Vaginal Cesarean Time to Start Sexual Relationship 40 days before After 40 days Using Contraceptive Methods Ye No Contraceptive Method Type (n:183)

0.66 ± 1.15 8.05 ± 10.54 6.01 ± 6.78 8.61 ± 10.72 7.67 ± 9.38

Z\x2 x2

4.545

0.337

x2 0.00 ± 0.0 7.64 ± 10.77 6.87 ± 8.32 7.64 ± 9.69 7.87 ± 8.86

2.409

4.545

x2 6.90 ± 9.52 6.84 ± 7.80 9.38 ± 11.10 9.23 ± 11.56

1.847

0.605

Z 6.40 ± 8.44 8.26 ± 10.05

-1.424

0.154

Z 8.53 ± 9.81 6.16 ± 8.83

-2.616

0.009

Z 8.06 ± 9.76 5.54 ± 8.07

Withdrawal 7.01 ± 8.76 Condom 8.45 ± 9.12 Tubal ligation 12.45 ± 14.53 Intrauterine device 6.83 ± 7.35 Pill 8.30 ± 10.75 Injection 12.00 ± 0 Method Satisfaction (n:183) Yes 8.21 ± 10.03 No 6.60 ± 6.07 Breastfeeding Situation Still breastfeeding 7.30 ± 9.42 Not breastfeeding 8.10 ± 9.61 Opinion about Current Sexual Life According to Pregnancy There is no difference 4.59 ± 6.01 Better 5.20 ± 8.86 Worse 17.86 ± 11.65

-2.20

0.028

2.159

0.827

Z -0.006

0.995

Z -0.824

0.410

64.798

0.00

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Discussion Pregnancy and childbirth indicate an important period within in a womanâ&#x20AC;&#x2122;s life. Hormonal, bodily, and social changes in this process often affect her physical well-being, mood, relationship, and sexual health. In this study, it was determined that roughly one quarter of the women (24.6%) suffered from sexual dysfunction according to their scale scores. Moreover, most of the women stated that their sexual lives were adversely affected in the postpartum period, and the scale scores of those who stated that they were adversely affected were significantly higher than others. In line with our study, Pauls (2008) also found that during the first 6 months of the postpartum period, there was a decrease in womenâ&#x20AC;&#x2122;s sexual drive, arousal, lubrication, and orgasm [10]. A study by Trutnovsky (2006) revealed that sexual function decreased in the first year following delivery [11]. The results of a study by Barret (2000) including 796 primiparas concluded that 62% of women experienced sexual pain in the first three months after delivery, and that this rate decreased to 31% at the sixth month [12]. A study conducted by Sahin (2009) relvealed that the average postpartum sexual satisfaction scores and total sexual satisfaction scores of women were significantly lower than the prenatal period [13]. According to the results, the breastfeeding behaviour, hormonal, physiological, and anatomical changes going on in the female body in postpartum period adversely affect the sexual function due to factors such as parenting role and spousal expectation. Sociological, physiological, psychological, cultural, and religious factors, alongside age, general health status, communication, interaction, and family relations among spouses also appear to have an effect on sexuality [1,2,7]. In our study, it has been determined that the increase in the number of years married adversely affects sexual function. In the literature, there is no conclusion that evaluates the relationship between sexual function postpartum period and length of marriage. However, in studies evaluating female sexual function, it has been discovered that sexual function is influenced by factors such as age and the number of children a women has [2,4,6]. In Turkey, being sexually active is generally approved of once women are married, having children after marriage is expected, having more than one child is usually encouraged, and woman is responsible for both child care and housework. Therefore, the reason behind the increase in the sexual function being parallel with increase of length of marriage in our study may be related to the increase in the number of children a woman has in direct proportion to the years she has been married, her ever growing traditional motherhood role, the responsibilities expected from women, and the communication and domestic problems stemming from a lack of spousal support. Although the time to start sexual activity after birth differs socially, the general view is that the mental and physical recovery of women who have gave birth will last for 6 weeks. The lochia going on during this period may cause difficulty with sexual intercourse; therefore it is appropriate to start sex 40 days after birth. In Turkey, usually starting sexual activity 40 days after birth culturally accepted. Almost all of the women in our study (93.3%) were found to have started sexual activity 40 days after birth. When the time initiation of sexual activity and the mean Tr-FSDS-R scores were compared with one another, it was determined that sexual function was stronger in women who started sexual intercourse

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after the 40th day. The 2013 Turkey Demographic and Health Survey (TNSA) also reported that postpartum sexual abstinence period in Turkey was 40 days, and that most couples abstained from sexual intercourse during this period [14]. This result may suggest that conforming with social values has a positive effect on sexual function. In a study conducted in the United States, 56.7% of women in the postpartum period had started sexual intercourse after 6 weeks [15]. Likewise, in a prospective study of women in Australia, 59% of women in the postpartum period started sexual intercourse after 6 weeks [16]. It is also reported that in a number of African countries, the time to start sexual activity is about 11 months later. We believe that these differences stem from different sociocultural values and religious beliefs [17]. Using contraception generally prevent unwanted pregnancies. In studies evaluating the sexual function of the women using contraception, one observes that there are different results in terms of both the use and type of method [18-20]. In our study, the TrFSDS-R score average was found to be significantly higher (p <0.05) among women using contraception than among those who did not, and that the most common method was the withdrawal method (41.5%). Contrary to our study, a study conducted by Hotun had determined that during the postpartum period, women mostly preferred effective methods (i.e. DMPA, RIA, condom), and that there was no significant relationship between postpartum sexual problems and sexual problems over all. When evaluated with regard to contraceptive methods used, the findings of the 2013 TNSA Survey supports the findings of our study, revealing that almost 1/4 of married women in Turkey use the traditional withdrawal method [14]. Golbasi (2017) had also reveal that the most preferred method is withdrawal method [5]. Higher incidences of sexual distress among women in Turkish study who use withdrawal method may be due to the fact that this method is not effective, and that women may have further troubles due to being concerned about getting pregnant again. Conclusion In conclusion, the majority of women started sexual activity after fourty days of postpartum. It was found that 3\4 of the women used any method of contraception and the method of withdrawal, which is a traditional method among the methods used, was in the first place. A significant proportion of women experience sexual problems during the postpartum period. In this process, nurses who are in closer communication with women need to provide information and counseling to women and their spouses about the sexual problems seen during this period, causes and possible solutions. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval The protocol for the research project has been approved by the research ethics committee of the Giresun University. The research confirms to the provisions of the Declaration of Helsinki in 1995 (as revised 2013). Eda Sahin ORCID:0000-0001-9421-7689 Ayten Senturk Erenel ORCID:0000-0002-0841-209

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function and body image: a prospective study. J Sex Med. 2008;5:1915-22.

World Health Organisation (WHO). Defining sexual health 2010. Available from: http://www. who.int/reproductivehealth/topics/sexual_health/sh_definitions/en/.

11. Trutnovsky G, Haas J, Lang PE. Women’s perception of sexuality during pregnancy and after birth. Aust N Z J Obstet Gynaecol. 2006;46:282-7.

Aslan E, Beji NK, Gungor I, et al. Prevalence and risk factors for low sexual function in women: a study of 1,009 women in an outpatient clinic of a university hospital in Istanbul. J Sex Med. 2008;5:2044-52.

12. Barrett G, Pendry E, Peacock J, et al. Women’s sexual health after childbirth. BJOG. 2000;107:186–95.

DeRogatis LR, Rosen R, Leiblum S, et al. The Female Sexual Distress Scale (FSDS): Initial validation of a standardized scale for assessment of sexually related personal distress in women. J Sex Marital Ther. 2002;28:317-30.

Erenel AS, Kitis Y. Kadın cinsel fonksiyonunun belirlenmesine yönelik bir çalışma. Turkiye Klinikleri. 2011;21:251-9.

Golbasi Z, Erenel AS, Turan Z. Gebelikten koruyucu yöntem kullanan kadınlarda cinsel fonksiyon bozukluğunun belirlenmesi. Gazi Sağlık Bilimleri Dergisi. 2017;1:9-17.

Leeman LM, Rogers RG. Sex after childbirth: postpartum sexual function. Obstet Gynecol. 2012;119:647-55.

Yee LM, Kaimal AJ, Nakagawa S, et al. Predictors of postpartum sexual activity and function in a diverse population of women. J Midwifery Womens Health. 2013;58:654-61.

Burri A, Spector T. Recent and lifelong sexual dysfunction in a female uk population sample: prevalence and risk factors. J Sex Med. 2011;8:2420-30.

Kitis Y, Erenel AS, Gürcüoğlu AE. Kadın cinsel sıkıntı ölçeği (female sexual distresss scale-revised): Türkçe’de geçerlik ve güvenirliği. I.Uluslarası ve II.Ulusal Kadın Hastalıkları ve Ana Çocuk Sağlığı Kongresi. 2016;7-8 Ekim, İzmir, Türkiye.

13. Sahin N. Kadınlarda postpartum dönemde cinsel yaşam. Zeynep Kamil Tıp Bülteni. 2009;40:125-30. 14. Hacettepe Üniversitesi Nüfus Etütleri Enstitüsü, “2013 Türkiye Nüfus ve Sağlık Araştırması”. Hacettepe Üniversitesi Nüfus Etütleri Enstitüsü. T.C. Kalkınma Bakanlığı and TÜBİTAK. 2014;75-94. 15. Sok C, Sanders JN, Saltzman HM, et al. Sexual behavior, satisfaction, and contraceptive use among postpartum women. J. Midwifery Womens Health. 2016;61:158-65. 16. McDonald EA, Brown SJ. Does method of birth make a difference to when women resume sex after childbirth? BJOG. 2013;120:823-30. 17. Desgre ́es-du-Louˆ A, Brou H. Resumption of sexual relations following childbirth: norms, practices and reproductive health ıssues in abidjan, coˆ te d’ıvoire. Reproductive Health Matters. 2005;13:155-63. 18. Lee JT, Tsai JL, Tsou TS, et al. Effectiveness of a theory-based postpartum sexual health education program on women’s contraceptive use: a randomized controlled trial. Contraception. 2011;84:48-56. 19. Lopez LM, Hiller JE, Grimes DA, et al. Education for contraceptive use by women after childbirth. Cochrane Database Syst Rev. 2010;20:CD001863. 20. Labbok MH. Postpartum sexuality and the lactational amenorrhea method for contraception. Clin Obstet Gynecol. 2015;58:915-27.

10. Pauls RN, Occhino JA, Dryfhout VL. Effects of pregnancy on female sexual

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):154-7

Objective and subjective cure rates of Ophira mini sling: Postoperative 36-month results Isil Koleli Inonu University Medical Faculty, Department of Obstetrics and Gynecology, Malatya, Turkey Received 04 October 2018; Accepted 23 October 2018 Available online 19.12.2018 with doi:10.5455/medscience.2018.07.8943 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract This study aimed to evaluate the objective and subjective cure rates of Ophira mini sling for female stress urinary incontinence (SUI) 36 months after surgery. A total of 58 patients who had SUI and were treated with Ophira mini sling between the years 2014 and 2015 were evaluated retrospectively. The objective cure rate was estimated with the negative cough stress test, and the subjective cure rate was estimated with the answer of “no leakage on coughing, sneezing” to question 3 in urinary distress inventory-6 (UDI-6). Incontinence impact questionnaire-7 (IIQ-7) and pelvic distress inventory-20 (PFDI-20) were also evaluated 36 months after surgery. The overall subjective cure rate was 90% (36/40), and the overall objective cure rate was 87.5% (35/40). The UDI-6, IIQ-7, and PFDI-20 scores improved significantly (P ˂ 0.001). No major complications were noted. Ophira mini sling could be good option for treating female SUI with high objective and subjective cure rates and no major complications. Keywords: Mini sling, Ophira, single-incision sling, stress urinary incontinence

Introduction The complaint of involuntary urinary leakage that the individual has when making effort or physical exertion (e.g., sporting activities, sneezing, coughing) has been defined as stress urinary incontinence (SUI) by the International Continence Society. Millions of adult women in the USA and Europe have urinary incontinence, and SUI is the most common female incontinence type [1,2]. Behavioral, mechanical, pharmacologic, and surgical interventions are made for the treatment. Of these, the most effective is surgical treatment, and standard mid-urethral slings (SMUS) are the most common operations. An incision is made under the urethra, and a sling tape is placed and inserted either into the obturator foremen or behind the pubic bone. SMUS are 1) retropubic sling comprises a tension-free vaginal tape (TVT), 2) an obturator sling comprises a transobturator tape (TOT). TVT was first described in 1995 by Petros and Ulmstein [3]. TVT and TOT have similar objective and subjective cure rates [4,5]. Visceral organ complication rate and bladder perforation rate are more in TVT [5]. The groin-hip pain rate in TOT ranges between 6.8% and 12% [6,7]. New-generation devices need to be developed due to the tape insertion into the retropubic area and obturator

*Coresponding Author: Isil Koleli, Inonu University Medical Faculty, Department of Obstetrics and Gynecology, Malatya, Turkey E-mail: isil.koleli@inonu.edu.tr

foramen blindly as well as the complication rate of mid-urethral sling. These new-generation slings are called mini slings because a single incision is made in the vaginal mucosa and the skin incision is not needed. They are also called single-incision mini slings (SIMS). Ophira is a kind of mini sling that was developed in 2007. It is fixed with the arms in the obturator internus muscle and has bilateral loose sutures for correcting the tension. Only a few studies evaluated the midterm results of Ophira mini sling. This study aimed to evaluate the objective and subjective cure rates of Ophira mini sling 3 years after surgery. Material and Methods A total of 58 patients who had SUI and were treated with Ophira mini sling between the years 2014 and 2015 at department of gynecology and obstetrics, Inonu Unıversity were evaluated retrospectively. Ethics approval was obtained from the Inonu University ethical committee (approval number 2018/15-2). When the patients complained about incontinence, the medical history, systemic and pelvic examination, and urine test were performed. If the urine test results were in the normal range, 72-h voiding diary and cough stress test (CST) were used for diagnosing SUI. The validity study of the Turkish scales (urinary distress inventory-6 (UDI-6), pelvic distress inventory-20 (PFDI-20) and incontinence impact questionnaire-7 (IIQ-7)) was performed 154

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before the operations [8,9]. The patients were examined in the first postoperative month and then annually. The UDI-6 score, IIQ-7 score, and PFDI-20 score were measured in every control appointment, and CST was performed as well. Question 3 in UDI-6 was used for assessing subjective success. If the answer to question 3 was “No leakage on coughing, sneezing,” it was assumed that the patient had subjective success. CST was performed postoperatively for assessing objective success. The study included 40 patients who came for the postoperative control. The patients were kept in lithotomy position with 300-mL bladder filling for evaluating CST. Bladder volume was estimated by ultrasonography. The exclusion criteria were as follows: (1) female patients who had anti-incontinence surgery previously; (2) female patients who had overactive bladder; (3) female patients who had neurologic disease or coagulation disorders; (4) pregnant women, (5) female patients who could not answer the question; (6) female patients with a postvoid residual (PVR) volume more than 100 mL, and (7) female patients with vulvovaginitis. The inclusion criteria were as follows: (1) female patients with SUI; (2) female patients who underwent Ophira mini sling procedure; (3) female patients who were CST positive preoperatively; (4) female patients who had/had not pelvic organ prolapse; and (5) female patients who could come for follow-up. Surgical technique Cefazolin (1 g) was administered for prophylaxis preoperatively. Surgeries were performed under general or epidural/spinal anesthesia. The patients remained in lithotomy position. An 18F Foley catheter was replaced with the bladder. Pelvic reconstructive surgery was performed, and the Ophira mini sling was inserted into the dissected mid-urethral tissue, which extended to the pubic rami. The vaginal wall was closed using 2/0 polyglactin sutures. The operation time was recorded for prolapse surgery and mini sling separately. The Foley catheter was removed within postoperative 24 hours, and the patient was discharged if the PVR volume was less than 100 mL. Statistical analysis Data were presented as means ± standard deviations, medians, or percentages. Student t test and the paired t test were used to compare pre- and postoperative continuous data. A P value less than 0.01 was considered to reflect statistical significance. All data were analyzed using IBM SPSS Statistics version 22, 2013 (IBM Corp, NY, USA). Results A total of 40 patients evaluated retrospectively. In the postoperative 36th month, the overall subjective cure rate was 90% (36/40) and the overall objective cure rate was 87.5% (35/40). The mean age of patients was 63 ± 11.2 years, and the mean body mass index was 27 kg/m2. The demographic data of patients are presented in Table 1. The mean operation time for mini sling was 11 ± 2.1 min. No major intraoperative and postoperative complications were recorded. The mean value for hospital stay was 2.1 ± 0.6 days. The postoperative urge incontinence was evaluated

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in two patients (5%), and it resolved with anticholinergic drugs. Postoperative urethral obstruction was diagnosed if the PVR volume was more than 100 mL. However, no urethral obstruction occurred. Table 1. Demographics and preoperative characteristics of patients Mean ± SD/ n Age (year)

63 ± 11.2

Body mass index (kg/m2)

27 ± 3.6

Gravidity

6.2 ± 2.6

Parity

5.2 ± 2.4

Comorbidities Hypertension

Diabetes mellitus

Coronary artery disease

Asthma

Rheumatoid arthritis Menopause

1 15

The operation data are shown in Table 2. No major bleeding was noted. The mean hemoglobin level was 12.5 ± 0.17 g/dL preoperatively and 11.4 ± 0.2 g/dL at 2 h after the surgery. No complication related to mesh was reported. Table 2. Operation data of patients Mean ± SD/ % of 40 Operation time

11 ± 2.1 min

Operations Vaginal hysterectomy Abdominal hysterectomy

37.5% 12.5%

Anterior colporrhaphy

45%

Posterior colporrhaphy

50%

LeFort

Abdominal hysterectomy

10%

Hemoglobin levels Preoperatively

12.5 ± 0.17 g/dL

2 h postoperatively

11.4 ± 0.2 g/dL

Complications Mesh erosion

Repeat incontinence surgery

PVR volume ≥100 mL De novo urge incontinence

0 5%

Hospital stay time

2.1 ± 0.6

Questions 1 and 2 of the UDI-6 questionnaire were related to irritation symptoms, 3 and 4 were related to SUI, and 5 and 6 were related to obstructive symptoms. The IIQ-7 included four domains: questions 1 and 2 are related with physical activity, questions 3 and 4 are related with travel, question 5 is related with social relationships, and questions 6 and 7 are emotional health questions. All the parameters of UDI-6, IIQ-7, and PFDI20 showed significant improvement in the third postoperative year (Table 3) (P ˂ 0.001). 155

doi: 10.5455/medscience.2018.07.8943 Table 3. Changes in UDI-6, IIQ-7, and PFDI-20 scores Preoperatively

Postoperatively

UDI 1-2

47.5 ± 17.2

25.9 ± 19.2

˂0.001

UDI 3-4

35.9 ± 3.5

5.9 ± 2.1

˂0.001

UDI 5-6

23.1 ± 3.9

4.3 ± 2.1

˂0.001

UDE total

35.8 ± 2.3

12 ± 1.6

˂0.001

IIQ1-2

2.3 ± 0.2

˂0.001

IIQ-3-4

2 ± 0.3

0.1 ± 0.08

˂0.001

IIQ-5

0.9 ± 0.01

0.07 ± 0.04

˂0.001

IIQ 6-7

1.5 ± 0.3

0.1 ± 0.08

˂0.001

IIQ total

6.5 ± 1

0.1 ± 0.1

˂0.001

PFDI-20

18.8 ± 1.3

3.1 ± 0.4

˂0.001

Discussion Several surgical methods have been developed for treating SUI after exploring pathophysiology. Other than retropubic colposuspension operations, midurethral slings (TVT and TOT) have been frequently used for treating SUI with high objective and subjective cure rates. Although SMUS is a minimally invasive method, SIMS has been developed to avoid complications of blunt transition from the retropubic area and obturator foramen. SIMS include tissue fixation system (TFS), Mini-Arc, AJUST, single-incision sling (SIS), Contasure-Needleless, and Ophira. Ophira (Promedon; Cordoba, Argentina) is made of type 1 polypropylene mesh; it is a kind of SIS. A fishbone-like TFS is present at the end of each arm. It can be fixed to the obturator internus muscle. At the same time, the advantage of Ophira is the possibility of correction after placing fixation. SMUS has no correction advantages (Figure 1).

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SIMS and SMUS other than TVT, based on the results of 29 RCTs, showed no significant difference between SMUS and SIMS with regard to short-, mid-, and long-term subjective cure rates. Although the midterm objective cure rates of SMUS and SIMS were not different, the long-term objective cure rates were higher in SMUS. SIMS was found to be associated with shorter operation time, less blood loss, less pain and less postoperative voiding dysfunction [10]. When AJUST, Mini-Arc, SIS, Ophira, TFS, and Contasure-Needleless were compared with SUMS, the lowest objective cure rates were observed in Ophira [odds ratio (OD), 0.50; 95% confidence interval (CI), 0.30–0.83] and highest objective cure rates were observed in TFS (OD, 1.67; 95% CI, 0.52–5.30) [10]. Palma et al [11] applied Ophira mini sling to 124 patients and reported the second- year subjective and objective cure rates as 91.6% and 85.3%, respectively. In Farzenah et al.’s [12] study including 72 patients (12–20 months), the objective cure rate was 88.6%. Smith and colleagues [13] applied Ophira mini sling to 30 patients; 93.3% reported subjective cure and 90% of the patients had a negative CST. In Yıldız et al.’s study evaluating the safety and efficacy of Ophira mini sling, the third-year objective cure, subjective cure, and failure rates were 83.8%, 6.4%, and 9.8%, respectively. The present study showed that the overall subjective cure rate was 90% (36/40), and the overall objective cure rate was 87.5% (35/40) in the postoperative 36th month. In the present study, the mean operation time was 11 ± 2.1 min. This value has been reported in the range of 7.9–20 min in the literature [12,14-16]. In TOT, a blind transition through the obturator foremen led to complications of vascular nerve and bladder injury. Groin pain, groin neuropathy, and abscess formation may occur after TOT operation, decreasing patients’ quality of life [17-19]. The complication rate is low during mini sling insertion due to the lack of transmission through the pubic ramus. Jurakova et al [16] did not experience any major intraoperative or postoperative complications in 95 patients treated with Ophira. No major complications related to SIMS have been reported in the literature. In the present study also, no major intraoperative or postoperative complication was reported. The propylene-induced complications (mesh erosion, dyspareunia) were not observed. The IIQ-7 and UDI-6 scores were found to be significantly improved in Yıldız et al.’s (third year) and Palma et al.’s (second year) studies [13,20]. In the present study, a significant improvement was observed in both questionnaire scores (P < 0.001). Post-Ophira de novo urge incontinence incidence ratio was 2.9% and 12.2% in Sharifiaghdas et al.’s [12], and Pascom et al.’s [20] studies, respectively. This rate was 6.4% in Guncer et al.’s study. It was 5% in the present study.

Figure 1. Ophira mini sling system In 2013, a TVT- Secur from SIMS was distracted from the market by the manufacturer (Ethicon) due to low second- and third-year objective and subject cure rates. In 2018, a review comparing

The limitation of this study was that all patients undergoing Ophira also underwent pelvic organ prolapse reconstruction at the same time. Despite additional operations, intraoperative hemorrhage was minimal and a decrease in the mean postoperative hemoglobin level was approximately 1.1 g/dL. The incidence of urinary incontinence increased with pelvic organ prolapse. When anti-incontinence surgery is combined with pelvic organ 156

doi: 10.5455/medscience.2018.07.8943

prolapse surgery, Ophira mini sling may be a good option due to the short operation time and less intraoperative and postoperative complications. Studies on the short- and long-term outcomes of Ophira mini sling are limited. Besides, no study has evaluated the long-term (10th year) outcomes yet. Conclusion

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2017:72;594-5. 8.

Cam C, Sakalli M, Ay P, et al. Validation of the Short Forms of the Incontinence Impact Questionnaire (IIQ-7) and the Urogenital Distress Inventory (UDI-6) in a Turkish Population. Neurourol Urodyn. 2007;26:129-33.

Celenay ST, Akbayrak T, Kaya S, et al. Validity and reliability of the Turkish version of the Pelvic Floor Distress Inventory-20. Int. Urogynecol J. 2012;23:1123-27.

In conclusion, the objective and subjective cure rates in the postoperative 36th month were higher in patients who underwent pelvic organ reconstruction and were treated with Ophira mini sling. For the treatment of SUI, Ophira mini sling can be a good option since there were no major complications while it provided short operation time and minimal intraoperative hemorrhage risk. Increasing the number of studies showing midterm results related to Ophira and conducting studies evaluating the long-term results may increase the feasibility of the operation.

10. Kim A, Kim MS, Park YJ, et al. An updated systematic review and metaanalysis: Clinical outcome of single-incision slings excluding TVT-Secur versus standard slings in surgical management of stress incontinence. BJU Int. 2018. Epub ahead of print

Financial Disclosure The authors declared that this study has received no financial support.

13. Smith PP, Dhillon RK, M. Baptiste AS, Arunkalaivanan. Comparison of singleincision mid-urethral tape (OphiraTM) and transobturator tape (ObtryxTM) sub-urethral sling procedures for female stress urinary incontinence. J Clin Med Res. 2013;5:53-7.

Ethical approval Ethics approval was obtained from the Inonu University ethical committee (approval number 2018/15-2). Isil Koleli ORCID: 0000-0003-1281-926X

References 1.

Ford AA, Rogerson L, Cody JD, et al. Mid-urethral sling operations for stress urinary incontinence in women. Cochrane database Syst Rev. 2015;7:6375.

Nitti VW. The prevalence of urinary incontinence. Rev Urol. 2001;3:2-6.

Ulmsten U, Petros P. Intravaginal slingplasty (IVS): an ambulatory surgical procedure for treatment of female urinary incontinence. Scand J Urol Nephrol. 1995;29:75-82.

Ogah J, Cody DJ, Rogerson L. Minimally invasive synthetic suburethral sling operations for stress urinary incontinence in women: a short version Cochrane review. Neurourol Urodyn. 2011;30:284-91.

Ford AA, Rogerson L, Cody JD, et al. Mid-urethral sling operations for stress urinary incontinence in women. Cochrane Database Syst Rev. 2017;7:6375

Cadish LA, Hacker MR, Modest AM, et al. Characterization of pain after inside-out transobturator midurethral sling. Female Pelvic Med Reconstr Surg. 2014;20:99-103.

Thomas TN, Siff LS, Jelovsek JE, et al. Surgical Pain After Transobturator and Retropubic Midurethral Sling Placement. Obstet Gynecol Surv.

11. Palma P, Riccetto C, Castro R, et al. Safety and efficacy of the ophira minisling system: One year follow-up from a multicenter international clinical trial. UroToday Int J. 2011;4:44. 12. Sharifiaghdas F, Nasiri M, Mirzaei M, et al. Mini Sling (Ophira) versus pubovaginal sling for treatment of stress urinary incontinence: A mediumterm follow-up. Prague Med. Rep. 2015;116:210-8.

14. Yildiz G, Ceylan Y, Ucer O, et al. Safety and efficacy of single-incision sling for female stress urinary incontinence: 3 years’ results. Int Urogynecol J. 2016;27:1667-71. 15. Taner CE, Okay G, Göklü Y, et al. Perioperative and postoperative complications after Ophira mini sling operations. Arch Gynecol Obstet. 2015:291;341-6. 16. Jurakova M, Huser M, Belkov I et al. Prospective randomized comparison of the transobturator mid-urethral sling with the single-incision sling among women with stress urinary incontinence: 1-year follow-up study. Int Urogynecol J. 2016;27:791-6. 17. Herschorn S. Midurethral sling complications. Can Urol Assoc J. 2017;6:1412. 18. Oliveira L, Dias M, Martins S, et al. Surgical Treatment for Stress Urinary Incontinence in Women: A Systematic Review and Meta-analysis. Rev Bras Ginecol e Obs. / RBGO Gynecol Obstet. 2018;40:477-90. 19. Foss Hansen M, Lose G, Kesmodel US, et al. Reoperation for urinary incontinence: a nationwide cohort study, 1998-2007. Am J Obstet Gynecol. 2016;214:26.3 20. Pascom ALG, Djehdian LM, Bortolini MAT et al. Randomized controlled trial comparing single-incision mini-sling and transobturator midurethral sling for the treatment of stress urinary incontinence: 3-year follow-up results. Neurourol Urodyn. 201837:2184-90.

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Medicine Science International Medical Journal

Medicine Science 2019;8(1):158-61

The association between TLR4 polymorphisms and pulmonary tuberculosis Refika Dilara Vaizoglu1, Harika Gozde Gozukara Bag2, Ceren Acar3 1 Inonu University, Faculty of Arts and Science, Department of Biology, Malatya, Turkey Inonu University, Faculty of Medicine, Department of Biostatistics and Medical Informatics, Malatya, Turkey 3 Inonu University, Faculty of Arts and Science, Department of Molecular Biology and Genetics, Malatya, Turkey 2

Received 05 October 2018; Accepted 05 November 2018 Available online 11.01.2019 with doi:10.5455/medscience.2018.07.8959 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Tuberculosis (TB) is a major health problem which causes many deaths every year in the world. According to the World Health Organization (WHO) report, 1.5 million people lose their lives due to tuberculosis in every year. Although some of the infected people are showing the symptoms, in some the disease never develops, even about 90% of the affected ones are improved by the immune system's response. As in many infectious diseases, the difference between the number of infected people and the number of sick people is caused by differences in balance between the host defense and the virulence of the organism. In this case, the genetic basis of the response to infectious agents needs to be investigated in order to understand the relationship between infectious diseases and host. For this purpose; we investigated the effects of TLR4 polymorphisms (rs4986790 & rs4986791) that are involved in immune system mechanisms against susceptibility to Mycobacterium tuberculosis (MTB). In order to understand the association we did genotyping in 65 TB patients from Malatya. The results of the genotyping showed no significant association to the single nucleotide polymorphisms (SNPs) mentioned, for rs4986790 the p value was 0.80 and for rs4986791 p value was 0,517 for the genotypes. The population size was the limiting factor for the statistical analysis and it should be also taken into account that a number of genes are taking part in the signal transduction pathway that TLR4 is involved. Keywords: MTB, TLR, polymorphism, genotyping, SNP

Introduction Tuberculosis, is caused by Mycobacterium tuberculosis and it is the leading cause of 1.5 million deaths annually around the world. Although 1/3 of the world population is infected, development of active pulmonary tuberculosis (PTB) depends on the interaction between the bacterium and host’s immune defense [1]. The disease can remain in the latent phase for a long time after infecting the affected individual. Although some of the infected people are showing the symptoms, some people never develop the disease phenotype, even about 90% of them are recovered by the immune system’s response. Why some people-exposed to the pathogen- do not develop the disease is not known. In order to gain insights about the subject, the researchers focus on the host’s immune response mechanisms that limit the active disease in those who are infected. Many studies performed up to date indicate that genetic factors of the host have an influence on the susceptibility to infection [2,3]. *Coresponding Author: Ceren Acar, .Inonu University, Faculty of Arts and Science, Department of Molecular Biology and Genetics, Malatya, Turkey, E-mail: ceren.acar@inonu.edu.tr

Toll-like receptors (TLRs) are membrane-spanning proteins that detect the conserved structure of pathogenic microorganisms which are called pathogen-associated molecular patterns (PAMPs) that therefore play a critical role in immunity. The toll-like super family has 10 members which are functional in human that recognize different microorganisms and microbial products that lead to activation of the immune response and cytokines [4]. Five molecules (My-D88, TRIF, Mal, TRAM and SARM), which are TIR-domain adapters of the TLR family, interact with all members of this family. TLR1, 2, 4, 6, 8 and may be TLR9 are thought to be involved in the recognition of Mycobacteria [5-7]. TLR4 is encoded on human chromosome 9q32-33, and it is reported to play a significant role in triggering off the innate immune response to MTB infection. The mycobacterial ligands recognized by TLRs are lipoarabinomannan, lipomannan, phosphatidylinositol mannose, and the 19-kDa lipoprotein. After recognition of these by receptors, the TLR signal pathway is activated by binding the TIR domain to MyD88 adapter protein [6,8]. IRAK-1, Toll / IL-1 receptor domain-containing adapter protein, and TIR-domaincontaining adapter-inducing IFN-β adapter protein participate in 158

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activation of the mitogen-activated protein kinase and nuclear factor-кꞵ in the nucleus. This increase the levels of inflammatory cytokines, especially TNF-α, then initiate the natural immune response to bacteria [3,9-11].

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Genomic DNA was extracted from peripheral blood stored with an anticoagulant using a commercial kit (PureLink® Genomic DNA Mini Kit; Invitrogen, Carlsbad, CA, USA), according to the manufacturers’ protocol. All blood and DNA samples were coded to ensure anonymity. All samples were genotyped using the TaqMan® SNP Assay (Applied Biosystems, Foster City, CA, USA): C_11722238_20 for rs4986790, and C_11722237_20 for rs4986791. We used the StepOnePlus™ Real-Time PCR System (Applied Biosystems,) for genotyping.

TLRs are transmembrane proteins which containing leucine rich repeats (LRR) in their extracellular domains that induce a natural immune response to many pathogens. The LRR region mutations may potentially disturb phosphorylation of TLR4 altering downstream signaling of inflammatory mediator activation, ultimately contributing to disease susceptibility. Thus, individuals who have these variations in TLR4 may prone to develop TB [12]. For this reason we focused on the TLR4 polymorphisms. The two mutations Thr399Ile (rs4986791) and Asp299Gly (rs4986790) of TLR4, which is found in the ectoplasmic LRR domain, have an important role in reducing cytokine response and increasing susceptibility to various infections by affecting the TLR4 receptor [13]. We aimed to investigate the role of this two TLR4 polymorphisms in patients with pulmonary tuberculosis from Malatya.

The data was summarized by count and percent. Hardy-Weinberg equilibrium was tested by a chi-square distribution with 1 df. Differences between groups due to allelic and genotypic distributions were analyzed by Pearson’s exact or Fisher’s exact tests. In comparisons the significance level was considered to be ≤0.05. Results 65 PTB patients and 75 age matched healthy control individuals were genotyped. Two single nucleotide polymorphisms of TLR4 rs4986790 and rs4986791 were investigated and no significant association was found between the disease susceptibility and the genotype frequencies of the SNPs that were mentioned. The results of the genotyping for each SNPs investigated were summarized in tables.

Material and Methods 65 Turkish PTB patients and 75 age- and sex-matched healthy control individuals are the subjects of this study. Patients were recruited from the Malatya Provencial Health Directorate and molecular analyses were carried out in the Department of the Molecular Biology and Genetics. The study was performed in accordance with the guidelines of the Declaration of Helsinki and was approved by our local ethics committee (Protocol #2013/155). All participants were fully informed about the study procedures and gave written consent before the study started.

The frequencies of the genotypes and alleles are given for rs4986790 for patients and controls are shown in Table 1 and gender differences of the genotypes are given in table 2. The results of the genotyping for rs4986791 are shown in Table 3 and gender related analysis is given in Table 4.

Table1. Rs4986790 Genotype and allele frequency table for patients and controls Group Control Patient

AA n (%) 70 (93.3) 59 (90.8)

AG n (%) 5 (6.7) 6 (9.2)

p 0.805

A n (%) 145 (96.7) 124 (95.4)

G n (%) 5 (3.3) 6 (4.6)

p 0.809

Table 2. Rs4986790 Genotype and allele frequency table according to gender AA

n (%)

Female

42 (91.3)

4 (8.7)

Male

87 (92.6)

7 (7.4)

Group

n (%)

Control

11 (91.7)

1 (8.3)

Patient

31 (91.2)

3 (8.8)

n (%)

Control

59 (93.7)

4 (6.3)

Patient

28 (90.3)

3 (9.7)

Female

Male

p 0.751 P 1.000 p 0.681

n (%)

86 (95.6)

4 (4.4)

181 (96.3)

7 (3.7)

n (%)

23 (95.8)

1 (4.2)

65 (95.6)

3 (4.4)

n (%)

122 (96.8)

4 (3.2)

59 (95.2)

3 (4.8)

p 0.751 p 1.000 p 0.686

Table 3. Rs4986791 Genotype and allele frequency table for patients and controls CC

n (%)

Control

67 (89.3)

8 (10.7)

Patient

61 (93.8)

4 (6.2)

Group

p 0.517

n (%)

142 (94.7)

8 (5.3)

126 (96.9)

4 (3.1)

p 0.526

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Table 4. Rs4986791 Genotype and allele frequency table according to gender CC

n (%)

Female

43 (93.5)

3 (6.5)

Male

85 (90.4)

9 (9.6)

Gender

n (%)

Control

11 (91.7)

1 (8.3)

Patient

32 (94.1)

2 (5.9)

n (%)

Control

56 (88.9)

7 (11.1)

Patient

29 (93.5)

2 (6.5)

Female

Male

p 0.751 p 1.000 p 0.713

Discussion TB is an infectious disease that is caused by MTB. About %30 of the world’s population is carrying the pathogen and at least tenth of it develops the active form of the disease. In Turkey Tuberculosis War 2017 Report, the incidence rate of Turkey in 2015 was 0.154 per thousand and case number was 12.550. At the same time according to this report case number decreased from 173 to 102 cases in five years (2010-2015) in Malatya [14]. The molecular mechanisms how MTB cause infection are unclear that is why it is difficult to fight with the disease. The host innate immune response is the first line of defense against invading pathogens and is vital for the initial defense against MTB and activation of the adaptive immune response [15]. Many studies showed that at least some infected people exhibit a powerful immune response to the infectious agent. The first step of immune response is induced by binding of PAMPs of the invading pathogen to host pattern recognition receptors (PRRs). These PRRs include the TLRs, C-type lectin receptors (CLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and the RIG-like receptors (RLRs) [8]. As the PRR encoding genes play an important role in host immunity, variants in these genes could lead to structural and functional changes in these receptors causing an altered immune response, and influence TB disease progression. PRRs is an important component of the host response to infection with MTB, which triggers inhibitory mechanisms via TLRs. The coordinated regulation of TLR signaling through their respective ligands might be important for controlling the extent of the host immune response to prevent the progression of MTB growth. TLR polymorphisms have shown a great impact on susceptibility to TB. Members of the population who have the certain genotype for TLRs may have affinity differences to MTB ligands therefore this may lead variations in signal transduction [15,16]. In our study we found no significant association related with the polymorphisms mentioned and the TB cases found in Malatya. These results are in accordance with the studies that are performed in Korean, Taiwan Chinese, Japan and Iranian populations [8,17]. Besides another study reported no association with Asp299Gly

n (%)

89 (96.7)

3 (3.3)

179 (95.2)

9 (4.8)

n (%)

23 (95.8)

1 (4.2)

66 (97.1)

2 (2.9)

n (%)

119 (94.4)

7 (5.6)

60 (96.8)

2 (3.2)

p 0.756 p 1.000 p 0.720

in Gambian population as well [18]. On the contrary Najmi et al reported a positive result in Indian populations especially for susceptibility to severe form of the disease for both of the SNPs that we also worked with [13]. On the other hand to our knowledge up to now there hasn’t been any study performed in our population yet related with the association of TLR4 polymorphisms and TB. Conclusion As a conclusion we showed that the two polymorphisms –Asp 299Gly and Thre399Ile- of TLR4 gene were not associated with the susceptibility to PTB in our patients from Malatya, Turkey. The differences of frequencies of both genotypes and alleles between controls and patients were so close. The reason for having no association may be the number of the patients that were studied, but according to Turkey Tuberculosis War Report 2017 [14] the case numbers in Malatya was 102 patients and we could only reach 65 of them who were regularly coming to the clinic. On the other side it should also be taken into account that many molecules take part in TLR signalization pathway in the immune response of the host to outsiders. So this gives us many candidate genes to investigate the association for the susceptibility to PTB in this group of patients. Acknowledgements The authors would like to thank the subjects for their participation in this study. We also thank Dr. Zeynep Arıca Kazgan and Prof. Dr. Barış Otlu for their help and support. This study was supported by Scientific Projects Coordination Unit of Inonu University with grant number 2015/69. Competing interests The authors declare that they have no competing interest. Financial Disclosure This study is supported by Scientific Projects Coordination Unit of Inonu University with grant, 2015/69 Ethical approval Prior to the study, the approval of the Ethics Committee of Inonu University (2013/155) Refika Dilara Vaizoglu ORCID: 0000-0003-4584-0954 Harika Gozde Gozukara Bag ORCID: 0000-0003-1208-4072 Ceren Acar ORCID: 0000-0003-1842-9203

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Ma X, Liu Y, Gowen BB, et al. Full-exon resequencing reveals tolllike receptor variants contribute to human susceptibility to tuberculosis disease. PLoS One. 2007;2:1–9.

Vaizoglu RD. Investigation of some TLR polymorphisms in tuberculosis patients in Malatya. Master thesis, Inonu University, Malatya, 2017.

Botos I, Segal DM, Davies DR. Review the structural biology of toll-like receptors. Struct Des. 2011;19:447-59.

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Accurate diagnostic algorithm for patients with rare pathology of thenar intramuscular lipomas Zafer Atbasi1, Yusuf Erdem2 Guven Hospital Department of Orthopedics and Traumatology, Ankara, Turkey 2 Gulhane Training and Research Hospital, Ankara, Turkey

Received 22 October 2018; Accepted 09 December 2018 Available online 21.01.2019 with doi:10.5455/medscience.2018.07.8968 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Intramuscular lipomas which are classified as the subgroup of infiltrative lipomas histologically, are seen rare in the hand. They often localized at the thenar eminence when they do occur in the hand. In such locations, lipomas must differentiate from ganglion cysts which is the most common hand mass. They may cause certain complications due to median nerve entrapment as ganglion cysts. Magnetic resonance imaging and histopathologic investigation are the most effective and reliable methods of confirming the diagnosis. Five patients with the symptoms of mild thumb pain, numbness in the radially innervated digits of hand, and difficulty while gripping objects were included in this study. Radiological assessment included plain radiography, ultrasonography (USG), magnetic resonance imaging (MRI) and electromyography (EMG). Excisional biopsy for all masses within marginal borders were performed. Pathological results revealed intramuscular lipomas. All symptoms were disappeared after excision of the masses. No recurrence and complication was observed at final follow-ups. Intramuscular lipomas are benign lesions with an excellent prognosis after adequate excisions and after clinical suspicious, algorithmic imaging approach in diagnosis can be used by any physician easily as we mentioned in the study. Keywords: Intramuscular, hand, lipoma

Introduction Lipomas are one of the most common benign soft tissue tumors. They are formed by mature white fat cells (i.e., lipocytes) [1-3]. They are histologically classified into three groups: angiolipoma, intramuscular (infiltrative) lipoma, and spindle cell lipoma. They rarely occur in the hand, where they may be superficial and deep. Deep soft tissue lipomas located under the deep fascia (sub muscular, intramuscular, or intermuscular) are less common than superficial lipomas [1-4]. Among those pathologies, intramuscular lipoma is a rare variant. In this report, we present the diagnostic and therapeutic algorithm of the intramuscular lipomas of the hand, especially seen under thenar site. Material and Methods 5 patients between April 2016 to May 2017 were admitted to outpatient clinic because of progressive intumescence of the hand

*Coresponding Author: Yusuf Erdem, Gulhane Training and Research Hospital, Ankara, Turkey, E-mail: yerdem81@gmail.com

that had first appeared recently. All patients were female with an average age of 56.6 years (range, 47 to 68 years). The masses were observed on right hand in three of the patients, whereas the remaining had on thenar site of left hands. In addition to this symptom, they reported mild thumb pain, slight numbness in the radially innervated digits of hand, and difficulty while gripping objects. Physical examination revealed large, deeply located masses in the thenar area of hands (Figure 1). The mass was stable and free from the underlying bone, but it became mobilized with muscle movements. The range of motion (ROM) of the thumb in affected hand was assessed fully, and there was no hypoesthesia. At first, ganglion cysts were thought at clinical assessment as the most common benign soft tissue tumors of hand prior to other softtissue masses, such as lipomas of the hand. Moreover it is difficult to differentiate lipomas from ganglion cysts by palpation only. İn distinction of such benign masses, ganglion cysts allow passage of light on trans-illumination while lipomas do not. However, positive Tinnel’s sign (compression neuropathy sign) may be helpful in confirming lipoma, which cause higher mass-related compression effect than ganglion cyst. As an initial radiological assessment, x-rays showed radio dense masses over the thenar area without any bony pathology. 162

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Figure 1. Clinical photograph of the hand before surgery, black arrow shows mass in the thenar eminence hand.

Ultrasonographies of the thenar area showed various size hyperechoic intramuscular solid masses. Subsequently, magnetic resonance imaging (MRI) revealed a well-defined intramuscular lipomas with regular borders and same signal intensity as mature adipose tissues (Figure 2). Masses also had a low-intensity signal on fat-suppressed MRI scans, suggestive of intramuscular lipoma. Finally, median nerve electromyography (EMG) was performed to assess the hypoesthesias of the patients, however no significant entrapment neuropathy was observed. Then we did not need to perform incisional biopsies.

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Figure 3. Thenar intramuscular lipoma. Coronal, sagittal and axial T1 and T2 MRI sections revealing bilobular high (T1) and low (T2) intensity signal mass with regions of well-defined margins in the area of thenar eminence.

Results The average operation time was 60 minutes (range, 50 to 65 minutes) and complications such as neurologic deficit, infection or recurrence were not observed postoperatively. Pathology revealed intramuscular lipomas for all samples (Figure 4). The patients were followed up for about one year postoperatively without any comorbidities. They had regained full range of movement of thumb, hand and wrist. 3 questions were asked to patients to consider any sign of recurrence clinically. One is about the numbness of the hand, the other is about the degree of the pain of the thumb, and the last question is related with cosmetic appearance of the thenar site of the hand to check if there is any residual tumor. All questions were answered in every clinical assessment, then no further imaging study or treatment modalities were performed.

Figure 2. Surgical steps. a) Blunt dissection of abductor pollicis brevis muscle after incision. b,c) excision of tumor. d) After hemostasis. e,f) Wound closure and excised lipoma measuring 3x2 cm

Surgical procedures An excision within marginal borders was planned for all masses. All patients had regional anesthesia with tourniquet applied of affected extremity. Surgeries were performed with thenar site incisions while the patients were under regional anesthesia. The fascias were opened, the abductor pollicis brevis muscles were separated by blunt dissections, and the masses were excised within marginal resection fields (Figure 3). Hemostasis was secured before closure, and the excision materials were sent to pathology for histopathological examination in diagnosis.

Figure 4. Histopathological examination of the lipoma. Lipocytes can be seen. 10x, magnification

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they can only be followed by periodic follow-ups. However, intramuscular lipomas are mostly symptomatic masses where the surgical treatment is inevitable. The recommended surgery is marginal or wide excision to prevent recurrences. Debulking is also an acceptable option if the mass is in an unsuitable area or if complete resection will lead to a functional impairment [15]. Patients in current study had disability of gripping function of the thumb and hypoesthesia of the radial innervated digits due to tumor mass effect. So we performed marginal excisions on all masses where the symptoms were disappeared after removal of tumors.

Figure 4. Histopathological examination of the lipoma. Lipocytes can be seen. 40x, 40x magnification

Discussion Lipomas are the most common soft tissue tumors and may be observed anywhere in the body. The exact etiology is unknown, however in a report, most of the intramuscular lipomas occur in large muscles exposed to trauma where the jointâ&#x20AC;&#x2122;s range of motion is big and much power is used [5]. They are usually localized superficially. Myhre-Jensen reported only 1â&#x20AC;&#x201C;2% deepseated lipomas in their large series [6]. Al-Qattan reported only 3 intramuscular lipomas in their series of 67 upper extremity benign fatty tumors [7]. Weiss and Goldblum classified deep-seated lipomas according to their locations as follows: intramuscular or intermuscular [8].

In radiological assessment, MRI is the most effective and reliable imaging method for diagnosing soft tissue tumors. Infiltration of the neighboring tissues visualized on MRI scans may raise suspicion of a liposarcoma. X-rays and computed tomography can be useful for the detection of tumor calcifications, which cannot be detected by MRI and ultrasonography [16]. Nuclear medicine imaging has not been used extensively in the diagnosis of intramuscular lipomas [17]. Ultrasonography shows the hyperechoic mass with irregular margins and skeletal muscle interdigitations, which create a striate appearance with the distinction of liposarcomas. These images allow confident diagnosis of intramuscular lipomas [9]. EMG should be included as a diagnostic modality if a patient has any nerve compression symptoms, as ours did. In addition, many authors recommend biopsy of the tumor to identify the lesion histologically in cases where no diagnosis has been made on the basis of imaging studies. Moreover, in case of giant lipomas, a biopsy should be performed to differentiate from liposarcoma (Table 1) [18].

Moreover intramuscular lipomas are uncommon and occasionally encapsulated, which causes abnormal invasion of soft tissues. They are also known as infiltrating lipomas due to their abnormal characteristic growth pattern. Though both terms (intramuscular and infiltrating) have been used interchangeably, the truth is that not all of them are infiltrating [9]. Lipomas are rarely observed in the hand and very few reports of hand lipomas have been published till now. Lee et al. reported six intramuscular lipomas of the hand, four of which were located in the thenar region and two of which were in the hypothenar area [10]. Zamora et al. reported a case of an intramuscular lipoma that was located in the thenar eminence and was associated with the median nerve distribution [9]. Cribb et al. reported 10 upper extremity lipomas, 5 of which were located in the hand. The number of lipomas in our study is compatible with the literature. The lipomas were in thenar, hypothenar, and wrist locations, and two of them caused paresthesia due to median nerve compression [11]. Schoffl reported a thenar-seated lipoma that caused bony destruction [12]. Zakaria reported five hand lipomas with thenar, midpalmar, and hypothenar localizations [13]. All of these previously described tumors were in intramuscular locations, and they rarely caused median nerve compression. Clinically, they can reach large sizes and cause hypoesthesia with compromised functionality of the hand, mainly with regard to gripping ability. Pain is a late and uncommon and usually observed in deep and large lipomas due to compression or expansion of the adjacent soft tissues [14]. If lipomas do not reveal any symptoms,

Table 1. A flowchart of the diagnostic and therapeutic algorithm of the palpable masses of the hand.

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As in abovementioned studies, it is considered that symptomatic lipomas should be excised surgically within marginal borders. Recurrence is extremely rare, but when it occurs, it is due to inadequate excision of the tumor [18]. Zamora et al. reported a recurrence 2.5 months postoperatively [9]. Postoperative infection, neural damage, and formation of a painful neuroma are encountered as surgical risks [19]. Our patients had no recurrence or postoperative complications at one-year follow-up. Conclusion Intramuscular lipomas are benign lesions with an excellent prognosis after adequate excision. Physicians should be mindful of the possibility that the mass may appear as a liposarcoma; therefore, they should manage treatment by using an appropriate algorithm that incorporates MRI and biopsy for accurate diagnosis. Clinical Message Palpable hand mass should not ignore as a simple case, especially when they are atypical localized. Sometimes it is actually difficult to clarify the diagnosis in such cases. The algorithm mentioned above may be a guide to get satisfactory results. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support. Ethical approval Ethical approval was received form our instutional review board. Zafer Atbasi ORCID:0000-0002-5837-7367 Yusuf Erdem ORCID:0000-0002-8685-2356

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Medicine Science International Medical Journal

Medicine Science 2019;8(1):166-8

Evaluation of the admitted forensic cases to the emergency department Feride Sinem Akgun Maltepe University, Faculty of Medicine, Department of Emergency Medicine, Istanbul, Turkey Received 30 November 2018; Accepted 02 January 2019 Available online 29.01.2019 with doi:10.5455/medscience. 2018.07.8971 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Forensic cases, whereas non-natural factors cause physical or behavioral damages, are mostly seen in the emergency departments (ED) of the hospitals. In this study, we aimed to contribute to the forensic records of our country by examining the demographic characteristics of the forensic cases who were admitted to our ED. Hospital records and forensic reports of the patients who were admitted to ED and accepted as forensic cases between 2014-2017 were retrospectively scanned, and evaluated. Age, gender, the reason for admission and results of the patients were examined. Data were recorded, and statistical analyzes were performed via SPSS v.16.0. A total of 824 forensic cases were admitted to the ED during the study period, and 61% (n = 503) were male. The mean age of the patients was 32,73 ± 15,65 years. Traffic accidents (n = 289; 35%) and occupational accidents (n = 208; 25.2%) were the most common causes of forensic case admissions. While 79.5% (n = 655) of the patients were discharged from the ED, 14.7% (n = 121) were hospitalized while 0.7% (n = 6) of the cases could not be saved despite all interventions. Traffic accidents and occupational accidents are among the most frequent forensic cases in our country, and it should be highlighted that these causes are preventable injuries. At the same time, while the rate of violence and sexual assault has been high all over the world, the reason that our study has no case admissions due to sexual assault and violence should be investigated. Keywords: Emergency department, forensic cases, occupational accident, sexual assault, traffic accident

Introduction As in all over the world, traffic accidents, violence, fighting, suicide, and related injuries are a significant health problem in our country. It is called a forensic case when a person, becomes physically or mentally ill by another person or peoples’ intent, negligence, imprudence or carelessness, and emergency departments (ED) are one of the most frequent the places where the first occurrences of these physical or behavioral damages caused by unnatural factors on humans are seen [1,2]. Forensic cases include traffic accidents; intoxication; assault; cutting-penetrating-crushing tool injuries; gunshot wounds; exposure to corrosive substances; falls or falls on hard bodies; burns; asphyxia; suspicious, sudden and unexpected deaths; occupational accidents and sexual assault [3]. These cases constitute an essential part of emergency applications. In addition to the responsibility of treating the patient, the physicians working in the emergency department have important *Coresponding Author: Feride Sinem Akgun, Maltepe University, Faculty of Medicine, Department of Emergency Medicine, Istanbul, Turkey E-mail: bfsakgun@hotmail.com

duties such as the reporting of traumatic lesions detected in the patient in forensic cases and reporting the case to the judicial authorities. This study aims to analyze the demographic and epidemiological characteristics of the cases evaluated as forensic cases in the Emergency Department of Medical Faculty Education and Research Hospital and to contribute to the records of our country. Material and Methods This research was carried out with the permission of Maltepe University, Clinical Research Ethics Committee, and numbered 2018/900/79. While all patients who were evaluated as forensic cases in ED between 01/01/2014 and 31/01/2017 were included in the study, cases of poisoning who were admitted to the pediatric emergency department were not included in the study. Patient information was obtained from ED patient records, forensic reports, and hospital information management systems (MediPro Software + Compass System) retrospectively. Patients’ gender, age, reasons of admission (traffic accidents, intoxications, blunt force injuries, cutting and drilling injuries, gunshot wounds, exposure 166

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Med Science 2019;8(1):166-8

to corrosive substances, falls or falls on hard bodies, burns, suspicious, sudden and unexpected deaths, occupational accidents and sexual assault) and their results (discharge, hospitalization, refusal of treatment, referral and death) were evaluated. Statistical analysis Statistical Package for Social Sciences (SPSS) 16.0 package program was used to analyze the data which were entered with a standard system to the computer. Descriptive numerical variables were reported as mean ± standard deviation (SD), frequency (%) and range (minimum-maximum). Independent two samples t-test was used to compare the mean values of two different sample groups for customarily distributed the quantitative variables.

Figure 1. Distribution of age groups according to gender

When the reasons of admission of forensic cases to ED were evaluated, it was observed that traffic accidents (n = 289, 35%) and occupational accidents (n = 208, 25.2%) were in first ranks. Among other reasons, there was no admission of sexual abuse or sexual assault, while blunt force injury, falling, cutting and drilling injuries, and poisoning had upper ranks. While there was male dominance among all admissions, the number of female poisonings was higher (n = 49) (Table 1).

Results Eight hundred and twenty-four (2.3%) of 39162 patients admitted to the ED of our hospital were evaluated as forensic cases. The ages of the cases ranged from 1 to 89 years, with a mean of 32.73 ± 15.65 years, of which 61% (n = 503) were male, and 39% (n = 321) were female. When the age ranges were considered, it was found that the cases were between 0-9 years of age with a minimum of 4.9% (n = 40) and 20-29 years of age with a maximum of 30.8% (n = 254) (Figure 1).

When the causes of occupational accidents (n = 208) were evaluated, male (74%) dominance was observed, while 112 cases were due to falling or falling on a foreign body and 72 cases had cutting and drilling injuries.

Table 1. Distribution of forensic cases according to gender and results Gender

TA (n)

OW (n)

BFI (n)

F (n)

CDI (n)

I (n)

ECS (n)

GW (n)

B (n)

SA (n)

CPA (n)

Female

139

Male

150

154

106

Total

289

208

160

135

117

Discharge

262

167

154

104

Refusal of Treatment

Hospitalization

Death

Referral

Total

289

208

160

135

117

Results

TA: Traffic Accident OA: Occupational Accident SA: Sexual Assault CDI: Cutting and Drilling Injury I: Intoxication BFI: Blunt Force Injuries F: Falls or Falls on Hard Bodies GW: Gunshot Wounds B: Burn CPA: Cardio-Respiratuar Arrest ECS: Exposure to Corrosive Substances

While 79.5% (n = 655) of patients who were admitted and evaluated in ED were discharged from the ED, 9.7% (n = 80) were hospitalized to internal medicine or surgery clinics and 5% (n = 41) were hospitalized to intensive care unit. 4,7% (n = 39) of the cases refused hospitalization when admission decision was made and signed consent form while 0.4% (n = 3) of the cases were referred to another center, 0.7% (n = 6) died (Table 1). When the results were evaluated according to causes, patients who were admitted with poisoning had higher rates of hospitalization (n=51, 42,15%) and discharge (n=15, 38,5%) without completing the treatment. Two of the patients who were brought with cardiopulmonary arrest were hospitalized to intensive care unit after interventions in the ED, and five of them could not be saved

despite all interventions. The reason of 5 of the six deaths in ED was falling from high (1 of them was work accident) while the cause of one is unknown. Discussion In this study which examined the forensic cases applying to the ED 2.3% of patients were forensic cases, this rate was 3.66% in Demircan et al’s [4] study and 7,01% in Korkmaz et al [5]. In our study, male gender dominance (61%) and young age (32.57 ± 16.2 years) were consistent with other studies in the literature. The most common range of age was 20-29, which is attributed to the fact that the young population is working in high-risk sectors, more in traffic and social life, and being more involved in judicial events [5,6]. 167

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In many studies conducted on the forensic cases applying to EDs in our country, the largest group of cases belong to traffic accidents [2,5,7]. This group covered 35% of our study and was in the first place at a high rate. This situation depends on the city, and the location where our hospital is located, the traffic is dense and complicated, and the traffic rules are not followed. The results of our study were similar to other studies in the literature showing that males are more likely to be admitted due to traffic accidents and blunt force injuries and women due to poisoning [5,8]. In 2006, Celbiş et al reported that women were mostly subjected to blunt force injuries and traffic accidents (n = 699,947; 31.1%; 42.2%). In the same study, 162 women (7.2%) presented with sexual assault due to family violence and were reported to be remarkable [9]. No sexual assault was found in our study. Although this situation is quite common in the world, there is a need for more detailed patient history and sociocultural data to understand why we do not encounter in our region. Occupational injuries and deaths constitute an important place in forensic medicine applications. The fact that most of the cases of occupational accidents are male is due to the role of men in our society, especially in heavy jobs, inexperienced people being more susceptible to work accidents and increased construction sector due to urban transformation [2, 10]. Similarly, falls are a common cause of injury, especially for the elderly, young and employees of various sectors. Most of the falls are caused by accident [4]. According to our study, 74,1% of those who had occupational accidents were males and 25,9% were females. One of our patients who died was brought to the emergency department due to a work accident. Our study, most of the occupational accidents are caused by falls and/or injuries due to falling objects, while Sayhan et al. [11] found that 40.6% of the cases had injuries due to sharp objects. The fact of high rates of the fall accidents in occupational accidents indicates the necessity of taking preventive cautions in this regard and the importance of occupational safety training and audits of the workplaces. In a study by Korkmaz et al. [5], 68.5% of patients were discharged from ED, and 25.7% were hospitalized. In 2012, Levent et al. [6] reported that 88.8% of the patients were discharged from the hospital, 2.5% were hospitalized, and 8.7% left the hospital before the completion of treatment. When the results of the patients were evaluated by causes, it was observed that the falls were with a higher number of hospitalizations compared to other causes. The patients who were admitted with suicide were the ones who left the ED without completing their treatment compared with other causes [7]. In our study, 79.5% (n = 655) of the patients were discharged from ED, while 9.7% (n = 80) were hospitalized to the internal medicine or surgery clinics and 5% (n = 41) were admitted to the intensive care unit. 4,7% (n = 39) of the patients refused the examination or treatment, signed a consent form and left the hospital. When the results were evaluated by causes, the patients who were hospitalized to the hospital with the highest number and did not accept the treatment were found to be the patients who were admitted with poisoning.

Med Science 2019;8(1):166-8

Conclusion The first step of the forensic examination of the patients who are considered as a forensic case is performed in the ED. Another task of the emergency physicians who are responsible for the initial intervention and treatment of all patients admitted to the hospital is to evaluate the forensic cases and to notify them to the relevant authorities. Traffic accidents and occupational accidents are in first ranks amongst the forensic cases in our country, and the important fact is that they are preventable. On the other hand, while it is noteworthy that violence and sexual assault rates have been high all over the world, it is not seen our region, and we think that this subject should be evaluated in more detail and carefully. Competing interests The authors declare that they have no competing interest. Financial Disclosure There is no financial support for this study. Ethical approval Maltepe University, Clinical Research Ethics Committee, and numbered 2018/900/79. Feride Sinem Akgun ORCID: 0000-0001-6537-866X

References 1.

Sharma BR. Clinical forensic medicine in the present day trauma-care system- an overview. Injury. 2006; 37:595-601

Yavuz MF, Baştürk P, Yavuz MS, et al. Evaluation of the forensic cases admitted to the Emergency Department of the Cerrahpaşa Medical Faculty. Turk J Forensic Sci. 2002;2:21-6.

Yener Z. The evaluation of the forensic reports referred to council of forensic medicine, Yalova region, Turkey, 2014-2016. Med Sci. 2018;7:283-9.

Demircan A, Keleş A, Guerbuez N, et.al. Forensic emergency medicine-sixyear experience of 13823 cases in a university emergency department. Turk J Med Sci. 2008;38:567-75.

Korkmaz T, Kahramansoy N, Erkol Z, et al. Evaluation of the Forensic Patients Presenting to the Emergency Department and Legal Reports. The Medical Bulletin of Haseki. 2012; 50: 14-20.

Levent S, Günaydın GP, Kavaklı HŞ, et al. A retrospective seasonal analysis of forensic cases admitted to an emergency department in a year. J Forensic Med. 2015;29:22-8.

Türkçüer İ, Gözlükaya A, Serinken M, et al. Application times of forensic cases to emergency department. Eurasian J Emerg Med. 2010;9:89-92.

Zeren C, Karakuş A, Çelikel A, et al. Evaluation of forensic cases in fmergency service, Mustafa Kemal University hospital of medical faculty. Med J Mustafa Kemal Univ. 2011;2:34-42.

Celbiş O, Gökdoğan MR, Kaya M, et al. Review of forensic assessments of female referrals to the branch of legal medicine, Malatya region, Turkey, 1996-2000. J Clin Forensic Med. 2006;13:21-5.

10. Asıldağ K, Akbaba M, Annaç M. Forensic medical evaluation of patients admitted to the emergency department due to the occupational accidents. Eur J Ther. 2017;23:49-54. 11. Sayhan MB, Sayhan ES, Yemenici S, et al. Occupational injuries admitted to the emergency department. J Pak Med Assoc. 2013;63:179-84.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):169-72

Anesthesia management in kidney transplantation patients: Retrospective evaluation Mukadder Sanli, Muharrem Ucar Inonu University Medicine Faculty, Department of Anesthesiology and Reanimation Malatya, Turkey Received 18 Febuary 2019; Accepted 22 Febuary 2019 Available online 27.02.2019 with doi:10.5455/medscience.2019.08.9018 Copyright ÂŠ 2019 by authors and Medicine Science Publishing Inc. Abstract Kidney transplantation comes first for treating and improving living standards in patients with end-stage renal disease. The developments in surgical techniques on kidney transplantation and the specific immunosuppressive agents contributed to improving the function of graft for more extended periods. In addition, developments of anesthesia also contributed to this success. The purpose of the study was to present anesthesia management applied on 40 kidney transplant recipients who were carried out from alive and cadaver donors with a current literature review. The ages, genders, accompanying systemic diseases, whether or not the graft was received from live donor or a cadaver, hot/cold ischemia times, anesthesia and surgery times of the participants were recorded. In addition, postoperative analgesia management, postoperative complications and hospital stays of the patients were also recorded. We believe that graft preservation and patient comfort will be increased with good analgesia management, graft protection, by using selected anesthetics and protecting the kidney blood flow, and by close hemodynamic follow-up in kidney transplant patients. Keywords: Anesthesia management, kidney transplantation, evaluation

Introduction

Material and Methods

Kidney transplantation comes first for treating and improving living standards in patients with end-stage renal disease. Kidney transplantation is the most common solid organ transplantation in Turkey as well as in the whole world and carried out mostly from live donors [1]. The developments in surgical techniques on kidney transplantation and the specific immunosuppressive agents contributed to improving the function of graft for more extended periods [2]. In addition, developments of anesthesia also contributed to this success.

Following the approval of Inonu University, Clinical Trials Ethics Committee (2019/46-01) was received; anesthesia records of 40 patients, who were admitted to Inonu University Medical Faculty Hospital, General Surgery Operating Room (between January 2018 and December 2018) were evaluated retrospectively.

Good anesthetic management and analgesia in kidney transplant recipient are essential for graft function and patient comfort [3,4]. The number of kidney transplantations increases with each passing year. In our study, the purpose was to present anesthesia management performed on 40 kidney transplant recipients who were carried out from alive and cadaver donors with a current literature review.

*Coresponding Author: Mukadder Sanli, Inonu University Medicine Faculty, Department of Anesthesiology and Reanimation Malatya, Turkey E-mail:mukaddersanli@gmail.com

The patients whose informed consents were received for anesthesia before the surgery were taken to the operation room without applying premedication. For standard monitoring, 3-channel electrocardiography, noninvasive blood pressure, and pulse oximetry were employed. Following the achieving peripheral intravenous (IV) access in the non-fistula arm, 1 mcg/kg fentanyl was applied. General anesthesia induction was achieved with propofol, fentanyl, lidocaine, rocuronium or cisatracurium. Anesthesia maintenance was carried out with desflurane and 50% oxygen-50% nitrous oxide. After the intubation, the patients were ventilated mechanically by using a volume-controlled mode. An invasive blood pressure monitorization was ensured by applying radial artery catheterization in the non-fistular arm. A central pressure monitorization was achieved by inserting a 3-way central venous catheter or dialysis catheter in the right jugular 169

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vein accompanied by USG. For body temperature monitoring, an esophageal heat probe was placed. Immune suppression infusion (ATG or simulect) was performed through a central route. Antibiotic prophylaxis, low molecular weight heparin 70 units/kg, methylprednisolone 15 mg/kg, and proton pump inhibitor were carried out. Intraoperative fluid management was performed with a conventional fluid management regimen. Isolyte-S was given 0.5 mL / kg / h infusion and intermittent bolus for maintain CVP 12-15 mmHg and MAP 60-80 mmHg. When the graft was inserted, it was infused with 20% mannitol 1.5 mL/kg and furosemide 2 mg/kg. To keep the mean arterial pressure above 60 mmHg, noradrenaline infusion was used; and for those who were hypertensive and had coronary artery disease, nitroglycerin infusion was used by changing the actual dose. The ages, genders, accompanying systemic diseases, whether or not the graft was received from live donor or a cadaver, hot/cold ischemia times, anesthesia and surgery times of the participants were recorded. In addition, postoperative analgesia management, postoperative complications and hospital stays of the patients were also recorded. For postoperative analgesia, the wound area infiltration block was performed with bupivacaine as 0.5 mg/kg at the end of the surgery. In addition tramadol 0.5 mg/kg and paracetamol 15 mg/ kg combination were used. The patients whose postoperative VAS scores (0: no pain, 10: intolerable pain) were ≥40 were given 0.5 mg/kg IV pethidine. The patients were taken to the general surgery transplant service after at least one hour of monitoring in the recovery unit. Results Forty patients were included in the study. Demographic and clinical data of the patients were presented in Table 1. Procedures during anesthesia management were presented in Table 2. The duration of cold ischemia of cadaveric donors was measured longer than living donors and maximal time was 1116 min. The fluid management was carried out Isolyte-S on all patients, colloid, blood, and blood products were not used. Some patients had comorbidities included that hypertension 12 (30%), hypertension and diabetes 3 (7.5%), diabetes 2 (5%), and one patient had sleep apnea 1 (2.5%). In a patient who had factor VII deficiency developed intraoperative renal artery thrombosis during surgery. In a patient, hemorrhage occurred on the 3rd day. In another patient was developed nasal mucor infection on the 30th day and the patient died. Eight patients were administered additional analgesic which was pethidine. The duration of hospital stay on living recipients was shorter, and the shortest was 5 days. It was found that there was prolonged hospital stay in cadaveric recipients up to 35 days.

Med Science 2019;8(1):169-72

Table 1. Demographic and Clinical Characteristics

Age (years) Sex (male/female) Weight (kg) Cadaveric/living live ASA III/IV Hemoglobin(mg/dL) Need for additional analgesics

Range

Mean ± std

7 – 61

38.90 ± 13.75

23 – 104

64.80 ± 17.25

8/32

21 – 30

24.95 ± 2.85

38/2

6.3 – 10.3

8.02 ± 1.06

29/11

Comorbidity None

Hypertension

Diabetes +Hypertension

Diabetes

FVII Deficiency

Sleep Apnea

none

hemorrhage

thrombosis

mortality

Complications

American Society of Anesthesiology, n: number of cases, Values are expressed as means ± SD and range( min-max) Table 2. Procedure datas Range

Mean ± std

Duration of anesthesia (min)

180-360

298.50±32.22

Duration of surgery (min)

170-320

253.50±30.93

Total crystalloid (mL)

600-4000

3062.50±833.80

Mannitol (mL)

30-150

93.75±26.57

Furocemid (mg)

80-180

131.50±18.05

Bupivacain (mg)

15-25

24.5±0.44

Duration of cold ischemia (min)

Blood Transfusions

67-1116

275.82±379.14

Duration of hot ischemia (min)

1.11-4

2.27±0.78

Duration of urinary flow (min)

3-34

7.96±8.81

Length of hospital stay (day)

5-35

10.95 ±10.38

Values are expressed as means ± SD and range( min-max)

Discussion When compared with dialysis in patients who have chronic kidney failure, kidney transplantation decreases costs by increasing both survival and patient comfort. Kidney transplantation is one of the most frequently-applied solid organ transplants, and there are cases for whom simultaneous pancreatic transplantations were carried out in the same session. In our center, simultaneous pancreatic transplantation has not been performed because no suitable cadavers were found. 170

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Since the cadaveric kidney transplantation may be carried out in a limited number in our country because there are not adequate cadavers, parallel to this, it is also made in a small number in our center. Although the number of kidney transplantation from cadavers is low, the fact that we had the technology needed to grow the graft in the earliest time was to the advantage of the graft. Live donor kidney transplantation is carried out in many centers as well as in our center in an increasing number [5]. Nowadays, receiving the graft from the live donor with laparoscopy and increasing the comfort of the postoperative period are the advantages. Although neuraxial and peripheral nerve blocks were used in kidney transplant patients, usually, general anesthesia is preferred. Propofol is the most frequently-preferred general anesthetic because of providing fast induction and recovery; and therefore, we preferred it in all cases. It was reported that pentothal was used as a IV anesthetic in pediatric kidney transplantation in anesthesia management [6]. Fentanyl was preferred by us as the narcotic analgesic. Although cis atracurium is the agent with the lowest renal elimination for the neuromuscular block, rocuronium was preferred mostly to ensure rapid induction and intubation because of gastric emptying being late in renal failure [7]. Although there were several publications that recommended to use suggammadex to reverse the neuromuscular block [8], we reversed it with neostigmine and atropine except for the patients who had difficult intubation as the duration of action was shorter compared to rocuronium. Although using sevoflurane is recommended by claiming that its elimination will not be a problem in maintaining anesthesia after the transplantation, we used desflurane in all of our cases. In a clinical study in which sevoflurane and desflurane were compared, the authors concluded that using it in live kidney transplantation did not differ in terms of early graft function [9]. A total of Isolyte –S was used by us for fluid replacement. The central venous pressure (CVP) was applied as a 12-15 mmHg range. In a study in which low-chloride balanced solutions were compared with normal saline, it was reported that balanced solutions provide a better acid-base balance [10]. In fluid management, traditional methods like CVP and renal vein fullness were used. In a clinical study in which esophageal doppler was used in fluid management, it was concluded that there were no differences in terms of volume differences when compared to the traditional method [11,12]. To keep the average arterial pressure over 60 mmHg is necessary to protect the graft in fluid management. Inotropic agents should be employed when needed to prevent hypotension attacks. In a clinical study in which the effects of inotropic use on graft function was investigated, more inotropic was needed especially in older recipients, and significant increases were determined in hospital stay and morbidity [13]. Analgesia management is essential in kidney transplant patients to maintain the graft function, improve patient comfort, and for early mobilization. The prolonged effects of narcotic analgesics bring together co-morbidity [14]. Peripheral nerve blocks and neuraxial blocks were employed for postoperative analgesia. The recommended issue in kidney recipient is to avoid nephrotoxic agents when multimodal analgesia regimen is chosen.

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Blocking of the parietal nociceptive afferent nerves via surgical‑site infiltration block by local anesthetics is widely used after major surgery [15,16]. In our cases, we preferred combination the bupivacaine with surgical- site infiltration block, IV tramadol, and paracetamol. The tendency to acidosis increases in kidney failure, and since the free fraction of local anesthetics will increase, the dose must be decreased [17]. For this reason, we used 0.5 mg/ kg bupivacaine to infiltrate the wound site. The neuro-axial blockade was avoided in our cases because of the low molecularweight heparin usage. In a study conducted by Jun et al. which was compared compare intrathecal morphine with ropivacaine injection on wound site in kidney recipients, it was concluded that intrathecal morphine provided better analgesia; however, patient comfort was not good because of respiratory depression and itchiness complaints [18]. Limitations There is a limitation on fluid management. Dynamic fluid management strategies were not performed because of lack of technology. Conclusion We believe that graft preservation and patient comfort will be increased with a good analgesia management. Using suitable anesthetics, close hemodynamic monitoring and adequate pain management can improve outcome in kidney transplant recipients. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support. Ethical approval The financial support for this study was provided by the investigators themselves. Mukadder Sanli ORCID: 0000-0003-1009-5536 Muharrem Ucar ORCID 0000-0002-1232-9829

References 1.

İnce İ, Ahıkalıoğlu A, Aksoy M, et al. Anaesthetic experience of 200 renal transplantation cases: A retrospective study. Abant Med J. 2016;2:118-26.

Ricaurte L, Vargas J, Lozano E, et al. Anesthesia and kidney transplantation. Transplant Proc. 2013;45:1386-91.

Wray CL. Advances in the Anesthetic Management of solid organ transplantation. Adv Anesth. 2017;35:95-117.

SarinKapoor H, Kaur R, Kaur H. Anaesthesia for renal transplant surgery. Acta Anaesthesiol Scand. 2007;51:1354 67.

Aydoğan MS, Çolak YZ, Pişkin T, ve ark. Böbrek transplantasyonu hastalarında anestezi yönetimi. Turgut Özal Tıp Merk Derg. 2013;20:318-21.

Michelet D, Brasher C, Marsac L, et al. Intraoperative hemodynamic factors predicting early postoperative renal function in pediatric kidney transplantation. Paediatr Anaesth. 2017;27:927-34.

Cooper RA, Maddineni VR, Mirakhur RK, et al. Time course of neuromuscular effects and pharmacokinetics of rocuronium bromide during isoflurane anesthesia in patients with and without renal failure. Br J Anaesth. 1993;71:222-6.

Staals LM, Snoeck MM, Driessen JJ, et al. Reduced clearance of rocuronium and sugammadex in patients with severe to end-stage renal failure: a pharmacokinetic study. Br J Anaesth. 2010;104:31-9.

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Karadeniz MS, Ciftci HS, Tefik T, et al. Comparison of two different inhalation anesthetics on grafted kidney function in patients undergoing renal transplantation surgery: Desflurane or sevoflurane? Transplant Proc. 2017;49:448-53.

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of prescription opioid use before kidney transplantation through linked registry and pharmaceutical claims data. Transplantation. 2015;99:187-96.

10. Wan S, Roberts MA, Mount P. Normal saline versus lower-chloride solutions for kidney transplantation. Cochrane Database Syst Rev. 2016;8:CD010741.

15. Beaussier M, El’Ayoubi H, Schiffer E, et al. Continuous preperitoneal infusion of ropivacaine provides effective analgesia and accelerates recovery after colorectal surgery: a randomized, double‑blind, placebo‑controlled study. Anesthesiology. 2007;107:461‑8.

11. Corbella D, Toppin PJ, Ghanekar A, et al. Cardiac output-based fluid optimization for kidney transplant recipients: a proof-of-concept trial. Can J Anaesth. 2018;65:873-83.

16. Forastiere E, Sofra M, Giannarelli D, et al. Effectiveness of continuous wound infusion of 0.5% ropivacaine by On‑Q pain relief system for postoperative pain management after open nephrectomy. Br J Anaesth. 2008;101:841‑7.

12. Calixto Fernandes MH, Schricker T, Magder S, et al. Perioperative fluid management in kidney transplantation: a black box. Crit Care. 2018;22:14.

17. Tsuchiya H, Mizogami M, Ueno T, et al. Cardiotoxic local anesthetics increasingly interact with biomimetic membranes under ischemia-like acidic conditions. Biol Pharm Bull. 2012;35:988-92.

13. Choi JM, Jo JY, Baik JW, et al. Risk factors and outcomes associated with a higher use of inotropes in kidney transplant recipients. Medicine (Baltimore). 2017;96:e5820. 14. Lentine KL, Yuan H, Tuttle-Newhall JE, et al. Quantifying prognostic impact

18. Jun JH, Kim GS, Lee JJ, et al. Comparison of intrathecal morphine and surgical-site infusion of ropivacaine as adjuncts to intravenous patientcontrolled analgesia in living-donor kidney transplant recipients. Singapore Med J. 2017;58:666-73.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):173-5

The relationship between sphincteratomy methods and post ercp pancreatitis Yahya Atayan Malatya Education and Researches Hospital Department of Gastroenterology, Malatya, Turkey Received 22 December 2018; Accepted 03 January 2019 Available online 08.02.2019 with doi:10.5455/medscience.2018.07.8983 Copyright ÂŠ 2019 by authors and Medicine Science Publishing Inc. Abstract Post (ERCP) pancreatitis (PEP) is the most commonly seen complication after endoscopic retrograde cholangio-pancreaticography (ERCP). It is associated with pancreatic hyperamylasemia and persistent abdominal pain. It can be classified as mild, moderate and severe. During ERCP, bile ducts or pancreatic duct can be cannulated using standard sphincteratomy or needle-tipped sphincteratomy methods and contrast material is injected in order to view these ducts. In this study, we aimed to examine whether the use of sphincterotomy methods and pancreatic canal interventions poses a risk in the development of PEP, which is the most common complication after ERCP. Of the 445 patients who underwent ERCP, 270 had standard sphincterotomy and 175 had Needle-knife sphincterotomy (NKS). Patients who were cannulated with pancreatic duct and injected with contrast agent during the procedure and patients who were diagnosed with PEP according to the revised Atlanta criteria, were included in the study. Of 445 patients, 187 were male (39.7%) and 258 were female (60.3%). After successful sphincterotomy, stone extraction basket and / or balloon procedure was applied to all patients. Of the 270 patients, 13(2.9%) patients developed PEP and 9 of these patients had pancreatic duct cannulation and contrast agent injection during the procedure. PEP development was statistically significant in patients with pancreatic duct cannulation (p <0.01). Of 175 patients who underwent NKS, procedure was successful in 168 (96%) patients but 27(6.1%) patients developed PEP. 18 of the patients who developed PEP had pancreatic duct cannulation and contrast material injection. PEP development was statistically significant in patients with pancreatic duct cannulation (p <0.01). We concludedthat the factors increasing the incidence of PEP, which is the most common complication after ERCP are repeated unsuccessful attempts, pancreatic canal entry and contrast agent injection during the procedur. And NKS was found to have higher PEP development compared to standard sphincteratomy. Keywords: Sphincteratomy, ERCP, Pancreatitis

Introduction Post-ERCP pancreatitis (PEP) is the most commonly seen complication after endoscopic retrograde cholangiopancreaticography (ERCP) which is used in diagnosis and treatment. It is associated with pancreatic hyperamylasemia and persistent abdominal pain. It can be classified as mild, moderate and severe. Although 75% of cases with PEP are benign self-limiting, 25% are moderate / severe and may even result in death [1]. In many large studies, the rate of PEP is found to be between 1.6-15.1% [2]. In some studies, the frequency ranging up to 24.4% has been reported [3]. The pathogenesis of PEP is not exactly known. The most frequently discussed theory is; the trauma developed during difficult cannulation of papillae causes edema. As a result, the papillae become narrower, preventing the passage of the pancreas into the intestine, resulting in pancreatitis attack and the activation of inflammatory pathways. Needle-knife

*Coresponding Author: Yahya Atayan, Health Sciences University, Malatya Education and Researches Hospital Department of Gastroenterology, Malatya, Turkey, E-mail: yahyaatayan@hotmail.com

sphincterotomy (NKS) refers to a technique in which electrocautery is used to enter the biliary and pancreatic duct in ERCP cases where standard sphincterotomy fails or is not preferred during ERCP. Which case will be evaluated as difficult ERCP, varies from study to study,The most common way of evaluation is the inability to perform choledochal cannulation without pre-incision papillotomy. In this study, we aimed to investigate the relationship between interventions during ERCP and PEP developement. Material and Methods 445 patients who underwent ERCP between January 2016 and October 2018, were included in the study. The ERCP indications of the patients were determined after confirming cholangitis by USG or MRCP in patients who were considered to have cholestasis under clinical and laboratory conditions. The decision to perform NKS during the ERCP procedure was made beacuse the bile duct could not be cannulated with the ERCP catheter or standard sphincterotomy within 10 minutes or after repeated pancreatic duct cannulation. After cannulation of the bile duct, all patients underwent stone extraction basket and / or balloon 173

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after sphincterotomy. PEP was diagnosed using revised Atlanta criteria. The patients were divided into two groups as standard sphincterotomy with direct cannulation and patients who underwent NKS as they couldn’t be cannulated. Furthermore, the patients were divided into subgroups as pancreatic duct cannulated patients and non-cannulated patients. Results Of 445 patients, 187 were male (39.7%) and 258 were female (60.3%). 270 (60.6%) patients underwent standard sphincterotomy while 175 (39.4%) patients underwent NKS. Hyperamylasemia was developed in 23 of 270 patients who underwent standard sphincterotomy after direct cannulation. 10 patients developed mild hyperamylasemia and 13(2.9%) patients developed PEP. In 9 of the patients who developed PEP, pancreatic duct cannulation and contrast agent injection were present during the procedure. In the other 4 patients, PEP developed although there was no pancreatic duct cannulation. PEP development was statistically significant in patients with pancreatic duct cannulation (p <0.01, table 1). Of 175 patients who underwent NKS, 168 (96%) patients had successful cannulation . 52 of 175 patients developed hyperamylasemia, while 25 patients had mild hyperamylasemia and 27(6.1%) patients developed PEP. PEP development was statistically significant in patients with NKS (p<0,01). Pancreatic duct cannulation and contrast agent injection was present in 18 of the patients who had developed PEP in the NKS group. 2 of these patients had moderate pancreatitis while one patient had severe pancreatitis. PEP developed in 9 patients, although they didn’t have pancreatic duct cannulation. PEP development was statistically significant in patients with pancreatic duct cannulation (p <0.01, table 1). It was determined that basket and / or balloon procedures performed in order to remove stones after bile duct cannulation did not increase the risk of PEP. Of 63 male patients who underwent NKS, 24 patients developed hyperamylasemia while 39 patients didn’t. Of 105 female patients, 28 patients developed hyperamylasemia while 77 patients didn’t. There was no significant difference in the risk of developing PEP between genders. Table 1. Patients who developed PEP and the applied procedures. NKS Standard sphincterotomy 175(39.4) 270(60.6)

Parameters

Patients

PEP not developed

405 (91)

148

257

Pancreaticduct cannulation 27 (6.1) and PEP

Without pancreatic duct cannulation and PEP

<0.01*

<0.01**

P value

13(2.9)

Results are expressed as number of patients and percent *P < 0.05 versus group II; **P < 0.05 versus group

Discussion In order to diagnose PEP, two of the three criteria should be met according to the revised Atlanta criteria: pain which is compatible with acute pancreatitis within the first 24 hours after ERCP, 3 fold increase in normal upper value of amylase or lipase and specific findings in abdominal imaging (MR, BT, USG) [4]. This

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classification is also grouped as mild, moderate and severe as acute pancreatitis. The risk of PEP in patients who undergo ERCP, varies depending on various factors. These factors may be related to the operator, associated with the patient or associated with the procedures [5,6]. Process related factors include difficult biliary cannulation, pancreatic duct injection, manometric procedure for oddi sphincter, needle knife sphincterotomy, pancreatic sphincterotomy, minor papilla sphincterotomy, biliary balloon sphincteroplasty and ampullectomy [7,8]. After ERCP, 35-70% of patients develop asymptomatic hyperamylasemia (without abdominal pain). Many maneuvers performed during ERCP can lead to the development of pancreatitis and other complications. In the pathogenesis of PEP, repeated cannulation attempts of papillae and repeated contrast agent injections into the pancreatic duct can cause damage to the canal epithelium and acinar cells [9]. Even though there are studies suggesting that standard sphincterotomy increases the risk of PEP development, the mechanism can not be described properly and cannulation efforts during the procedure are thought to be related to interventions before or after sphincterotomy [10]. In cases where the standard cannulation is insufficient, NKS is applied. NKS is difficult to administer, but has been shown to be a safe procedure when performed by an experienced endoscopist at appropriate indication [11]. In order to reduce the risk of repeated traumatic intervention in difficult cannulation, NKS may increase the success rate and reduce the risk of complications. In the study of Zhou PH et al., of 91 difficult cannulation patients NKS was applied in 43 patients. The success rate was 91% and average time was 5,6 minutes with a complication rate of 9%. The success rate of patients who were included in cannulation studies with standard sphincterotomy was 75%, time duration of the procedure was 20,2 minutes, and the complication rate was 15% [12]. Similarly, in our study, the success rate was 60.6% (270 of 445 patients) in patients who underwent direct cannulation and then standard sphincterotomy. We performed NKS to 175 patients because of difficult cannulation or multiple pancreatic cannulations, and the success rate was 96% (168 patients). In a retrospective study by Ahmadi et al., 79 ERCP patients underwent standard sphincterectomy, 67 patients in the first attempt and 5 patients on the second attempt, Operation failed in 7 patients. The success rate was 91%, complication rate was 10% in 8 patients, bleeding was observed in 5 (6%) patients and PEP was developed in 3 (4%) patients [13]. In the retrospective study of SiddiquiAR et al., NKS was applied in 59 of 515 ERCP patients and the success rate was 95% (56 patients). The complications developed related to the procedure were PEP in 3 patients (5%) and bleeding in 3 patients [14]. In a retrospective study by Lawrence C et al., 510 patients had undergone ERCP and 25 (6.4%) of 395 (77.5%) cases who had NKS, developed PEP [15]. In the study of Bailey AA et al., 94 of 732 ERCP patients underwent NKS due to difficult cannulation. Cannulation was performed successfully in 80 patients. 14 patients (14.9%) developed PEP and after standard sphincteratomy, 38 (6.1%) of 638 patients developed PEP and it was concluded that there was an increasing number of interventions in the papillary cannulation of the PEP incidenceincreasing factor [16]. Similarly, in our study, in 270 of 445 patients with ERCP, successful sphincterotomy was performed after direct cannulation and PEP was developed in 13 patients as a complication. 9 of these patients had pancreatic duct intervention 174

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and contrast agent injection. NKS was performed in 175 of the patients due to difficult cannulation and procedure was successful in168 patients. PEP clinic was developed in 27 patients and 18 of these patients had pancreatic duct intervention and contrast agent injection.

Badalov N, Tenner S, Baillie J. The Prevention, recognition and treatment of post-ERCP pancreatitis. JOP 2009;10:88-97.

Mariani A, Giussani A, DiLeo M, et al. Guide wire biliary cannulation does not reduce post-ERCP pancreatitis compared with the contrast injection technique in low-risk and high-risk patients. Gastrointest Endosc. 2012;75:339-46.

Conclusion

Choudhary A, Bechtold ML, Arif M, et al. Pancreatic stents for prophylaxis against post-ERCP pancreatitis: a meta-analysis and systematic review. Gastrointest Endosc. 2011;73:275-82.

Singh P, Das A, Isenberg G, et al. Does prophylactic pancreatic stent placement reduce the risk of post-ERCP acute pancreatitis? A meta-analysis of controlled trials. Gastrointest Endosc. 2004;60:544-50.

Freeman ML, Guda NM. Prevention of post- ERCP pancreatitis: a comprehensive review. Gastrointest Endosc. 2004;59:845-64.

As a result, in our study; In accordance the studies conducted in the literature, NKS, was found to have higher PEP development compared to standard sphincteratomy but the main risk factors are repeated unsuccessful attempts, frequent pancreatic with cannulation and contrast agent injection during the procedure. Therefore, in case of extension of the ERCP procedure, we think that NKS may decrease the risk of developing PEP without increasing the number of failed procedures. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support. Ethical approval Ethics committee approval was not taken due to retrospective study. Yahya Atayan ORCID: 0000-0003-2076-1934

References 1.

Freeman ML. Adverseoutcomes of ERCP. Gastrointest Endosc. 2002;56:27382.

Loperfido S, Angelini G, Benedetti G, et al. Major early complications from diagnostic and therapeutic ERCP: a prospective multicenter study. Gastrointest Endosc. 1998;48:1-10.

Testoni PA, Bagnolo F. Pain at 24 hours associated with amylase levels greater than 5 times the upper normal limit as the most reliable indicator of post-ERCP pancreatitis. Gastrointest Endosc. 2001;53:33-9.

Lerch MM. Classifying an unpredictabledisease: therevised Atlanta classification of acutepancreatitis. Gut. 2013;62:2-3.

10. Akashi R, Kiyozumi T, Tanaka T, Mechanism of pancreatitis caused by ERCP. Gastrointest Endosc. 2002;55:50-4. 11. De Weerth A, Seitz U, Zhong Y et al, Primary precutting versus conventional over- the-wire sphincterotomy for bile duct access: a prospective randomized study. Endoscopy. 2006;38:1235-40. 12. Zhou PH, Yao LQ, Xu MD, et al. Application of needle-knife in difficult biliary cannulation for endoscopic retrograde cholangiopancreatography. Hepatobiliary Pancreat Dis Int. 2006;5:590-4. 13. Ahmad I, Khan, AA, Alam, A, Butt AK, et al. Precut papillotomy outcome. Journal of the college of physicians and surgeons- Pakistan: JCPSP, 2005;15:701-3. 14. Lawrence C, Romagnuolo J, Cotton PB.et al. Post-ERCP pancreatitis rates do not differ between needle- knife and pull- type pancreatic sphincterotomy techniques: a multi endoscopist 13-year experience. Gastrointest Endosc. 2009;69:1271-5. 15. Siddiqui AR,Niaz SK. Needle knife papillotomy for cannulating difficult papilla; two years experience. JPMA. J Pak Med Assoc. 2008;58:195-7. 16. Bailey AA, Bourke MJ, Kaffes AJ. Needle- knife sphincterotomy: factors predicting its use and therelationship with post-ERCP pancreatitis. Gastrointest Endosc. 2010;71:266-71.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):176-9

The impact of anatomical, prosthetic features, and implant location on quality of life among locator-retained mandibular overdenture wearers Guler Yildirim Avcu Inonu University Faculty of Dentistry, Department of Prosthodontics, Malatya, Turkey Received 17 December 2018; Accepted 29 January 2019 Available online 13.02.2019 with doi:10.5455/medscience.2018.07.8993 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The aim of this study is to evaluate the impact of anatomical, prosthetic features and implant location on quality of life (QoL) after treatment with locator-retained mandibular overdentures. Thirty patients with locator-retained mandibular overdentures were included in this study. The study examined the following: (1) demographic characteristics, (2) intraoral measurements, (2a) the age of the prosthesis, (2b) the distance between the implants, (2c) the distance between the alveolar crest and the hypothetical line that crosses two implants (2d) the crest section, (2e) tissue quality, (2f) the arc form, (3) measurements of the prosthesis, (3a) freeway space, (3b) the distance between the canines, (3c) the top of the canine/the distance between the distal teeth of the second molar tooth, (3d) the canine/molar angle, and (3e) the arc form saved. After the measurements were made, patients were asked to mark the VAS (100 mm) scale to indicate their satisfaction with their prostheses and to complete the OHIP-14 questionnaire. A multivariate linear regression analysis was performed using OHIP-14 and VAS variables. The multivariate linear regression analysis showed gender and the distance between the alveolar crest and the hypothetical line that crosses two implants (2c) as the most important factor affecting anatomic, prosthetic features and implant location on QoL (p <0.05). The satisfaction of patients using mandibular overdenture prosthesis may vary depending on many factors. According to this study, the implants should be positioned on the same linear line and at the most distant position for patient satisfaction. Keywords: Overdenture, implant, quality of life, satisfaction

Introduction Edentulism is a dentition defect that is deﬁned as the loss of all permanent teeth in the maxilla and/or mandible [1]. It has a serious impact on eating, talking, facial appearance and quality of life (QoL). Therefore, completely edentulous patients are disabled according to the World Health Organization’s (WHO) criteria [1, 2]. The prevalence of edentulism has declined, according to patient age, and is expected to decline further in the future, as quality of life and life expectancy have increased and are expected to continue to increase [3]. The basic goal of oral rehabilitation is to improve patients’ impaired oral functions.[4] The conventional treatment for edentulism was a complete denture;[5] however, conventional complete denture wearers have common complaints such as poor retention and stability of mandibular dentures [6], decreased chewing ability, and residual bone resorption [2,7]. Studies have shown that insufficient complete denture retention and stability are related to patient *Coresponding Author: Guler Yildirim Avcu, Inonu University Faculty of Dentistry, Department of Prosthodontics, Malatya E-mail: guler_yldrm@hotmail.com

satisfaction or QoL [8,9]. Treatment with endosseous implants signiﬁcantly improves chewing ability, retention, and stability [10]. While the choice of a complete denture still depends upon the patients’ requirements and wants, the treatment of edentulous mandibula using 2 implant-retained overdentures has become the first option of rehabilitation for edentulous patients [11,12]. A number of QoL questionnaires might be used for evaluating patient satisfaction [13]. Many factors are affected by oral healthrelated quality of life (OHRQoL), such as age, pathologies, periodontal diseases, tooth loss, and prosthesis wear and age, as well as sociodemographic, educational, psychosomatic, dietetic, and economic factors [14]. The Oral Health Impact Profile (OHIP49 [15,16] OHIP-20, OHIP-14 [17]) questionnaire is the most accepted measurement document in the literature. The OHIP survey was reliable and valid relating to valuation of OHRQoL. OHIP-14, OHIP-20 and the OHIP-EDENT are short forms of this survey that have received reassuring assessments of reliability and validity [18]. Some other questionnaires in the literature related to prostheses are the visual analogue scale (VAS) [19], oral healthrelated quality of life (OHRQoL) [10], quality of life related to function, aesthetics, socialization, and thoughts (QoLFAST-10) [20], quality of life with implant-prostheses (QoLIP-10) [21], oral 176

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aesthetic-related quality of life (OARQoL), and quality of life associated with dental aesthetic satisfaction (QoLDAS-9) [22]. Prosthodontics research has mainly revolved around the QoL of completely edentulous patients whose oral health and functions have been restored with implant-retained overdentures. The satisfaction of patients using mandibular overdenture prosthesis may vary depending on many factors. However, it is not clear in the literature which factor most impacts their QoL. The aim of this study was to evaluate the impact of prosthetic and anatomical features on the QoL for individuals with locator-retained mandibular overdentures. The null hypotheses tested were that 1) oral anatomy, 2) prosthesis features and 3) implant location have no impact on QoL. Material and Methods The present study is a retrospective analysis on 30 patients (9 male, 21 female; 44-83 years old, Figure 1) whose implant supported prosthetic restorations were conducted in the Department of Prosthodontics, Inonu University. The experimental protocol was approved based on the ethical standards of the Declaration of Helsinki. Prior to the study, the approval was obtained from the Ethics Committee of Inonu University. (20/11/2018) The following measurements were recorded: 1. Demographic characteristics 2. Intraoral measurements a. The age of the prosthesis b. The distance between the implants (linear, millimeter) c. The distance between the alveolar crest and the hypothetical line that crosses two implants d. Crest section (round/retentive/sharp/irregular) e. Tissue quality (firm /hyperplastic/mobile) f. Arc form (square/oval/triangle)

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Statistics v23.0; IBM Corp). The relationship among implant location, oral anatomy, prosthesis features and QoL was investigated, and a stepwise multivariate linear regression was conducted. The statistical analyses were performed with the significance level set at p values of 0.05 Result This study included 30 patients with a mean age of 62 that 21 were females with a mean age of 59 years, and nine were males with a mean age of 66 years. The average OHIP score of females was 7.1 and 3.6 for males. The averages of VAS scores were 79.2 % and 86.5 % respectively for females and males. The age of the prosthesis was found to be close to the average values for females (23.5 months) and males (22 months). The QoL with OHIP mean score was used as a dependent variable, whereas age, gender, age of the prosthesis, the distance between the implants, the distance between the alveolar crest and the hypothetical line that crosses two implants, crest section, tissue quality, arc form crest, freeway space, the distance between the canines, the top of the canine/the distance between the distal teeth of the second molar tooth, canine/ molar angle, and arc form prostheses were used as independent variables (Table 1). After a multivariate linear regression analysis (Table 2), it was shown that among the factors evaluated, gender and the distance between the alveolar crest and the hypothetical line that crosses two implants (2c) were significantly associated with QoL of locator-retained mandibular overdenture wearers (p<0.05). The other factors showed no significant effect (p>0.05). The model constructed for 2c showed the value of adjusted R2; 0.321 and the model constructed for 2c and gender showed the value of adjusted R2; 0.413 (Table 2). There was no statistically significant effect between VAS scores and independent variables. Table 1. Multiple linear regression analysis results (Stepwise) Independent variables

Beta In

sig

Partial Correlation

3. Measurements of the prosthesis a. Freeway space b. The distance between the canines (millimeter) c. The top of the canine/the distance between the distal teeth of the second molar tooth (millimeter) d. Canine/molar angle e. Arc form (square/oval /triangle)

1.age

-0,241

-1,522

0,141

-0,297

Gender

-0,333

-2,213

0,037

-0,412

2a. age of the prosthesis

,019

0,104

0,918

0,021

2b. distance between the implants

,054

0,284

0,779

0,058

2d. Crest section/round

-,196

-1,208

0,239

-0,239

2d. Crest section/sharp

,196

1,208

0,239

The volunteers then answered the OHIP-14 questionnaire. After the measurements were made, patients were asked to mark the VAS (100 mm) scale to indicate their satisfaction with their prostheses.

2e. Tissue quality/firm

-,218

-1,334

0,195

-0,263

2e.Tissue quality/ hyperplastic

-,022

-0,135

0,894

-0,028

2e. Tissue quality/mobil

,229

1,382

0,18

0,271

2f. Arc form/square

-,218

-1,334

0,195

-0,263

The OHIP is a validated and reliable questionnaire that includes 7 base problems such as functional limitation, pain, psychological discomfort, physical disability, psychological disability, social disability, and handicap [6,23]. All items were scored on a Likert scale ranging from 0 (very positive) to 4 (very negative) that were summed to calculate an overall score ranging from 56 showed the maximum negative score, to 0 a perfect QoL appreciation. The volunteersâ&#x20AC;&#x2122; responses were scored as very often, 4; fairly often, 3; occasionally, 2; hardly ever, 1 and never, 0.

2f. Arc form/oval

-,022

-0,135

0,894

-0,028

2f. Arc form/ triangle

,229

1,382

0,18

0,271

3a. freewayspace

,035

0,213

0,833

0,043

3b. distance between the canines

,084

0,4

0,693

0,081

3c. distance between the canine and molar

,058

0,351

0,729

0,071

3d. Canine/molar angle

-,207

-1,297

0,207

-0,256

3e. Arc form/square

-,094

-0,567

0,576

-0,115

Analyses were performed with statistical software (IBM SPSS

3e. Arc form/oval

,022

0,135

0,894

0,027

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Table 2. Multiple linear regression analysis for quality of life Model

Std. Error

(Constant)

1.000

Distance between the alveolar crest and the hypothetical line that crosses two implants

Sig.

1.617

0.618

0.542

1.500

0.411

0.590 3.649

0.001

(Constant)

5.901

2.677

2.204

0.37

Distance between the alveolar crest and the hypothetical line that crosses two implants

1.532

0.383

4.004

0.001

Gender

-3.755 1.697

Beta

.602

13.315 0.001

-.333 -2.213 0.037 10.145 0.001

; R2 (Adj): 0.321 b; R2 (Adj): 0,413

Discussion Patient satisfaction is the most important factor determining the success criteria of implant-retained mandibular overdenture prostheses, one that depends on many anatomical factors such as salivary fluidity, viscosity, quality of the alveolar crest, and resilience of soft tissues. Other factors that impact a patientâ&#x20AC;&#x2122;s satisfaction with the prothesis are chewing, speech, aesthetics, psychological effects, and the use of a metal or acrylic base prosthesis, retention and stability. In addition, some other factors such as location and number of implants, type of prosthesis and holder type may affect the QoL. This study investigated the relationship between QoL and anatomical, prosthetic features and implant location. The H1 and H2 hypotheses were accepted, and H3 hypothesis was rejected. In this study, the distance between the alveolar crest and the hypothetical line that crosses two implants impact on QoL was found to be 32 % (p<0,05). The fulcrum axis is the hypothetical line that crosses two implants where rotation movement occurs due to the location of the implant in implant-retained mandibular overdenture prostheses. In order to prevent this movement, the implants must be placed at the most distal and most anterior location. This ratio increased to 41 % when gender factor was added. Significant consensus has been reached that implant-retained mandibular overdentures can provide important advantages to edentulous patients compared with complete dentures [1]. The effects of various prostheses on QoL have been investigated in many studies, but there are no studies determining which of the anatomical and prosthetic features impact patientsâ&#x20AC;&#x2122; degree of satisfaction. Preciado et al. [14] only investigated how demographic features, implant-retained overdenture prosthesis features and oral lesion presence impact QoL. They reported that overdenture prostheses with implant retainers improve QoL regardless of implant location, retentive system and antagonist. The major finding of this study is that the distance between the alveolar crest and the hypothetical line that crosses two implants is the most important factor impacting QoL. This is directly related to implant location. Scherer et al. [24] evaluated effect of implant location and different attachment systems on the retention and

stability of 2-implant mandibular implant overdentures that was positively affected QoL and concluded the retention and stability is significantly affected by implant location and abutment type. The vertical retention, horizontal stability and anteroposterior stability increased when the implant position was located distally. Similar results were found in this present study. In addition Ball and Locator attachments have higher levels of retention and stability than O-ring and ERA. Shayegh et al. [25] evaluated the effect of distance between the implants on the retention of overdentures and the 23 mm distance was found better performance. This present study, mean of distance between the implants was showed 24.3 mm. One limitation of the research protocol followed here is that the included patients were all from a university dental clinic and the small sample size. Second limitation is that patients who have more than two implants were not included in the study. Lee et al. [26] found no statistically significant difference between 2 and 4 implants for the quality of life of the mandibular implant retained overdentures wearers in their systematic review about the number of implants. Another limitation is that different types of implantsupported overdenture have not been compared. Trakas et al. [27] mentioned their review that there is no significant difference in patient satisfaction either by ball or bar/clip attaching mechanisms. Naert et al. [28] concluded that ball attachment grup was showed the best retention and patient satisfaction at year 10. FernandezEstevan et al. [29] found that mandibular overdentures retained with the locator system produced good outcomes in terms of QoL and females were more dissatisfied than male. In addition, they found that age factor had a significant effect on OHIP scores. In this present study, the degree of satisfaction was lower in females than males. In this study, the factors such as anatomical, prosthetic features, and implant location were investigated in terms of affecting the quality of life and the effect percentages. Factors such as the number of implants, attachment type, implant angulation, different opposite arc prostheses, salivary viscosity, changes of nylon retention, relining, and readjustments should be part of future studies. More number of patients and a longer period of observation would yield more consistent results. 178

doi: 10.5455/medscience.2018.07.8993

Conclusion Locator-retained mandibular implant overdentures improve the quality of life of edentulous patients. The satisfaction of patients using mandibular overdenture prostheses may depend on many factors, but the location of the implants is very effective in increasing their satisfaction. Within the limitations of the current investigation, the following conclusion may be drawn; the implants should be positioned on the same linear line but at the most distal position to increase patient satisfaction and fameles were more dissatisfied than male among locator-retained mandibular overdenture wearers. Competing interests The authors declare that they have no competing interest.

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11. Matthys C, Vervaeke S, Jacquet W, et al. Impact of crestal bone resorption on quality of life and professional maintenance with conventional dentures or locator-retained mandibular implant overdentures. J Prosthet Dent. 2018;120:886-94. 12. Cakir O, Kazancioglu HO, Celik G, et al. Evaluation of the efficacy of mandibular conventional and implant prostheses in a group of Turkish patients: a quality of life study. J Prosthodont. 2014; 23:390-6. 13. Preciado A, Del Río J, Lynch CD, et al. Impact of various screwed implant prostheses on oral health-related quality of life as measured with the QoLIP–10 and OHIP–14 scales: A cross-sectional study. J Denti. 2013;41:1196-207. 14. Preciado A, Del Río J, Suárez-García MJ, et al. Differences in impact of patient and prosthetic characteristics on oral health-related quality of life among implant-retained overdenture wearers. J Dent. 2012;40:857-65.

Financial Disclosure All authors declare no financial support.

15. Yamamoto S, Shiga H. Masticatory performance and oral health-related quality of life before and after complete denture treatment. J Prosthodont Res. 2018;62:370-4.

Ethical approval The approval was obtained from the Ethics Committee of Inonu University. (20/11/2018).

16. Jenei Á1, Sándor J2, Hegedűs C, et al. Oral health-related quality of life after prosthetic rehabilitation: a longitudinal study with the OHIP questionnaire. Health Qual Life Outcomes. 2015;13:99.

Guler Yildirim Avcu ORCID: 0000-0002-8461-7774

17. Husain FA, Tatengkeng F. Oral health-related quality of life appraised by ohip14 between urban and rural areas in kutai kartanegara regency, indonesia: pilot pathfinder survey. Open Dent J. 2017;11:557.

References 1.

Sánchez-Siles M, Ballester-Ferrandis JF, Salazar-Sánchez N, et al. Long-term evaluation of quality of life and satisfaction between implant bar overdentures and conventional complete dentures: A 23 years retrospective study. Clin Implant Dent Relat Res. 2018;20:208-14.

Zhang L, Lyu C, Shang Z, et al. Quality of life of implant-supported overdenture and conventional complete denture in restoring the edentulous mandible: a systematic review. Implant Dent. 2017;26:945-50.

Reissmann DR, Enkling N, Moazzin R, et al. Long-term changes in oral health-related quality of life over a period of 5 years in patients treated with narrow diameter implants: A prospective clinical study. J Dent. 2018;75:84-90.

Al-Imam H, Özhayat EB, Benetti AR, et al. Oral health-related quality of life and complications after treatment with partial removable dental prosthesis. J Oral Rehabil. 2016;43:23-30.

Celebić A, Knezović-Zlatarić D, Papić M, et al. Factors related to patient satisfaction with complete denture therapy. J Gerontol A Biol Sci Med Sci. 2003;58:948-53.

Sivaramakrishnan G, Sridharan K. Sridharan. Comparison of implant supported mandibular overdentures and conventional dentures on quality of life: a systematic review and meta-analysis of randomized controlled studies. Aust Dent J. 2016;61:482-8.

Sharma AJ, Nagrath R, Lahori M. A comparative evaluation of chewing efficiency, masticatory bite force, and patient satisfaction between conventional denture and implant-supported mandibular overdenture: An in vivo study. J Indian Prosthodont Soc. 2017;17:361-72.

Limpuangthip N, Somkotra T, Arksornnukit M. Modified retention and stability criteria for complete denture wearers: A risk assessment tool for impaired masticatory ability and oral health-related quality of life. J Prosthet Dent. 2018;120:43-9.

Schuster AJ, Marcello-Machado RM, Bielemann AM, et al. Short-term quality of life change perceived by patients after transition to mandibular overdentures. Braz Oral Res. 2017;31:5.

10. Policastro VB, Paleari AG, Leite ARP et al. A randomized clinical trial of oral health-related quality of life, peri-implant and kinesiograph parameters in wearers of one-or two-implant mandibular overdentures. J Prosthodont. 2018. [Epub ahead of print]

18. Kutkut A, Bertoli E, Frazer R, et al. A systematic review of studies comparing conventional complete denture and implant retained overdenture. J Prosthodont Res. 2018;62:1-9. 19. MacEntee MI, Walton JN, Glick N. A clinical trial of patient satisfaction and prosthodontic needs with ball and bar attachments for implant-retained complete overdentures: three-year results. J Prosthet Dent. 2005;93:28-37. 20. Castillo-Oyagüe R, Suárez-García MJ, Perea C, et al. Validation of a new, specific, complete, and short OHRQoL scale (QoLFAST-10) for wearers of implant overdentures and fixed-detachable hybrid prostheses. J Dent. 2016;49:22-32. 21. Perea C, Del Río J, Preciado A, et al. Validation of the ‘Quality of Life with Implant Prostheses (QoLIP-10)’questionnaire for wearers of cement-retained implant-supported restorations. J Dent. 2015;43:1021-31. 22. Perea C, Preciado A, Río JD, et al. Oral aesthetic-related quality of life of muco-supported prosthesis and implant-retained overdenture wearers assessed by a new, short, specific scale (QoLDAS-9). J Dent. 2015;43:1337-45. 23. Geckili O, Bilhan H, Bilgin T. Bilhan. Impact of mandibular two-implant retained overdentures on life quality in a group of elderly Turkish edentulous patients. Arch Gerontol Geriatr. 2011;53:233-236. 24. Scherer MD1, McGlumphy EA2, Seghi RR, et al. Comparison of retention and stability of two implant-retained overdentures based on implant location. J Prosthet Dent. 2014;112:515-21. 25. Shayegh SS, Hakimaneh SM, BaghaniMT, et al. Effect of interimplant distance and cyclic loading on the retention of overdenture attachments. J Contemp Dent Pract. 2017;18:1078-84. 26. Lee JY, Kim HY, Shin SW. et al. Number of implants for mandibular implant overdentures: a systematic review. J Adv Prosthodont. 2012;4:204-9. 27. Trakas T, Michalakis K, Kang K, et al. Attachment systems for implant retained overdentures: a literature review. Implant Dent. 2006;15:24-34. 28. Naert I, Alsaadi G, Quirynen M. Prosthetic aspects and patient satisfaction with two-implant-retained mandibular overdentures: a 10-year randomized clinical study. Int J Prosthodont. 2004;17:401-10. 29. Fernandez-Estevan L, Montero J, Otaolaurruchi EJS, et al. Patient-centered and clinical outcomes of mandibular overdentures retained with the locator system: A prospective observational study. J Prosthet Dent. 2017;117:367-72.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):180-5

The effects of different agents preferred for general anesthesia on lactate and liver enzymes in patients undergoing laparoscopic cholecystectomy Mehmet Sargin1, Ahmet Topal2, Mehmet Selcuk Uluer3, Eray Yasar2, Seref Otelcioglu2 2

1 Selcuk University Medical Faculty, Department of Anesthesiology and Reanimation Konya, Turkey Necmettin Erbakan University, Meram Medical Faculty, Department of Anesthesiology and Reanimation, Konya, Turkey 3 Konya Training and Research Hospital, Department of Anesthesiology and Reanimation, Konya, Turkey

Received 05 December 2018; Accepted 14 December 2018 Available online 26.12.2018 with doi:10.5455/medscience.2018.07.8949 Copyright ÂŠ 2019 by authors and Medicine Science Publishing Inc. Abstract In this study, we aimed to evaluate the effects of different agents used for anesthesia maintenance on liver enzymes and lactate changes in patients undergoing laparoscopic cholecystectomy using CO2 pneumoperitoneum with constant pressure. Seventy-five patients planned to undergo laparoscopic cholecystectomy operation have been randomly divided into 3 groups. Liver function tests have been evaluated preoperatively and postoperatively in the 24th hour. Arterial blood samples for lactate level determination were obtained: (T_1) immediately before pneumoperitoneum, (T_2) 10 min after pneumoperitoneum, (T_3) 30 min after pneumoperitoneum, (T_4) 60 min after desufflation of CO2. Patients scheduled to undergo laparoscopic cholecystectomy operation. The possible effects of different agents used for anesthesia maintenance on liver enzymes and lactate changes in patients undergoing laparoscopic cholecystectomy. In comparison of lactate values, there were no differences between the three groups in T_1, T_2 and T_4 measurements (P=0.059, P=0.108, P=0.225). However, in the T_3 measurements, lactate values are lower in the Group P, compared to Group S and D (P=0.001, P=0.001). Postoperative AST and ALT values are lower in the Group P, compared to Group S and D (P<0.001, P<0.001) and postoperative ALP and LDH values are lower in the Group D and Group P, compared to Group S (P =0.001, P<0.001). There were no differences between the three groups in postoperative GGT values (P=0.056). It was concluded that propofol had a positive effect on postoperative AST and ALT values, and peroperative lactate changes in comparison to sevoflurane and desflurane. Keywords: Sevoflurane, desflurane, propofol, lactate, liver enzymes

Introduction With introduction of laparoscopy in surgery, laparoscopic cholecystectomy (LC) has been adopted as golden standard in surgical treatment of cholelithiasis and gall bladder diseases [1]. Carbon dioxide (CO2) pneumoperitoneum (PP) is used in revealing adequate imaging and surgical site in laparoscopy. Laparoscopic cholecystectomy has several advantages such as short durations of hospital stay, minimal postoperative pain, fast-track recovery, and better cosmetic results [2]. However, PP is related to some adverse effects including cardiovascular, respiratory, renal and acid base balance [3-5].

*Coresponding Author: Mehmet Sargin, Selcuk University Medical Faculty, Department of Anesthesiology and Reanimation Konya, Turkey, E-mail: mehmet21sargin@yahoo.com

While some of these adverse effects are related to acidemia and hypercapnia following the absorption of CO2 through peritoneal cavity, others are direct results of increased intraabdominal pressure (IAP) due to continuous gas insufflation [4,5]. One of the important haemodynamic changes is the transient reduction in hepatic blood flow, which is caused by PP [6-9]. Experimental and clinical studies have shown a reduction in gastric, hepatic, peritoneal and splanchnic blood flow due to increased intraabdominal pressure [10,11]. The pressure and duration of the PP have been shown to affect the degree of hepatic ischemia and therefore cause elevation of liver enzymes [7,12,13]. The effect of different PP pressures on liver enzyme changes has been evaluated and there are not enough studies evaluating the effects of agents used in anesthesia maintenance. In this study, we aimed to evaluate the effects of different agents 180

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used for anesthesia maintenance on liver enzymes and lactate changes in patients undergoing LC using CO2 PP with constant pressure (12 mmHg). Material and Methods Institutional ethics committee approval and written consent from patients were obtained for this prospective, randomized study. Seventy-five patients between the ages of 18-65 yr, ASA (American Society of Anesthesiologists) physical status I and II, scheduled to undergo routine LC under general anesthesia, were studied. Patients with morbid obessity (body mass index > 35 kg/m2), high levels of enzymes before operation, positive serology for hepatitis B or C viruses, cerebrovascular, respiratory, cardiovascular and metabolic disease were excluded from the present study. And also patients with acute cholecystectomy were excluded from the present study. The patients were randomized, by using a computer-generated block randomisation, into 3 groups: Group S (n:25) = Sevoflurane, Group D (n:25)= Desflurane, Group P (n:25)= Propofol (Fig.1). Routine monitors (consisting of a pulse oximeter, 3-lead ECG and a non-invasive blood pressure cuff ) were applied. Fasting periods were in accordance with ASA guidelines, and no one premedicated. Anesthesia was induced with propofol (2 mg/ kg) and remifentanil (1 μg/kg), and endotracheal intubation was facilitated using atracurium. After induction, volume-controlled mechanical ventilation (tidal volume adjusted to 8 mL/kg with no application of positive end-expiratory pressure (PEEP) and respiratory rates were adjusted to achieve an end-tidal carbon dioxide (ETCO2) of 30 to 35 mmHg) was initiated. All patients were ventilated with the same anesthetic machine (Drager Primus - Germany). Anaesthesia was maintained using sevoflurane 1–2% in an oxygen ⁄ air mixture and remifentanil (0,25 µg/kg/ min) in Group S, desflurane 3–6% in an oxygen ⁄ air mixture and remifentanil (0,25 µg/kg/min) in Group D and propofol 6-12 mg/ kg/h and remifentanil (0,25 µg/kg/min) in Group P to maintain systolic blood pressure within 80% to 100% of the baseline value. The CO2 PP was introduced with a closed Veress needle tecnique, and the intraabdominal insufflation pressure was limited to 10-12 mmHg. After introduction of the four trocars and insufflation of CO2, the patient was placed in the reverse Trendelenburg position, using up to 30˚ of head-up tilt. Heart rate (HR), mean blood pressure (MBP) and oxygen saturation (SpO2) values were continuously recorded from awake status to post-anesthesia care unit (PACU) discharge [baseline (t_0), immediately after induction (t_1), 2 min after intubation (t_2), immediately after pneumoperitoneum (t_3), every 10 minutes during pneumoperitoneum (t_4-6), immediately after desufflation of CO2(t_7), immediately after extubation (t_8), arrival in the PACU (t_9) and PACU discharge (t_10)]. No other medication was administered to the patients prior or after the operation except for i.v. antibiotics and tramadol for postoperative pain control. Saline and dextrose solutions were given to al patients for the first 24 hours. Blood samples were taken from a superficial vein in the antecubital region of each patient before the operation as a part of routine preoperative

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preparation and 20-24 hours after the operation for comparison of the liver enzyme [aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and gamma-glutamyltransferase (GGT)] level alterations. Arterial blood samples for lactate level determination were obtained from radial artery cannul : (T_1) immediately before pneumoperitoneum, (T_2) 10 min after pneumoperitoneum, (T_3) 30 min after pneumoperitoneum, (T_4) 60 min after desufflation of CO2. Statistical analysis Sample size calculation was based on our prior study with 18 patients (also their data were not included in the study). The primary outcome variable was the value of lactate levels 30 min after pneumoperitoneum. When a mean and standard deviation (SD) of the lactate values (30 min after pneumoperitoneum) between groups lactate values were taken to be 1.15 (0.19), 1.43 (0.21) and 0.88 (0.13) as was determined based on a preliminary study in 18 patients, 18 subjects were required for an α value of 0.05 and a power of 95%. Thus, 25 subjects were included to cope with an expected loss. Statistical analyses were performed with SPSS 15.0 software (SPSS Institute, Chicago, IL, USA). Normal distributions of data were assessed using the Kolmogorov–Smirnov test. Demograraphic data were compared between the groups by using an One-Way ANOVA test. Lactate and liver enzyme values and hemodynamic changes between time points within the group were compared by using univariate ANOVA with post hoc comparisons using Bonferroni correction. A P-value <0.05 was considered statistically significant. Results A total of 75 patients were enrolled in the study and all patients completed the investigation. Figure 1 shows the CONSORT flow chart detailing patient recruitment. Data analysis was performed on the three groups. No patient was withdrawn from the study after induction of anesthesia. Patients demographic data are summarised in Table 1 and there were no significant differences between the three groups regarding age, gender, weight, height, body mass index (BMI), ASA physical status and operation time (P=0.212, P=0.846, P=0.935, P=0.945, P=0.924, P=0.820, P=0.919, respectively). Changes in HR and MBP is seen in figure 2. The measurements of hemodynamic parameters (HR and MBP) were statistically similar between three groups in all measurement timepoints [baseline (t_0), immediately after induction (t_1), 2 min after intubation (t_2), immediately after pneumoperitoneum (t_3), every 10 minutes during pneumoperitoneum (t_4-6), immediately after desufflation of CO2(t_7), immediately after extubation (t_8), arrival in the PACU (t_9) and PACU discharge (t_10)] (P=0.150, P=0.474, P=0.465, P=0.616, P=0.482, P=0.881, P=0.929, P=0.528, P=0.165, P=0.612, P=0.883, and P=0.888, P=0.496, P=0.687, P=0.652, P=0.762, P=0.526, P=0.714, P=0.644, P=0.911, P=0.742, P=0.635, respectively). 181

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Comparison of lactate values between the groups are summarised in Table 2 an there were no significant differences between the three groups in T_1, T_2 and T_4 measurement timepoints (P=0.059, P=0.108, P=0.225, respectively). However, in the T_3

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measurement timepoint, lactate values are significant lower in the Group P, compared to Group S and D (P=0.001, P=0.001, respectively).

Table 1. Comparison of patientsâ&#x20AC;&#x2122; baseline characteristics between the groups Patientsâ&#x20AC;&#x2122; baseline characteristics

Group S (n=25)

Group D (n=25)

Group P (n=25)

47.74 (11.15)

43.12 (13.22)

49.56 (14.77)

0.212

10 (40%) / 15 ( 60%)

11 (44%) / 14 (56%)

9 (36%) / 16 (64%)

0.846

ASA (I / II)

18 (72%) / 7 (28%)

19 (76%) / 6 (24%)

17 (68%) / 8 (32%)

0.820

Height; cm

161.76 (9.26)

160.56 (10.80)

162.60 (6.57)

0.945

Weight; kg

75.08 (9.64)

76.32 (12.37)

75.80 (13.72)

0.935

BMI (kg/m2)

28.79 (3.94)

28.32 (4.29)

28.68 (4.93)

0.924

Operation time; min

47.64 (4.34)

46.05 (4.62)

47.16 (4.74)

0.814

Group S (n=25)

Group D (n=25)

Group P (n=25)

T_1

0.87 (0.17)

0.90 (0.25)

1.02 (0.26)

0.059

T_2

1.17 (0.31)

1.15 (0.31)

1.01 (0.27)

0.108

T_3

1.30 (0.32)

1.33 (0.26)

1.04 (0.32) * #

0.001

T_4

1.38 (0.40)

1.06 (0.24)

0.99 (0.28)

0.225

Age; years Gender (M/F)

Values are mean (SD) or number (proportion) Table 2. Comparison of lactate values between the groups. Measurement timepoints Lactate; mmol/L

Values are mean (SD). T_1; immediately before pneumoperitoneum, T_2; 10 min after pneumoperitoneum, T_3; 30 min after pneumoperitoneum, T_4; 60 min after desufflation of CO2. * compared to Group S, p=0.001 # compared to Group D, p=0.001

Table 3. Comparison of liver enzyme values between the groups IU/L

Group S (n=25)

Group D (n=25)

Group P (n=25)

AST; preoperative

24.88 (9.33)

20.60 (5.11)

21.12 (3.53)

0.057

AST; postoperative

49.36 (22.49)

42.96 (13.12)

26.76 (5.25)* #

<0.001

ALT; preoperative

28.12 (15.66)

21.04 (7.60)

23.48 (5.88)

0.063

ALT; postoperative

55.00 (32.12)

41.60 (14.04)

27.28 (6.79) * #

<0.001

ALP; preoperative

80.01 (33.00)

67.40 (34.96)

64.64 (7.15)

0.122

ALP; postoperative

97.40 (52.45)

69.36 (30.39) *

66.32 (6.56) *

0.001

GGT; preoperative

24.76 (17.55)

19.84 (18.99)

20.64 (8.59)

0.498

GGT; postoperative

39.40 (27.87)

30.00 (28.84)

22.96 (9.69)

0.056

LDH; preoperative

113.36 (26.61)

96.36 (50.27)

122.40 (56.65)

0.138

LDH; postoperative

228.68 (62.28)

147.72 (60.55) *

145.52 (61.87) *

<0.001

Values are mean (SD). * compared to Group S, p<0.001 # compared to Group D, p=0.001

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no significant differences between the three groups in preoperative measurements (P=0.057, P=0.063, P=0.122, P=0.498, P=0.138 respectively). However, postoperative AST and ALT values are significant lower in the Group P, compared to Group S and D (P<0.001, P<0.001, respectively) and postoperative ALP and LDH values are significant lower in the Group D and Group P, compared to Group S (P =0.001, P<0.001, respectively). There were no significant differences between the three groups in postoperative GGT values (P=0.056). Discussion The results of this study have shown that propofol maintenined anesthesia provides lower lactate and liver enzyme values than sevoflurane and desflurane maintenined anesthesia in patients undergoing LC.

Figure 1. CONSORT flowchart detailing patient recruitment

Laparoscopy is a well-established method, used in several surgical procedures, and often performed in the Trendelenburg position. To facilitate laparoscopic surgical manipulation, a PP is usually induced through carbon dioxide insufflation. Today, the increase in liver enzymes such as AST, ALT after non-complicated LC has become a well-known finding [14]. Factors such as; increased intraperitoneal pressure, cauterization used to provide hemostasis during LC, manipulation of external bile ducts and general anesthesia have been shown as possible causes of the increase in liver enzymes [15]. However, the most widely accepted reason among these causes is transient hepatic ischemia, which is caused by increased intraperitoneal pressure. Various studies have reported that, portal venous pressure, which provides about half of the hepatic blood flow, is between 7-10 mmHg and PP at 14 mmHg pressure is the main cause of transient hepatic ischemia during LC [6,12,16-17]. In addition, PP pressures below 12-15 mmHg have been shown to reduce normal hepatic blood flow and induce hepatic ischemia at different degrees [18]. However, whichever of these reasons is valid, the effect of the preferred anesthetic agents in the maintenance of general anesthesia to liver enzyme changes after LC has not been evaluated before. In a study in which sevoflurane was preferred in anesthesia maintenance and the change in AST, ALT, ALP, GGT and LDH values at 24 h after LC was assessed, higher rates of AST, ALT changes are shown, compared to Group S in our study [14]. The change in GGT values of this study is similar to the values in our study, but the ALP results are not consistent with our results. Hasukic et al evaluated the changes in liver enzymes after LC and 14 mmHg PP pressure was used in their studies and they preferred propofol in anesthesia maintenance [9]. Similar to present study, they have evaluated AST, ALT, ALP, GGT and LDH values preoperatively and postoperatively at 24 hours. However, in this study, increases of AST and ALT by more than twice were shown, compared to Group P in our study. In addition, the operation times in this study are quite long from the operation times of our study.

Figure 2. Changes in heart rate and mean blood pressure

Comparison of liver enzyme (AST, ALT, ALP, GGT and LDH) values between the groups are summarised in Table 3 and there were

Studies of Tan et al., evaluating AST and ALT changes on postoperative 1st day after LC, showed an increase in AST and ALT values, similar to the results in Group S and D in our study[16]. In addition, similar PP pressures were used in this study. However, no information was provided about the induction and maintenance of 183

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anesthesia in this study. In another study that did not mention the preferred agents for anesthesia induction and maintenance, it was shown that the increase in AST and ALT 24 hours after LC, was higher than the increase in Group S and D in our study. But there was no increase in the ALP values different from our study [19]. Pneumoperitoneum pressures were preferred in this study, similar to our study. However, unlike our study, longer surgery durations were noted. Unlike the results of many studies evaluating the alteration of liver enzymes after LC, Bickel et al. have shown that there is no significant change in AST, ALT, ALP, GGT and LDH after LC [20]. However, in this study, there is no information about which agents are preferred in the induction and maintenance of anesthesia. Ibraheim et al. evaluated the change in lactate levels during LC and sevoflurane was preferred for anesthesia maintenance [21]. In this study, lactate values were evaluated similar to the measurement times in our study. The increase in lactate levels in the patient groups in which used the PP pressures similar to our study, was higher than in Group S in our study. However, the low number of patient populations in this study and differences in baseline values may be considered probable causes for this difference. In another study evaluating the change in lactate levels during and after LC, a 12 mmHg PP press was preferred, similar to our study [22]. Intraoperative lactate measurement times were similar to the measurement times in our study, and unlike our study results, there was no increase in lactate levels during LC. In this study, preferred anesthetic agents for induction and maintenance of anesthesia were not mentioned. Despite all these studies, it is clear that the role of anesthetic agents in assessing liver enzyme changes and intraoperative lactate levels after LC has not been adequately assessed. Given the fact that the most important cause of transient ischemia of liver during LC is a decrease in hepatic blood flow, the use of agents used in anesthesia maintenance is more evident. Because, in various clinical and experimental studies, propofol was clearly shown to increase hepatic blood flow [23,24]. Meierhenrich et al evaluated the effect of propofol and desflurane anesthesia on human hepatic blood flow [23]. In this study it has been shown that propofol was associated with significantly greater blood flow index in the right hepatic vein and middle hepatic vein compared with desflurane and propofol anesthesia was associated with significantly greater hepatic blood flow than desflurane anesthesia. In an experimental study of Zhu et al, has been shown that propofol increases total hepatic blood flow, primarily by increasing hepatic portal venous flow [24]. In our study, we evaluated the effects of sevoflurane, desflurane and propofol on the liver enzymes after LC and intraoperative lactate levels. In patients who prefer propofol in anesthesia maintenance, lower increases in liver enzymes and lactate changes are shown relative to the patient in whom sevoflurane and desflurane are preferred. This is because we believe that the increase in the hepatic blood flow caused by propofol. The present study included some limitations. Bispectral index

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(BIS) monitoring was not performed, and this is one of the limitations. Other parameters used to evaluate liver function such as bilirubin were not evaluated. Conclusion In conclusion, propofol, compared with sevoflurane and desflurane, was found to cause less change in liver enzymes and lactate levels in LC operation. These changes under sevoflurane and desflurane anesthesia do not affect the perioperative and postoperative morbidity and mortality in the patient population in which there is a low clinical significance and no serious comorbid pathologies, but we believe that these changes can cause significant consequences in critical patients. In conclusion, our study results suggest no relationship between the NLR and PLR and PDPH in the preoperative and early postoperative period in patients who undergoing cesarean section. However, further large-scale studies are required to establish a definite conclusion. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethical approval Institutional ethics committee approval was obtained (Necmettin Erbakan University, Meram Medical Faculty Ethics Committee , 2013/82). Mehmet Sargin ORCID:0000-0002-6574-273X Ahmet Topal ORCID:0000-0001-9832-9741 Mehmet Selcuk Uluer ORCID:0000-0002-5699-8688 Eray Yasar ORCID:0000-0003-1466-8194 Seref Otelcioglu ORCID:0000-0002-4352-5064

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17. Jakimowicz J, Stultiens G, Smulders F. Laparoscopic insufflation of the abdomen reduces portal venous flow. Surg Endosc. 1998;12:129-32.

24. Zhu T, Pang Q, McCluskey SA, et al. Effect of propofol on hepatic blood flow and oxygen balance in rabbits. Can J Anaesth. 2008;55:364-70.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):186-91

Synthesis and the effect of a novel benzoxazole compound on breast cancer cell line Funda Kosova1, Ozlem Temiz Arpaci2, Ercument Olmez3, Ibrahim Tuglu4 1 Celal Bayar University School of Health Vocation, Manisa, Turkey Ankara University Pharmacy Faculty, Department of Pharmaceutical Chemistry, Ankara, Turkey 3 Celal Bayar University Medical Faculty Department of Pharmacology, Manisa, Turkey 4 Celal Bayar University Medical Faculty, Department of Histology and Embryology, Manisa, Turkey 2

Received 03 January 2019; Accepted 30 January 2019 Available online 21.02.2019 with doi:10.5455/medscience.2019.08.9006 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Breast cancer today is the most frequent cancer among women, and the second most common cause of cancer deaths among women. The aim of this study was to synthesize a new benzoxazole derivative, scan it for anti-cancer potential by MTT test using different breast cancer cell lines, and examine its effects on NF-κB and apopitosis-related proteins (APAF-1, cytochrome C, caspase-3, bcl-2) by the western blot method. newly-synthesized benzoxazole compound was applied to breast cancer cell lines (MDA-MB, MCF-7) and its cytotoxicity was measured quantitatively by MTT test. Later, the level of its effects on NF-κB and apopitosis-related proteins (APAF-1, cytochrome C, caspase-3, bcl-2) were examined by the western blot method. In our study, the structure of the synthesized new 5-[4-chlorobutanamido]-2(p-methylphenyl)benzoxazole was proved by elemental analysis, 1H NMR and mass spectroscopy analysis methods. When the toxic effects of the application of the compound on the cell lines was examined by MTT, it had a greater toxic effect on MCF-7 when compared with MDA-MB, and IC50 levels were lower. When the protein was examined in immunohistochemistry with regard to VEGF, eNOS and TUNEL, it was observed that it caused a reduction in VEGF and an increase in eNOS and TUNEL. In the assay of the proteins by western blot, when benzoxazole compound was added to the MDA and MCF-7 cell line, there was no difference from the control group in Apaf-1 and BCL-2 levels, but a reduction was observed in caspase and Nfkβ levels compared with the control group. When the compound was added to the MDA-MB cell line, an increase was shown in the Cytochrome C level compared to the control group, but no difference was seen in the MCF-7 cell line. It is felt that this synthesized new benzoxazole compound increases apopitosis by reducing the activation of Nfkβ, and in this way has shown an effect of inhibiting tumor growth in cancer treatment. In addition, it is felt that this can provide hope in cancer treatment by the improved phase studies. Keywords: Benzoxazole compounds, NF-κB, APAF-1, sitokrom C, caspase-3, bcl-2

Introduction Cancer; is a disease which caused by changes in critical genes that control cell proliferation, differentiation and survival. Continuous and uncontrolled proliferation of cells causes cancer [1,2]. Cancer and apoptosis are common in the cell population dynamics [3]. Cancer is one of the most common causes of death in the world. In the last decade there have been great advances in the diagnosis and treatment of these patients. However, the prognosis of some cancers is very poor. Apoptosis and angiogenesis are important factors for growth and differentiation, but are also important for tumor invasion and metastasis. Nuclear Factor kappa B (NF-κB) has been

*Coresponding Author: Funda Kosova, Celal Bayar University School of HealthVocation,Manisa, Turkey E-mail: fundakosova@gmail.com

shown to play an important role in both apoptosis and angiogenesis mechanisms.Apoptosis is a controlled and programmed cell death process [4], which is activated by three pathways by intracellular and extracellular signals, regulated by many proteins.In the early 1970s Kerr et al, found that apoptosis was associated with the elimination of potential cancer cells and tumor development [5]. Adams and Cory’s shown that a strong relationship between apoptosis irregularity and cancer pathogenesis [6]. Takayama et al. shown that proliferation of tumor cells and escape of apoptotic cell death are present [7]. Wang et al. stated that apoptotic activity in breast cancer would be initiated by combined treatment regulating caspase cascade [8]. Li et al reported that Bcl-2 was effective in the early diagnosis and treatment of breast cancer [9]. NF-kB is mainly active and located in the nucleus. In some cancers (such as some Hodgkins and diffuse large B-cell lymphoma cells), due to chronic stimulation of the IKK pathway, the IkB genes may be mutated and damaged. Furthermore, the Rel / NF-kB transcription 186

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factors of many human lymphoid cancer cells proliferate or mutate, leading to activation of NF-kB. Continuous Rel / NF-kB activity protects cancer cells from apoptosis and, in some cases, allows them to grow. Thus, in many antitumor therapies, many currents inhibit the growth of the tumor by blocking NF-kB activity [10]. In recent years, benzoxazoles and analogs of heterocyclic arms such as benzimidazoles, benzothiazoles and benzoxazines have been found to be antibacterial and antifungal [1,11], antiviral [12], and topoisomerase-inhibiting and anti-tumor activities [13]. The new series of benzothiazolers have stated that they have a very potent inhibitory effect against in vivo and in-vitro human breast cancer cell lines [13]. Previous studies have reported that some benzoxazole compounds [11,14]. Especially 5-ethylsulfonyl-2-(p-nitrophenyl)benzoxazole was found very potent compound for antitumoral activity. In the light of the findings, it is aimed to synthesize a specific benzoxazole compound.

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Crystallization was done by adding distilled water and the crude product was obtained drying the filtrate under ambient conditions. Finally, the compound was prepared as original product (Figure 1). The structures was supported by spectral data. The 1H-NMR and mass spectra and elemental analysis results agree with those of the proposed structures. Physical and spectroscopic data for compound is listed in below. 2-(p-methylphenyl)-5-[4-chlorobutrylamido]-benzoxazole C18H17ClN2O2.Yield 61 (%). M.p.161-163°C; 1H-NMR (400MHz,CDCl3-d6): δ2.21-2.27 (2H, t), 2.44 (3H, s), 2.59-2.62( 2H, t), 3.67-3.71 (2H,t), 7.32-7.34(2H, d, j=7.6), 7.41-7.51 (3H, m), 7.88 (1H, s), 8.11-8.13( 2H, d, j=8.4). LC-MS: m/ (%X)z 329.5(100, M+H) 331.5(33, M+H+2)

Then, we aimed to investigate the levels of the anti-apoptotic protein bcl 2 and angiogenic NF-κBproteins by cytochrome-c, caspase anti 9 and APAF-1 (Apoptosis activating factor), which are apoptotic active on breast cancer line. So that we aimed to investigate the effect ofa new benzoxazole compound on the levels NF-κB, bcl 2, cytochrome-c, caspase-9 and APAF-1which are markers for apoptosis in breast cancer cell culture. Material and Methods Synthesis of Benzoxazole Compound The chemicals and solvents were purchased from Sigma-Aldrich Co. (Taufkirchen, Munich Germany) and Fisher Scientific (Pittsburgh, PA, USA) and used without further purification. Silica gel HF254 chromatoplates (0.3 mm) were used for TLC and chloroform was employed as mobile phase. Melting point was recorded on a Stuart Scientific SMP 1 (Bibby Scientific Limited, Stone, Staffordshire, UK) and is uncorrected. NMR spectra was recorded on a Varian Mercury 400 MHz NMR spectrometer (Palo Alto, CA, USA) in CDCl3; tetramethylsilane (TMS) was used as an internal standard. The mass spectra was recorded on a Waters ZQ Micromass LC-MS spectrometer (Milford, MA, USA) using the ESI (+) method. Elemental analyse was performed on an LECO 932 CHNS (St. Joseph, MI, USA) instrument and result was within ±0.4% of theoretical value. Synthesis studies were carried out by researcher in the Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University.Firstly, 5-Amino-2-(p-methylphenyl)-benzoxazole was synthesized by heating 0.02 mol 2,4-diaminophenol•2 HCl with 0.02 mol p-methylbenzoic acid in 25 g polyphosphoric acid (PPA) and stirring for about 1 h at 160-200ºC. Then, the residue was poured over ice and the solution was neutralized with 10% NaOH solution. The observed precipitate was filtered and recrystallizated with ethanol. Subsequently, 3-Chlorobutryl chloride (0.02 mol) was added over a period of 1 h to a stirred, ice-cooled mixture of 5-Amino-2-(p-methylphenyl)-benzoxazole (0.02 mol), sodium bicarbonate (0.02 mol), diethyl ether (40 ml), and water (20 ml). The mixture was stirred overnight. The residue formed was filtered off, washed with water and dissolved in ethanol.

Figure 1. Synthesis of new benzoxazole compound

Cell Culture Cell culture studies were maked by Celal Bayar University medical faculty, department of Histology and embiryology. A human breast cancer cell line MCF-7 and MDAMB were obtained from the American Type Culture Collection (ATCC, Manassas, VA). The cells were maintained in DMEM F-12 medium supplemented with 10% FCS, 1% L-glutamine and 1% penicillinstreptomycin at 37 ° C in a 5% CO 2 incubator. The morphology of the cells was examined on alternate days using a phase contrast inverted microscope (CK40-F200; Olympus, Tokyo, Japan) and photographed. All experiments were repeated for three times Benzoxazole compound application The compound was prepared as a 1 μ g/ml stock solution, which was diluted for use to 100, 50, 25, 12.5 and6.25 μ l solutions in dimethylsulfoxide (DMSO).The same volume of DMSO was used as the vehiclecontrol for Heterocyclic compounds experiments at a final concentrationof 0.1%. MTT Assay Mitochondrial functions of MCF-7 and MDA-MB cells were determined by MTT as an indicator of viable cells. This method is a colorimetric assay for measuring the reduction of yellow, water soluble MTT dye to a purple formazan product by active mitochondria. MTT stock solution (50 g MTT + 10 ml PBS) can be stored in the refrigerator. All PBS in solutions was adjusted to pH 7.4. The culture medium was removed from the culture wells, then 200 µl/well MTT solutions (1 ml stock solution of MTT + 9 ml growth medium) was added and the plate was incubated for 3 h under culture conditions. MTT solution was removed, then 200 µl DMSO was added to each well, and spectrophotometric measurements were performed using a microplate reader at 570 nm with a 690 nm reference filter 187

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Western blot analysis The Cells were centrifuged at 12,000× g at 4 °C for 15 min and supernatant (cytosolic extract) were used. Protein concentrations were determined by a dye-metalbased colorimetric protein assay [10]. Commercially available Pierce 660 nm protein assay reagent (Pierce/Thermo Scientific, Rockford, IL) which is not affected by the levels of the reducing agents. An equal amount (30 μg) of protein was applied to each well and proteins were separated in a 12% sodium dodecyl sulphate polyacrilamide gel electrophoresis (SDS-PAGE). After electrophoresis proteins were transferred to PVDF membrane. Membrane were blocked with 3 % nonfat dry milk. Anti-mouse (Biovision, USA) cytochrome c, and antimouse monoclonal IgG AIF (Santa Cruz Biotechnology, TX, USA) were used as a primary antibody and alkaline phosphatase conjugated anti-mouse (Invitrogen, NY, USA) was used as a secondary antibody. β-actin primary antibody (Genscript, USA) was used in loading control analysis for normalization. The signal was detected on PVDF membrane by BCIP/NBT Substrate (Invitrogen, NY, USA). Membranes were scanned using densitometer (Bio-Rad, GS-800) and signal intensity was determined by Quantity One Software (Bio-Rad, CA, USA) to compare expression levels among groups. Normalized three independent experiment results were done.

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When the compound was added on the MDA and MCF-7 cancer cell line, we found that BCL-2 level was similar compare to control group (Figure 4). When the benzoxazole compound was added on the MDA and MCF-7 cancer cell line, we found that Caspaselevel was decreasedcompare tocontrol group (Figure 5). When the compound was added on the MDA cancer cell line, we found that Cytochrome C level was increasedbut was similar on MCF-7cancer cell line compare to control group (Figure 6). When the compound was added on the MDA and MCF-7 cancer cell line, we found that Nfkβ level was decreasedcompare to control group (Figure 7).

Statistical analysis Statistical significance was determined using the SPSS 15.0. Significance (IC50 levels) was defined as p ≤ 0.05. Results In this project, we synthesized a new benzoxazolecompound. We looked at purity controls of the compound by thin layer chromatography and melting degrees. We applied MTT test to the benzoxazolecompound and we determined the mitochondrial functions of the cells and thus the cell density of the cells as colorimetric. Those with anticancer potential in terms of survival were separated. Then the remaining group was VEGF, eNOS and TUNEL. Here, the IC50 dose was given the most appropriate response. And than, we examined the effects of the compound which is the most suitable for bioactivity on different breast cancer cell line, NF-κB, and apoptosis (APAF-1, cytochrome C, caspase-3, bcl-2) related proteins with western blot method.

Figure 2. Cells that are semiconfluent and confluent in MCF-7 and MDA-MB breast cancer cell lines.

As a result, we carried out biological activity studies on the benzoxazolecompound. The structure of the synthesized compound was proved by elemental analysis, 1H NMR and Mass spectroscopic analysis methods (Figure 1). Although MCF-7 cells were adherent, adherent, and islandsshaped semiconfluent, the cells showed apoptotic morphology with P / 22 GBMA administration, proliferation stopped and the majority died. MDA-MB cells were found to be proliferated and died similarly after administration (Figure 2).

Figure 3. The effect of Apaf-1 on MDA ve MCF-7 breast cancer line

Compared with MCF-7, MDA-MB cells were found to be more resistant and less dead at the same dilutions, which was significantly more significant (p <0.001). (Table 1). When benzoxazole compound was added on the MDA and MCF-7 cancer cell line, we found that Apaf-1 level was similar compare to control group (Figure 3).

Figure 4. The effect of BCL-2 on MDA ve MCF-7 breast cancer line

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Figure 5. The effect of Caspase on MDA ve MCF-7 breast cancer line

Figure 6. The effect of Cytochrome C on MDA ve MCF-7 breast cancer line

Figure 7. The effect of Nfkβ on MDA ve MCF-7 breast cancer line

Discussion Cancer is a disease which appears when cells multiply in a uncontrolled way with sometimes fatal consequences, and which has been much more commonly seen in recent times.Breast cancer today is the most frequent cancer and the second most common cause of cancer deaths among women. Some types of breast cancer are very resistant to drug treatment. Breast cancer today is the most frequent cancer and the second most common cause of cancer deaths among women. Endogenous estrogen excess is also thought to play a significant role [15].High endogenous estrogen level has been shown to increase the progression of postmenaposal carcinoma in the breast [16,17]. The aim of this study was to synthesize a new benzoxazole derivative which will investigate for anti-cancer potential by MTT test using different breast cancer cell lines. Moreover, The relation of this effect with apopitosis-related proteins such as APAF-1, cytochrome C, caspase-3 and bcl-2 with NF-κBby the western blot will be examined. In 1958, benzoxazole ring was found to have antitumoral effects [18]. Bis (2-hydroxyethyl) amino group, N - ((p-bis (2-hydroxyethyl) amino) phenyl) formimidoyl structure [19], (2(benzodioxan-5-yl) The presence of effective antitumoral activity

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in the benzoxazole compounds carrying the cityl group [20] allowed the researchers to concentrate on the antitumoral effect on this ring system.In another study, have been synthesized which 7-substituted-2-phenylbenzoxazole, benzimidazole derivative with 4-substituted-2-phenylbenzoxazole compounds and this compounds have been reported to have cytotoxic activity on mammals with lower DNA binding propertieson S. typhimurium [21,22]. Sato et al., found that AJI9561 compound obtained from Streptomyces sp. AC9561 and showed that alsoantitumor activity [23]. In another study, the UK-1 compound has a broad spectrum and potent antitumoral activity (IC50 value around 20 nM) on leukemia, lymphoma and some solid tumor cells. [24]. Lage et al., has been found that some 2,5-disubstituted carboxazole, substituted benzoxazine and benzamide-derived compounds were to be highly effective against cancer cells ,(stomach, breast, pancreas, fibrosarcoma and melanoma) [25]. In the light of this information, in this study, it is aimed to evaluate the antitumoral activities of this study for the first time by synthesizing novel derivative that carry the benzoxazole ring as the main structure. Apoptosis is a form of programmed cell death characterized by the morphological changes carried out by the caspases and regulated by Bcl ve 2 family proteins [26]. Cancer cells reduce the expression of pro-apoptotic Bcl-2 members; they may increase the expression of anti-apoptotic Bcl-2 members or inactivate Apaf-1 expression [27]. Decrease in Bcl-2 levels leads to apoptosis, while increased in BCL-2 levels protect from death in the cells [28]. Bcl - 2 is like a guard of the mitochondria due to its presence outside the mitochondria and keeping the cytochrome in the mitochondria. Watson et al. states that the expression levels of the anti-apoptotic Bcl-2 was increased in colon cancer [29]. Cytochrome c is a protein belonging to the electron transport chain in the inner membrane of the mitochondria. After the cytochrome c is released from the mitochondria to the cytosol, it binds to the cytosolic apoptotic protease activation factor-1 (Apaf-1) for create apoptosm and binds with procaspase-9 for create apoptosm [30,31]. Apaf-1 is the cytosolic protease activation factor. The induction of apaf-1 occurs by the release of cytochrome c from mitochondria, cytochrome c is the activator of Apaf-1 [32]. Wright et al. found that Apaf -1 and caspase-9 were required for cytochrome-c induced apoptosis [33]. Caspases which are important role in apoptosis, are cysteinedependent aspartate protease family. Cytochrome-c and apaf-1 facilitate the destruction of procaspaz-9 and the formation of active caspase-9 in the presence of ATP. Caspase-9 activates caspases, such as caspase-3 and caspase-7, called caspase cascade [24]. Procaspase-9 is involved in apoptosm and caspase-9 becomes activated and than caspase-9 aktivates caspases such as caspase-3 [34]. NF-kappa B (NF-κB, Nuclear Factor kappa B) is a transcription factor. It is inactive in the cytoplasm. Moves to the nucleus when activated. There are 5 types: NF-toB1, NF-elerB2, RelA (p65), RelB and c-Rel.Rel or NF-kappaB (NF-kB) In addition, these transcription factors continuously activate sites of disease including cancer, arthritis, chronic inflammation, asthma, neurodegenerative diseases and heart diseases [10,35). Many studies have been crosslinked between MAPK p38 and NF-yolB pathways. Gochman et al. clearly demonstrated the involvement of the MAPK p38 pathway 189

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in IKK activation. IKK inhibitors decrease IırBα phospharylation after exposure to peroxynitrite [35]. In this study compared to MDA-MB, MCF-7 cells had a more toxic effect and IC50 levels were lower. In a previous study, a similar compound was used in vivo and in vitro, and its size-reducing effects were determined in both culture medium and tumor tissue [36]. It is understood that increased oxidative stress and apoptosis due to aggressive and invasive in the cancer cell line is induced by this compound and cause more cell death [37,38].Another effect of BTHB was on cell death. The dilutional effect of direct toxic effect was replaced by apoptosis in cell death mechanisms at IC50 level. Drifting to apoptotic death was easier with MCF-7, but less with MDA-MB. Previous studies have shown that other similar compounds that support apoptosis and apoptosis are used as caspase and other activators as signaling pathways [37,39]. It has been shown by immunohistochemical staining that the use of the benzoxazole compounds have already increased the oxidative stress present at the basal level and enriched the environment for free radicals. In previous studies, it has been suggested that ambient stress reduces the progression of cancer cells and leads to death of cells [40,41]. In our studies found that were compared with tamoxifen as a positive control, indicating that our findings would have a similar effect. H40 points to the absence of toxic effects of benzoate compounds on normal cells in negative control studies on non-invasive breast cell lines. However, it is to be understood that there is no toxic effect in normal somatic cells and in vivo conditions in the healthier primary culture. In this sense, it is consistent with the findings of our study [39,42,43]. As a result, it is thought that this compound can be used in the treatment of cancer. In our study, in the determination of the proteins by western blot, we found that when the benzoxazole compound was added to the MDA and MCF-7 cell lines, there was no difference between the control group of Apaf-1 and BCL-2, whereas the level of caspase and Nfkβ decreased compared to the control group. Cytochrome C levels were higher in MDA-MB cells compared to the control group and no difference was found in MCF-7 cell lines.

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Financial Disclosure All authors declare no financial support. Ethical approval Consent of ethics was approved by the local ethics committee. Funda Kosova ORCID:0000-0001-8070-5067 Ozlem Temiz Arpaci ORCID:0000-0002-2485-345X Ercument Olmez ORCID:0000-0003-3535-2471 Ibrahim Tuglu ORCID:0000-0002-0569-8415

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Consequently, in our study show that the benzoxazole ring system is structural similar to the heterocyclic adenine and guanine bases in the structure of nucleic acids. This suggests that this group of compounds can exhibit many chemotherapeutic effects over different pathways. We have found that this newly obtained heterocyclic compound is more effective in MDA-MB cell lines. We believe that this benzoxazole compound enhances apoptosis by decreasing the activation of Nfkβ and thus, by inhibiting the growth of the tumor in cancer treatments. As an advanced stage of this study, we plan to investigate how the benzoxazole compound can act on proteins in the angiogenic pathway. If we obtain useful results from this study, then we are planning to carry out studies to support our findings in animal cancer models, which is a higher stage of this study. Therefore, the application of heterocyclic compound appears to to contribute to the treatmentof breast cancer. By the help of heterocyclic compound breast cancer treatment may help survival of cancer patients.

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The effects of nitrofurantoin on rat urinary bladder contraction Emine Kacar1, Zubeyde Ercan2, Fatih Tan1, Gokhan Zorlu2, Ozgur Bulmus1, Ihsan Serhatlioglu2 Firat University, Faculty of Medicine, Department of Physiology, Elazig, Turkey Firat University, Faculty of Medicine, Department of Biophysics, Elazig, Turkey

Received 18 October 2018; Accepted 11 January 2019 Available online 08.02.2019 with doi:10.5455/medscience.2018.07.8987 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Nitrofurantoin is a drug used in the antibacterial treatment of urinary tract infections (UTIs) for over 60 years. The aim of our study was to investigate the possible effects of nitrofurantoin, which is commonly used as a urinary tract antiseptic, on bladder contractions in male rats. Bladder tissues obtained from male Sprague-Dawley rats were used in the study (n=24). After decapitation, bladder tissues were suspended in an isolated organ bath of 5 ml containing a Krebs-Ringer bicarbonate solution by applying a tension of 1.5 grams. Nitrofurantoin was administered to three groups at doses of 50, 500 and 1000 μM, respectively. The area, peak-to-peak (p-p) and frequency values of bladder contractions were analyzed before and after administration of nitrofurantoin. The data obtained from the analysis were evaluated using the Paired T-Test in the IBM SPSS Statistics Software. Nitrofurantoin was observed to have an inhibitory effect on bladder contractions at all doses. The decrease in the area and peak-to-peak values was statistically significant at all doses (P<0.05). It has been observed that nitrofurantoin inhibited bladder contractions. Based on these findings, it is thought that the fact that frequent urination, which is commonly seen in UTIs, is reduced after nitrofurantoin therapy may be due to the inhibitory effect of nitrofurantoin on bladder contractions. Keywords: Contraction, nitrofurantoin, tissue bath, urinary bladder

Introduction Urinary tract infections are the most common bacterial infection in all age groups [1]. While Escherichia coli (E. coli) is responsible for 80% of the UTI cases, other organisms (e.g., Klebsiella, Enterobacter, Pseudomonas,enterococci, staphylococci) can lead to UTIs [2]. The most common symptoms are dysuria, polyuria, pollakiuria, suprapubic discomfort, and flank pain. The most important diagnostic criterion is the presence of clinical symptoms [3]. Until urine culture results are obtained, broad spectrum antibiotics such as penicillins or beta-lactams, cephalosporins, fluoroquinolones and carbapenems can be started empirically [3]. The treatment option can be changed according to urine culture results [4]. However, nitrofurantoin is still a first-choice drug in the antibacterial treatment of urinary tract infections for over 60 years in the world [5,6]. *Coresponding Author: Emine Kacar, Firat University, Faculty of Medicine, Department of Physiology, Elazig, Turkey E-mail: dreminekacar@hotmail.com

Nitrofurantoin is a broad-spectrum bactericidal antibiotic. It is used effectively in the treatment of UTIs caused by E. coli, Klebsiella spp., Enterobacter spp., Enterococcus spp. and Staphylococcus aureus. It exhibits antimicrobial activity by both interfering the synthesis of proteins embedded in the cell wall and the DNA synthesis of Gram-positive and Gram-negative bacteria [7]. Moreover, another cause of recurrent UTI is urinary incontinence. Urinary incontinence develops due to anatomic disorder associated with vaginal delivery [8] and postmenopausal estrogen deficiency [9] in women and due to benign prostatic hypertrophy (which is more common among older) in men [10]. In addition, recurrent UTI in both genders is one of the major causes of urinary incontinence [11]. In other words, urinary incontinence and recurrent UTI cause each other. One of the most important reasons for this is that hyperreflexia occurs in the external urethral sphincter and the detrusor muscle during UTI. This also causes urinary incontinence. While this situation is improved with the treatment of UTI, recurrent UTI may lead to permanent hyperreflexion in the external urethral sphincter and the detrusor muscle [12]. This situation creates a serious social problem and negatively affects people’s social lives. 192

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To cope with this situation, they have to constantly use urine pads. This also constitutes another source of infection depending on the hygiene of urine pad, as well as adversely affecting the quality of life of persons [13]. However, it has been focused on an effective antibacterial treatment in fighting with UTI for years. Bladder hyperactivity caused by UTI and pathological and psychological problems associated with this have been ignored. The major problem in the treatment of UTI is that the multiple antibiotic resistance occurs as a result of frequent prescription of antibiotics due to recurrent UTI [14]. As antibiotic resistance develops, treatment response decreases and infection recurs [15]. This creates a severe vicious cycle in the treatment and prevention of UTIs. However, nitrofurantoin is an oral antibiotic that plays a key role in the treatment of acute uncomplicated cystitis (AUC) caused by multidrug-resistant gram-negative bacilli. This makes it superior to other antibiotics [16]. Moreover, recent studies have shown that the use of prophylactic nitrofurantoin as a single oral dose for 6-12 months in women with recurrent urinary tract infection reduced the frequency of recurrent urinary tract infection [17]. All these properties are the main reasons why nitrofurantoin is a first-line drug in the treatment and prophylaxis of UTI. However, the effect of this drug, which is so effective in UTIs, on the changes in bladder contraction due to infection is unknown [18]. The contraction of the smooth muscle of the bladder is regulated partly by the purinergic signal. It occurs when extracellular purines like ATP and UTP are released in neuromuscular junctions as neurotransmitters or as a response to environmental stress from somatic cells and when they bind to P2X (1-7) receptors [19]. In studies conducted so far, the effect of the ADP on bladder contraction has been focused on especially for the activity of P2X1 signaling pathway. However, in recent studies, it has been claimed that the P2Y signaling pathways of the ADP might also be employed; and studies have been conducted to determine which sub-type of the P2Y receptor family is effective (Figure 1) [20-22].

Med Science

Studies to date have focused particularly on the antibacterial activity of nitrofurantoin. There is no study investigating the efficacy of ancan bladder on the contractile activity of smooth muscle. The contractile activity of the bladder is an important result as UTI is a major cause. Therefore, in our study, we aimed to reveal the possible efficacy of nitrofurantoin on contractile activity of bladder. In previous studies, the inhibitory activity of nitrofurantoin on some smooth muscles such as the uterus is known. Based on this information, we think that nitrofurantoin has similar efficacy on bladder smooth muscle, and it can be used in cases of overactive bladder, except for its antibacterial use alone. so that UTM’s most important in the treatment of overactive bladder is one of the reasons we believe we can develop a new perspective. Material and Methods 24 male Sprague-Dawley rats weighing 200-250 g that were obtained from the Firat University Experimental Research Center were used in the study. Animals were decapitated without anesthesia in order to avoid myorelaxant effect of anesthesia. Their bladders were removed. Then, strips (each approximately 2 mm wide x 8 mm long) were prepared from bladder tissues. They were placed in an isolated organ bath of 5 ml that contained a Krebs-Henseleit solution (composition in mM: NaCl 118, KCl 4.7, MgSO4. 1.2, CaCl2 1.25, KH2PO4 1.2, NaHCO3 25, glucose 11, EDTA. 0.03) and was continuously ventilated with 95% O(2)/5% CO2. Then, a tension of 1.5 gr was applied. It was waited for about 45-60 minutes for regulating spontaneous contractions. The bathtubs were washed with a Krebs–Henseleit solution for 15 min. Contractions were recorded by MP150WS for Windows (Biopac Systems Inc, CA, USA) with the help of a physiological power converter (FDT05, Commat Ltd, Ankara, Turkey). After spontaneous contractions were regulated, nitrofurantoin was intervally administered to three groups at doses of 50, 500 and 1000 μM, respectively. All data were normalized with respect to the basal area, peak-to-peak (p-p) and frequency expressed as percent of basal values of contractions were analyzed before and after administration of nitrofurantoin. Statistical Analysis All values were expressed as mean ± standard deviation (M±SD). All statistical analysis was performed using the SPSS for Windows Version 12.0. Statistical evaluation was performed using the Paired T-Test. A p-value of less than 0.05 was considered statistically significant. The obtained data were statistically normalized Results

Figure 1. Mechanically induced signaling from the urothelium in response to membrane stretch. Release of a number of potent mediators occurs in response to urothelial stretch eliciting both autocrine- and paracrine-mediated effects. AA, adrenergic agonist; ADO, adenosine; AR, adrenergic receptor; BK, maxi K channel; EMC, extracellular matrix; ENaC, epithelial sodium channel; Entpd3, ectonucleoside triphosphate diphosphohydrolase 3; EP, PG receptor; NGF, nerve growth factor; P2Y, purinergic receptor Y; SAC, stretch-activated ion channel; trkA/B, tyrosine kinase receptors for nerve growth factor; TRP, transient receptor potential channel. [23]

First Findings (50 µM Nitrofurantoin) After bladder sections were placed in an isolated organ bath containing a Krebs-Henseleit solution, they were followed for about 60 minutes for regulating spontaneous contractions due to tension. During this time, organ bath wells were replaced with fresh Krebs-Henseleit solution every 15 min, and then 50 μM nitrofurantoin was administered (Figure 2). This dose was about 1/10 of the dose administered per kilogram in human. The mean area values before and after administration of 50 µM nitrofurantoin were 100±0.0 and 69±8.3, respectively. The mean peak-to-peak values before and after administration of 50 µM nitrofurantoin were 100±0.0 and 49.7±5.1, respectively. The mean frequency 193

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values before and after administration of 50 µM nitrofurantoin were 100±0.0 and 83.8±5.2, respectively. According to these results, it was observed that 50 µM nitrofurantoin led to a statistically significant reduction in the area (Figure 3), peakto-peak (Figure 4) and frequency (Figure 5) values of bladder contractions when compared with pre-administration (p<0.05).

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values before and after administration of 500 µM nitrofurantoin were 100±0.0 and 38.3±6.9, respectively. The mean peak-to-peak values before and after administration of 500 µM nitrofurantoin were 100±0.0 and 40.1±3.6, respectively. The mean frequency values before and after administration of 500 µM nitrofurantoin were 100±0.0 and 24.7±9.6, respectively. According to these results, it was observed that 500 µM nitrofurantoin led to a statistically significant reduction in the area (Figure 3), peakto-peak (Figure 4) and frequency (Figure 5) values of bladder contractions when compared with pre-administration (p<0.001).

Figure 2. Administration of 50 μM nitrofurantoin

Figure 5. Frequency (counts/10 min). Data are presented as the mean± SEM for all groups. * p<0.05 (n=7)

Figure 3. Area under the curve. Data are presented as the mean± SEM for all groups. * p<0.05 (n=7).

Figure 6. Administration of 500 µM Nitrofurantoin

Figure 4. Peak to peak. Data are presented as the mean± SEM for all groups. * p<0.05 (n=7)

Second Findings (500 µM Nitrofurantoin) After bladder sections were placed in an isolated organ bath containing a Krebs-Henseleit solution, they were followed for about 60 minutes for regulating spontaneous contractions due to tension. During this time, organ bath wells were replaced with fresh Krebs-Henseleit solution every 15 min, and then 500 μM nitrofurantoin was administered (Figure 6) This dose was about the dose administered per kilogram in human. The mean area

Third Findings (1000 µM Nitrofurantoin) After bladder sections were placed in an isolated organ bath containing a Krebs-Henseleit solution, they were followed for about 60 minutes for regulating spontaneous contractions due to tension. During this time, organ bath wells were replaced with fresh Krebs-Henseleit solution every 15 min, and then 1000 μM nitrofurantoin was administered. This dose was about twice the dose administered per kilogram in human. The mean area values before and after administration of 1000 µM nitrofurantoin were 100±0.0 and 70.2±6.3, respectively. The mean peak-to-peak values before and after administration of 1000 µM nitrofurantoin were 100±0.0 and 46.6±6.7, respectively. The mean frequency values before and after administration of 1000 µM nitrofurantoin were 100±0.0 and 62.1±4.9, respectively. According to these results, it was observed that 1000 µM nitrofurantoin led to a statistically significant reduction in the area (Figure 3), peakto-peak (Figure 4) and frequency (Figure 5) values of bladder contractions when compared with pre-administration (p<0.05). 194

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In the light of these findings, it was observed that nitrofurantoin led to a statistically significant inhibition on spontaneous bladder contractions at doses of 50, 500 and 1000 μM (p <0.05). The most significant inhibition was observed at 500 μM nitrofurantoin (p<0.001). As a result, it was shown that nitrofurantoin had an inhibitory effect on bladder contractions. Discussion According to the findings we obtained in this study, nitrofurantoin had an inhibitory effect on spontaneous bladder contractions. Considering the drug dose administered per kilogram in the treatment, three different doses of nitrofurantoin (50 µM=1/10 of the treatment dose, 500 µM= the treatment dose, and 1000 µM= twice the treatment dose) led to a statistically significant reduction in the area, peak-to-peak (p-p) and frequency values of bladder contractions (p<0.05). However, the most significant inhibition was observed at 500 μM nitrofurantoin. Nitrofurantoin is a broad-spectrum bactericidal antibiotic. It is used effectively in the treatment of UTIs caused by E. coli, Klebsiella spp., Enterobacter spp., Enterococcus spp. and Staphylococcus aureus. It exhibits antimicrobial activity by both interfering the synthesis of proteins embedded in the cell wall and the DNA synthesis of Gram-positive and Gram-negative bacteria and nitrofurantoin, a non-specific attack on bacterial ribosomal proteins, leads to the inhibition of bacterial enzymes involved in carbohydrate synthesis and high concentration of DNA, RNA and total protein synthesis [7]. Nitrofurantoin is a drug used in the antibacterial treatment of urinary tract infections for over 60 years [6]. While its use in older individuals is still a matter of debate, nitrofurantoin is still a firstchoice drug in most urinary system infections in premenopausal and postmenopausal women [5]. Moreover, nitrofurantoin is an oral antibiotic that plays a key role in the treatment of AUC caused by multidrug-resistant gram negative bacteria [16]. Recent studies have shown that the use of prophylactic nitrofurantoin as a single oral dose for 6-12 months in women with recurrent urinary tract infection reduced the frequency of recurrent urinary tract infection. The effects on bladder contractions of nitrofurantoin, which is commonly used in the treatment of UTI, were not investigated. One of the most frequent causes of recurrent urinary tract infections is urinary incontinence that occurs due to changes in bladder contraction, and also recurrent urinary tract infections cause urinary incontinence [8-11]. This study that we performed in the light of these information showed that nitrofurantoin had an inhibitory effect on bladder contractions besides antibacterial activity. This finding we obtained suggests that the underlying mechanism responsible for nitrofurantoin is so effective in the treatment of recurrent UTI is not solely dependent on antibacterial activity. Changes in bladder smooth muscle contraction are shown to be a major factor in the development of recurrent urinary tract infection and urinary incontinence. In other words, while UTI changes bladder activity, deterioration of bladder smooth muscle contraction triggers UTI [19]. Therefore, in addition to antibacterial therapy, inhibition of bladder contraction is also important. Recent studies clearly show that urinary tract infection changes bladder contraction; however, the underlying physiopathological mechanisms have not been clarified [25,26]. Furthermore, a recent study has found

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that symptoms such as frequent urination, nocturia, urgency which are caused by an increase in bladder activity due to urinary tract infection have been improved by appropriate antibiotherapy. In this context, it has been determined that the use of sequential, combined antibiotic therapy (ciprofloxacin 500 mg bid, cephalexin 500 mg tds, doxycycline 100 mg bid) against Gram-positive and Gram-negative bacteria in individuals with overactive bladder significantly reduced the symptoms [27]. However, there is no study on the direct effect of these antibiotics on bladder contractile activity. As a result, nitrofurantoin inhibits bladder contractions according to our findings. Based on these findings, it is suggested that nitrofurantoin will not only be used as an antibactural drug, but also as a pharmacological agent that can be used in the treatment of overactive bladder or urinary incontinence pathologies which is a very important cause of urinary tract infection. Further studies are needed to explain which nitrodfurantoin inhibits bladder contractions using physiological mechanisms. Our study is the first study on the efficacy of nitrofurantoin on bladder contractions. There is very little study investigating the efficacy of nitrofurantoin in the literature on smooth muscle contractile activity, and in this study, we aim to explain this pathophysiological mechanism in our further study since its mechanism of action is not described. The current study has limitations. First of all, it is an in vitro study and these results must also be confirmed by in vivo studies. New studies must can be designed to clarify its mechanism of action. Also possible additive effect of nitrofurantoin to tocolytics may be subject to further studies. Conclusion It has been found that nitrofurantoin (a broad spectrum antibiotic) had an inhibitory effect on spontaneous bladder contractions. Moreover, our study has shown that not only was there a reduction in bladder activity due only to antiinflammatory effect, but also did nitrofurantoin directly inhibit bladder contractile activity. These data suggest that the only underlying mechanism responsible for the use of prophylactic nitrofurantoin in women with recurrent urinary tract infection reduces the frequency of recurrent urinary tract infection is not dependent on the bactericidal effect. We think that the findings we obtained may shed light on the underlying mechanism responsible for the use of prophylactic nitrofurantoin in recurrent urinary tract infections reduces the frequency of recurrent urinary tract infection. Further studies are needed to explain the molecular mechanism underlying the inhibitory effect of nitrofurantoin on bladder contraction. When all these data were taken into account, it has been found that nitrofurantoin, which is an important pharmacological agent in the treatment and prevention of urinary tract infections, inhibited spontaneous bladder contractions. Competing interests The authors declare there is no conflict of interest with regard to data presented in this article. Financial Disclosure All authors declare no financial support. Ethical approval All animal use procedures were approved by the Firat University Animal Experiments Local Ethics Committee and rats were treated in accordance with the national and international laws and policies on the care and use of laboratory animals.

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doi: 10.5455/medscience.2018.07.8987 Emine Kacar ORCID: 0000-0002-1585-7248 Zubeyde Ercan ORCID: 0000-0002-5294-8771 Fatih Tan ORCID: 0000-0003-2995-4628 Gokhan Zorlu ORCID: 0000-0002-6453-9772 Ozgur Bulmus ORCID: 0000-0001-7736-402X Ihsan Serhatlioglu ORCID: 0000-0002-2384-7971

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Masajtis-Zagajewska A, Nowicki M. New markers of urinary tract infection. Clin Chim Acta. 2017;471:286-91.

Cueto M, Aliaga L, AlĂłs JI, et al. Executive summary of the diagnosis and treatment of urinary tract infection: Guidelines of the spanish society of clinical microbiology and infectious diseases (SEIMC). Enferm Infecc Microbiol Clin. 2017;35:314-20.

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14. Majeed A, Alarfaj S, Darouiche R, Mohajer M. An update on emerging therapies for urinary tract infections. Expert Opin Emerg Drugs. 2017;22:53-62. 15. Ahmed H, Davies F, Francis N, et al. Long-term antibiotics for prevention of recurrent urinary tract infection in older adults: systematic review and metaanalysis of randomised trials. BMJ Open. 2017;7:1-7. 16. Cunha BA, Cunha CB, Lam B, et al. Nitrofurantoin safety and effectiveness in treating acute uncomplicated cystitis (AUC) in hospitalized adults with renal insufficiency: antibiotic stewardship implications. Eur J Clin Microbiol Infect Dis. 2017;36:1213-6. 17. Price JR, Guran LA, Gregory WT, McDonagh MS. Nitrofurantoin vs other prophylactic agents in reducing recurrent urinary tract infections in adult women: a systematic review and meta-analysis. Am J Obstet Gynecol. 2016;215:548-60. 18. Weng TI, Chen WJ, Liu SH. Bladder instillation of Escherichia coli lipopolysaccharide alters the muscle contractions in rat urinary bladder via a protein kinase C-related pathway. Toxicol Appl Pharmacol. 2005;208:163-9. 19. Burnstock G. Introductory overview of purinergic signaling. Front. Biosci. 2011;3:896-900. 20. Suzuki H, Kokubun S. Subtypes of purinoceptors in rat and dog urinary bladder smooth muscles. Br. J. Pharmacol. 1994;112:117-22

Muller AE, Verhaegh EM, Harbarth S, et al. Nitrofurantoinâ&#x20AC;&#x2122;s efficacy and safety as prophylaxis for urinary tract infections: a systematic review of the literature and meta-analysis of controlled trials. Clin Microbiol Infect. 2017;23:355-62.

21. McMurray G, Dass N, Brading AF. Purinoceptor subtypes mediating contraction and relaxation of marmoset urinary bladder smooth muscle. Br. J. Pharmacol. 1998;123:1579-86.

Shakti L, Veeraraghavan B. Advantage and limitations of nitrofurantoin in multi-drug resistant Indian scenario. Indian J Med Microbiol. 2015;33:47781.

22. Aronsson P, Andersson M, Ericsson T, Giglio D. Assessment and characterization of purinergic contractions and relaxations in the rat urinary bladder. Basic Clin. Pharmacol. Toxicol. 2010;107:603-13.

Busby-Whitehead JM, Johnson TM. Urinary incontinence. Clin Geriatr Med 1998;14:285-96.

23. Hill WG. Control of urinary drainage and voiding. Clin J Am Soc Nephrol. 2015;10:480-92.

Robinson D, Cardozo L. Estrogens and the lower urinary tract. Neurourol Urodyn. 2011; 30: 754-7.

24. Balachandran AA, Wildman SS, Strutt M, Duckett J. 2016. Is chronic urinary infection a cause of overactive bladder? Eur J Obstet Gynecol Reprod Biol. 201:108-12.

10. Edwards JL. Diagnosis and management of benign prostatic hyperplasia. Am Fam Physician. 2008;77:1403-10. 11. Buzelin JM. Female urinary incontinence. Which assessments? Which treatment?. Ann Urol. 1998;32:83-8.

25. Khasriya R, Sathiananthamoorthy S, Ismail S, et al. Spectrum of bacterial colonization associated with urothelial cells from patients with chronic lower urinary tract symptoms. J Clin Microbiol. 2013;51:2054-62.

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13. Ando M, Nagamatsu H, Tanizawa A, et al. Clinical analysis of urinary incontinence in the institutionalized elderly. Nihon Hinyokika Gakkai Zasshi. 1991;82:1299-304.

27. Vijaya G, Cartwright R, Derpapas A, et al. Changes in nerve growth factor level and symptom severity following antibiotic treatment for refractory overactive bladder. Int Urogynecol J. 2013;24: 523-8.

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Does augmentation with antipsychotic agents affect the medication adherence of the child with obsessive-compulsive disorder? Tayfun Kara1, Semra Yilmaz2, Duygu Kinay3, Ismail Akaltun4 1

Alanya Alaaddin Keykubat University, Faculty of Medicine, Department of Child and Adolescent Psychiatry, Alanya, Turkey Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Department of Child and Adolescent Psychiatry, Istanbul, Turkey 3 Bilecik State Hospital, Department of Child and Adolescent Psychiatry, Bilecik, Turkey 4 Gaziantep Dr. Ersin Arslan Training and Research Hospital, Department of Child and Adolescent Psychiatry, Gaziantep, Turkey 2

Received 28 September 2018; Accepted 30 Octaber 2018 Available online 26.12.2018 with doi:10.5455/medscience.2018.07.8944 Copyright ÂŠ 2019 by authors and Medicine Science Publishing Inc. Abstract Antipsychotic agents can be used for augmentation when the response to treatment is insufficient in children with obsessive compulsive disorder. Our aim was to investigate adherence to treatment between patients with and without antipsychotic augmentation and factors potentially related to this. One hundred fourteen children and adolescents aged 8-18 years diagnosed with OCD and still receiving treatment were included in the study. Fifty-two subjects were received antipsychotic therapy for augmentation, while 62 were not receiving it. All subjects were evaluated using a sociodemographic data form, the 8-item Morisky Medication Adherence Scale (MMAS-8), and the Udvalg for Klinikse Undersegelser (UKU) side-effects rating scale. The results were then subjected to statistical analysis. Total MMAS-8 scores were statistically significantly lower in the augmentation group than in the monotherapy group (p: 0.01). Sex, receipt of psychotherapy and family monitoring of treatment had no effect on total MMAS-8 scores (p: 0.949, p: 0.394, and p: 0.198, respectively). Higher UKU side-effect rating scale scores were determined in the augmentation group compared to the monotherapy group (p<0.05). Correlation analysis revealed that UKU total score (r:-0.272, p:0.003) and UKU psychological side-effects subscale score (r:-0.263, p:0.005) were significantly inversely correlated with MMAS-8 total scores. Side-effects deriving from medications affected adherence to treatment more significantly than several other environmental factors in children with OCD. Our findings show the need for side-effects, and particularly psychological side-effects, the frequency of which increases with augmentation, to be monitored in terms of adherence to treatment. Keywords: Adherence, medication adherence, antipsychotic, augmentation, obsessive compulsive disorder

Introduction Obsessive compulsive disorder (OCD) is characterized by the presence of obsessions, involuntary, repetitive or intrusive thoughts, and unnecessary repetitive behaviors or mental activities. It is a frequent cause of distress for children and adolescents [1]. OCD is a psychiatric disorder that can begin in childhood and affects 1-2% of the population [2]. It causes numerous problems with adverse impacts on childrenâ&#x20AC;&#x2122;s academic functions, peer relations and home life. Pharmacotherapy and psychotherapy are used in the treatment of OCD. Cognitive behavioral therapy (CBT) is one psychotherapeutic method successfully used in childhood, *Coresponding Author: Tayfun Kara, Alanya Alaaddin Keykubat University, Faculty of Medicine, Department of Child and Adolescent Psychiatry, Alanya, Turkey E-mail: tayfunkara@hotmail.com

and also in the adult literature [3]. Pharmacotherapy studies have shown the efficacy of serotonin reuptake inhibitors (SRIs) in the treatment of young people with OCD [4]. However, a satisfactory level of symptom improvement may not be achieved in a significant proportion of children with OCD. Approximately one in three or four of these children fails to respond to first-line treatment, and complete remission of OCD symptoms is not achieved in 46% of cases [5]. Treatment-refractory OCD cases are treated using pharmacological augmentation strategies, the most widespread method, involving the addition to medication of an antipsychotic agent [6]. Studies have shown the effectiveness of augmenting SRI pharmacotherapy in OCD with low-dose typical and atypical antipsychotics. However, it is still unclear which antipsychotic agent is more effective in this augmentation therapy [7]. Medication adherence is defined as the extent to which the behavior 197

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of an individual using a medication responds to the medication use advice of a health service provider. Studies have shown that failure to comply with medication therapy advised by the physician renders the treatment ineffective and can lead to a decrease in health-related quality of life in patients with psychiatric disorders [8]. Approximately 30-50% of patients with chronic disease fail to take medications as prescribed, for which reason failure to adhere to medication therapy represents a general public health problem [9]. It is very important to increase adherence to treatment in clinical psychiatry. Establishing a therapeutic relationship with patients requires understanding their needs and adjusting treatment accordingly. This can only be achieved when the effectiveness of treatment, the side-effect burden, and its acceptability to patients are monitored on a regular basis [10]. Adherence is frequently low in psychiatric treatments, affecting 15-25% of hospitalized patients and 50% of outpatients. Twenty percent of psychiatric patients do not take their medications, and 30-50% of purchased drugs are not consumed. Low treatment adherence can have serious consequences, and is associated with high direct and indirect costs associated with recurrence, readmission, chronification, and low productivity [11]. Non-adherence to medication is also reported to be widespread in the pediatric population. Medication adherence rates in pediatric patients range between 11% and 93%. Poor adherence to treatments results in prolonged duration of disease for children and in difficulties in the patient-physician relationship [12]. One review reported that long-term medication therapy and the prescription of numerous drugs reduced medication adherence in children [13]. Drug side-effects are known to impact on adherence to treatment and are of major importance [14].

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carried out [15]. As recommended in the guideline, agents were added for augmentation to patients without sufficient responses to treatment with SSRI over at least 12 weeks. Medication adherence was assessed using the 8-item Morisky Medication Adherence Scale (MMAS-8). This scale, with confirmed reliability and validity in Turkish, classifies the medication behavior of the individual completing it with eight self-report items. Total scores lower than 6 indicate low adherence, scores of 6-8 indicate moderate adherence, and scores greater than 8 indicate high adherence [16,17]. The Udvalg for Klinikse Undersegelser (UKU) side-effects rating scale was used to assess side-effects caused by the medications used. This scale, developed by Lingjærde et al., is used to assess clinical side-effects associated with psychotropic drug use. It consists of subscales evaluating psychological, neurological, autonomic, and other side-effects. Each item consists of four options scored between 0 and 3, with “0” indicating no side-effect and “3” a severe side-effect. The presence or absence of a causal relation between symptoms and the medication used is assessed by the investigator following evaluation. The investigator prioritizes clinical observations when there is thought to be a discrepancy between the patient’s own symptoms and information obtained at interview [18].

Adherence to treatment is affected by factors related to the medication prescribed, the environment and the patient. The purpose of this study was to investigate adherence to treatment in children and adolescents with and without augmentation of medical treatment and factors potentially related to this.

Descriptive statistics (mean, standard deviation, minimum, median, and maximum) were used to define continuous variables. The Mann Whitney U test was employed to examine relations between two independent, non-normally distributed continuous variables. The chi-square test (or Fisher’s Exact test where applicable) was used to examine relations between categorical variables. Significance was set at 0.05. Analyses were carried out on MedCalc Statistical Software version 12.7.7 (MedCalc Software BVBA, Ostend, Belgium; http://www.medcalc.org; 2013).

Material and Methods

Results

The study was performed at the Bakırköy Dr. Sadi Konuk Training and Research Hospital Child and Adolescent Mental Health and Diseases polyclinic. One hundred fourteen subjects age 8-18 years were included. Fifty-two participants were receiving antipsychotic agents for augmentation for treatment of OCD, while 62 were using no such agents. Two groups were constituted, augmentation and monotherapy. An information form consisting of structured multiple choice questions to be completed in writing was prepared by psychiatric specialists to determine cases’ sociodemographic and clinical characteristics. The forms were completed by patients and their families. Ethical committee approval was obtained for the study (No. 2017-03-17 dated 15.05.2017), and verbal and written consent was given by all participants and their parents. Patient enrolment was performed between June 2017 and June 2018. Patients consisted of subjects diagnosed with OCD following clinical evaluation by a child and adolescent psychiatry specialist working in this field based on DSM-V criteria. Subjects with comorbid psychiatric disorders or known organic diseases were excluded. Patients receiving multidrug therapies (more than two medications) or whose forms could not be accurately analyzed were also excluded. The OCD treatment protocol published by the American Academy of Child and Adolescent Psychiatry (AACAP) is used as a treatment guideline in the center where the study was

The 114 subjects in our study were divided into two groups based on receipt of augmentation therapy. The augmentation group consisted of 52 patients, and the monotherapy group of 62. The age range in the augmentation group was 8-18, with a mean age of 13.04+2.67. The age range in the monotherapy group was also 8-18, with a mean age of 13.08+2.98. The augmentation group consisted of 31 boys and 21 girls, and the monotherapy group of 32 boys and 30 girls. The two groups were similar in terms of age and sex distributions (p: 0.802, and p: 0.451, respectively). Mean duration of treatment was 1.3+1 years in the augmentation group and 1.1+1.05 years in the monotherapy group. Although duration of treatment was longer in the augmentation group, the difference was not statistically significant (p: 0.072). The augmentation and monotherapy groups were similar in terms of receipt of psychotherapy (p: 0.146) and of treatment being monitored by families (p: 0.099) (Table 1). Duration of augmentation therapy was 0.51+0.32 years. Mean time to transition to augmentation was 0.81+0.89 years. The most commonly used SRIs in both groups were sertraline and fluoxetine. The most commonly used antipsychotics in the augmentation group were risperidone in 52% and aripiprazole in 36.6%. Distributions of the drugs used by the groups are shown in Table 1. 198

doi: 10.5455/medscience.2018.07.8944

At statistical analysis, MMAS-8 total scores were significantly lower (indicating poor adherence to treatment) in the augmentation group compared to the monotherapy group (p: 0.01). At the same time, scale score distributions revealed lower levels of adherence to treatment in the augmentation group and higher levels of adherence in the monotherapy group. Distributions of MMAS-8 total scores based on sex, receipt of psychotherapy and family monitoring of treatment revealed that these factors had no effect on total MMAS8 scores (p: 0.949, p: 0.394, and p: 0.198, respectively) (Table 2).

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Our data were subjected to correlation analyses with MMAS8 total scores in order to compare the effect on adherence to treatment. No statistically significant correlation was determined between participants’ ages (r: -0.039/p: 0.681) or times to diagnosis (r: -0.127, p: 0.179) and adherence to treatment. No significant correlation was also determined between times to transition to augmentation therapy (r: 0.171, p: 0.226) and duration of augmentation therapy (r: 0.115, p: 0.417) and adherence to treatment. Significant inverse correlation was determined between UKU total scores (r: -0.272, p: 0.003) and UKU psychological side-effect subscale scores (r: -0.263, p: 0.005) and MMAS-8 total scores (Table 3). Adherence to treatment decreased as UKU total and psychological side-effects scores increased.

Comparison of UKU side-effect scale scores revealed higher total scores (greater side-effects) in the augmentation group compared to the monotherapy group. The difference was statistically significant (p<0.001). All UKU subscale scores were also higher in the augmentation group than in the monotherapy group (Table 2).

Table 1. A comparison of the groups’ sociodemographic characteristics and medications Augmentation Group (n=52)

Monotherapy Group (n=62)

Mean±SD Median (Min-Max)

13.04+2.67

13.08+2.98

13.5 (8-18)

1.3+1

1.1+1.05

1 (0.5-5)

0.75 (0.5-6)

Age

Time to diagnosis

Sex

Psychotherapy

Treatment monitored by family

Principal medication

Antipsychotic

0.802

0.072

p**

Male

59.6

51.6

0.451

Female

40.4

48.4

Yes

36.5

22.6

63.5

77.4

Yes

61.5

77.4

38.5

22.6

n (Mean dose)

Sertraline

34 (83,8 mg)

65.4

45 (66,8)

72.6

Fluoxetine

8 (40 mg)

15.4

13 (26,9)

21.0

Clomipramine

9 (88,9 mg)

17.3

1 (75 mg)

1.6

Citalopram

0.0

2 (30 mg)

3.2

Fluvoxamine

1 (100 mg)

1.9

0.0

Other

0.0

1 (20 mg)

1.6

Risperidone

27(0,91 mg)

Aripiprazole

19 (4,9 mg)

36.6

Olanzapine

2 (5 mg)

3.8

Quetiapine

2 (75 mg)

3.8

Other

2 (3 mg)

3.8

0.146

0.099

*Mann-Whitney U p. **Fisher’s Exact p, Numbers in bold text denote significant differences (p<0.05)

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Table 2. Comparison of MMAS-8 and UKU side-effect scores Augmentation Group (n=52)

Monotherapy Group (n=62)

Mean±SD Median (Min-Max)

4.6+1.9

5.6+1.9

5 (1-9)

6 (2-8)

Age

Morisky-Adherence

0.010

Low

61.5

48.4

Moderate

30.8

30.6

High

7.7

21.0

Mean±SD Median (Min-Max) Male

Female

5.2+1.6

5.1+2.3

5 (2-8)

5 (1-9)

Receiving psychotherapy

No psychotherapy

5.4+2.1

5.1+1.9

5 (2-9)

5 (1-9)

Family monitoring

No family monitoring

MMAS-8 Total

5+1.9

5.5+2.05

5 (1-9)

6 (2-9)

Augmentation Group (n=52)

Monotherapy Group (n=62)

Mean±SD Median (Min-Max)

10.4+7.1

4.9+5.7

10 (0-34)

3 (0-28)

6.1+3.9

3.05+2.9

6 (0-16)

2 (0-10)

0.85+1.6

0.24+0.7

0 (0-7)

0 (0-3)

UKU-Total UKU-Psychological UKU-Nuerological UKU-Autonomic UKU-Other

1.8+2.4

1.08+2.3

1 (0-12)

0.7 (0-9)

1.6+1.9

0.6+1.3

0.949

0.394

0.198

<0.001 <0.001 0.003 0.001

<0.001 1 (0-9) 0 (0-6) * Mann–Whitney U test, The 8-item Morisky Medication Adherence Scale (MMAS-8), and the Udvalg for Klinikse Undersegelser (UKU) side-effects rating scale, Numbers in bold text denote significant differences (p<0.05) Table 3. Adherence to treatment-related correlation analyses MMAS-8

For all subjects

Augmentation group

UKU-Psychological

-0.263

0.005

UKU-Neurological

-0.129

0.170

UKU-Autonomic

-0.165

0.079

UKU-Other

-0.103

0.277

UKU-Total

-0.272

0.003

Time to diagnosis

-0.127

0.179

Age

-0.039

0.681

Duration of augmentation

0.115

0.417

Time to transition to augmentation

0.171

0.226

Rho (p) Spearman Correlation Analysis, The 8-item Morisky Medication Adherence Scale (MMAS-8), and the Udvalg for Klinikse Undersegelser (UKU) side-effects rating scale, Numbers in bold text denote significant differences (p<0.05)

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Discussion Studies have shown that OCD frequently follows an inflexible course in a chronic pattern, and that long-term treatment may be necessary to prevent relapse. Preliminary data have shown that patients whose symptoms recur following medication discontinuation respond positively but with relatively lower effectiveness compared to the first treatment when the same drug is resumed [19]. These observations underline the need to determine markers of treatment dependence in OCD. Although adult-based studies have been performed, ours is the first study to assess medication side-effects and adherence to treatment in a pediatric OCD population. OCD has a tendency to chronification, and the importance of early treatment has been shown in the literature. Recovery can be achieved with monodrug or multidrug medication and psychotherapy. Psychotherapy is effective, but pharmacotherapy is widely employed as the first and sole form of treatment [20, 21]. In one study of 246 children diagnosed with OCD and with a mean age of 11.9 years, SRIs were general prescribed (55%), and antipsychotics were added, either alone or in combination with another medication, in 22%. The level of receipt of psychotherapy plus at least one medication was 36% [22]. The rate of antipsychotic use was higher in our study (45%). Only 33 (29%) of the 114 patients in our study were receiving psychotherapy. However, the rates of psychotherapy receipt were very low in and similar between both the augmentation and monotherapy groups. Although pharmacotherapy represents the current foundation of OCD treatment due to the availability of effective medication, CBT is also reported to be effective in the disease [23]. Wilson and Roman reported that problems concerning difficulty of access to CBT and inadequate education represented the greatest obstacles to the use of this effective therapeutic method [24]. We attributed the low psychotherapy and high augmentation rates in our study to difficulties in accessing psychotherapy. Non-adherence to treatment is common in patients with OCD. Sixty-one percent of patients with OCD receiving drug therapy are reported either to use their medications less frequently and/ or at lower doses, or else to discontinue the medication entirely [25]. This has been attributed to medication side-effects (78%), insufficient therapeutic efficacy (41%), and high levels of concern over drug use (41%) [26]. In our study, we focused on the effect on adherence to treatment of one of these causes, medication side-effects. Establishing an augmentation strategy resulting in fewer drug side-effects has been reported to increase adherence to treatment in cases in which an antipsychotic agent is added for augmentation in patients with refractory OCD [27]. In our study, total UKU side-effect rating scale scores and psychological subscale scores were directly correlated with adherence to treatment. At the same time, patients receiving augmentation had higher side-effect scale scores. The probable side-effects of the antipsychotics administered for augmentation in order to increase patients’ adherence to treatment in fact reduced adherence to treatment. Non-adherence to treatment can be reduced either by selecting medication that will cause fewer side-effects, or else by providing information for patients. Patients generally experience concerns over side-effects. It may be useful to provide advice about side-effect management strategies in order to reduce this fear

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to a minimum; written prescription information can be provided, and follow-up visits at intervals of 1-4 weeks can be performed following the first visit [28]. The side-effect profile of various pharmacological agents used to treat children with refractory OCD is problematic. Therefore, before considering augmentation strategies for OCD in children, it is recommended that all possible efforts should first be made to ensure that patients have received the best first-line treatment [5]. One of the main limitations of this study is that patient-based characteristics that might affect adherence to treatment and types of obsession and compulsion were not evaluated. Another important limitation is that severity of OCD and therapeutic efficacy were not examined. Previously, in evaluating adherence to treatment in OCD, obsessions with violent content and hoarding symptoms, and the presence of lower introspection levels, have been observed to exhibit an adverse effect on adherence [27]. Due to our study’s cross-sectional design, it reveals the relation between adherence to treatment and side-effects in statistical terms, rather than showing a causal effect between them. In our study, families’ economic and social status were not evaluated. Non-adherence to treatment is reported to be widespread in low-income patients starting treatment due to chronic disorders [29]. However, since both groups in our study consisted of subjects under monitoring by a public hospital and from a single center, we think that the probability of this affecting our results is low. Conclusion Lower adherence to treatment in the pediatric OCD population was significantly associated with more drug-related side-effects. More side-effects observed with augmentation, and particularly psychological side-effects, were related to lower adherence to treatment. Psychoeducation for children and families concerning the treatment of OCD and potential drug side-effects will contribute to increasing adherence to treatment. We think that in managing the treatment of children with OCD, physicians should take particular care over potential medication-related side-effects, and that this will enhance the success of treatment by increasing adherence to it. We think that although adult studies are already available, further studies are needed on the subject of patientrelated characteristics on adherence to treatment in pediatric OCD. Competing interests The authors declare that they have no competing interest Financial Disclosure The authors declared that this study has received no financial support Ethical approval Ethical committee approval was obtained for the study (No. 2017-03-17 dated 15.05.2017), and verbal and written consent was given by all participants and their parents. Tayfun Kara ORCID: 0000-0002-2156-3457 Semra Yilmaz ORCID: 0000-0002-6527-2432 Duygu Kinay ORCID: 0000-0002-6586-2838 Ismail Akaltun ORCID: 0000-0002-9938-9276

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):203-7

The risks and benefits of non-predictive splenectomy: The necessity of splenectomy and early postoperative outcomes Yusuf Gunay, Ilhan Tasdoven Zonguldak Bulent Ecevit University Faculty of Medicine, Department of General Surgery, Zonguldak,Turkey Received 18 January 2019; Accepted 07 February 2019 Available online 22.02.2019 with doi:10.5455/medscience.2019.08.9011 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Although, most splenectomy is predictive due to preoperative tests, sometimes the decision to perform the splenectomy is made intraoperatively for non-primary splenic diseases. The aim of this study to investigate the risks, benefits and necessity of non-predictive of splenectomy and early outcomes. Splenectomy was performed as predictive splenectomy (PS) for primary splenic diseases and non-predictive splenectomy (Non-PS) for non-primary splenic diseases. Preoperative, operative, and 1-month postoperative data included to study. Between June 2012 and July 2018, 108 patients underwent splenectomy. Of these patients, 67 (62%) had PS for primary splenic disease, and 41 (38%) had non-PS due to non-primary splenic diseases. Patients with PS were statistically younger compared to Non-PS patients (52.82 ± 15.07 vs. 44.32 ± 19.23 years, p = 0.022). The most common cause of splenectomy in the PS group was immune thrombocytopenic purpura (ITP) in 16 (23.9%) and splenic trauma in 16 (23.9%), whereas in the non-PS group the major causes were gastric cancer in 16 (39%) and pancreas cancer in 10 (24.4%). Patients in the PS group had significantly lower postoperative hospital stay day (11.2 ± 7.3 vs. 6.4 ± 4.2, p = 0.001). The total complication rate was statistically higher in the non-PS patients (31.7% vs. 10.4%, p = 0.012). However, no significant differences were found in the postoperative infection rates (17% in non-PS versus 7.5% in PS, p = 0.22). Even if the preoperative investigation does not show any indication for splenectomy, but the surgeon has intraoperative concerns about sub-optimal oncological surgery without splenectomy, we recommend that the surgeon should perform the splenectomy. Keywords: Splenectomy, post splenectomy, splenomegaly

Introduction Splenectomy is the curative treatment for disease and is applied to patients with a spleen injury, splenic malignancy and abscesses or cysts that involve all of the spleen, tumors, and metastasis [1]. Moreover, splenectomy can be considered for some hematological diseases, such as ITP, hemolytic anemia, and hematological malignancies [1-3]. Although splenectomy is considered a safe procedure [4], it can cause fatal postoperative complications, such as infections, thrombocytosis, portal vein thrombosis [5,6]. Although, most splenectomy is predictive due to preoperative diagnostic images and laboratory values, sometimes the decision to perform the splenectomy is made intraoperatively. As reported in the literature, the suspicion of splenic hilum invasion by nonsplenic intraabdominal cancer might force the surgeon to make intraoperative decision to perform splenectomy with gastric, pancreas, colon or other intraabdominal organ resection to achieve *Coresponding Author: Yusuf Gunay, Zonguldak Bulent Ecevit University Faculty of Medicine, Department of General Surgery, Zonguldak, Turkey E-mail: drygunay@gmail.com

optimal cancer surgery [7]. There is controversy about whether intraoperative decisions can lead to unnecessary splenectomy and fatal complications. However, avoiding intraoperative splenectomy decisions might lead to unsatisfactory cancer surgery. The aim of this study was to investigate the risk and benefits of non-predictive splenectomy and early outcome of predictive (preoperative indication) versus non-predictive (intraoperative indication) splenectomy. Material and Methods Between June 2012 and July 2018, 108 patients underwent splenectomy. Splenectomy was performed as predictive splenectomy (PS) for primary splenic diseases and non-PS for non-primary splenic diseases. Splenectomy performed for non-PS included cases of gastric cancer, pancreas cancer, colon cancers, and other intraabdominal cancers. Preoperative images and laboratory findings were used for diagnoses. The preoperative evaluation showed no pathology in non-PS patients, and the decision for splenectomy in patients with non-PS was made intraoperatively due to concerns about non-splenic malignancy invasion to the spleen 203

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or splenic hilum lymph node metastasis. In this study, patients were divided into two groups based on the cause of splenectomy: splenectomy for PS versus non-PS. Preoperative, operative, and 1-month postoperative data included age, gender, indications for splenectomy, preoperative and postoperative platelets and WBC (white blood count), postoperative splenectomy-related complications (bleeding, infections, hematological changes), pathological diagnosis, hospital and ICU (intensive care unit) stay, and death in the first postoperative month. An early outcome was defined as 1 month after surgery.

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identify differences, further statistical analysis showed significant increases at 1 week postoperation (211.4 ± 354.8/µL) and 1 month postoperation (245.8 ± 385/µL) (p = 0.001 and 0.001 respectively, Figure 1). However, the increase in platelet number from 1 week postoperation to 1 month postoperation was not statistically significant in the PS group ((464,80±281,9/µL vs 483,61±570,5/ µL, p > 0.05). Table 1. Indications for splenectomy Group Non-PS (n=41)

PS (n=67)

Amenia

3 (4.5 %)

Hamartom

1 (1.5 %)

Hemangiom

2 (2.9 %)

Hemolytic Anemia

5 (7.5 %)

Hypersplenism

2 (2.9 %)

ITP

16 (23.9 %)

Lymphoma

1 (1.5 %)

Spleen Abcess

4 (6 %)

Spleen Cyst

2 (2.9 %)

Spleen Hydatic Cyst

2 (2.9 %)

Spleen Infarction

9 (13.4 %)

Results

Spleen Malignancy

2(2.9 %)

Splenomegaly

2 (2.9 %)

Between June 2012 and July 2018, 108 patients underwent splenectomy. Of these patients, 67 (62%) had PS, and 41 (38%) had non-PS.Of the 67 patients who underwent total splenectomy in the PS group, 9 (13.4%) had a laparoscopic splenectomy. There were no statistical differences in group regarding male gender (35% in PS vs 45% in non-PS p = 0.314). Among these patients, 55.6% (60) were female, and 44.4% (48) were male. The mean age of the patients was 47.70 ± 18.1 years (range: 18-86 years. Patients with PS were statistically younger compared to Non-PS patients (52.82 ± 15.07 vs. 44.32 ± 19.23 years, p = 0.022). Indications for splenectomy are outlined in Table 1. The most common cause of splenectomy in the PS group was immune thrombocytopenic purpura (ITP) in 16 (23.9%) and splenic trauma in 16 (23.9%), whereas in the non-PS group the major causes were gastric cancer in 16 (39%) and pancreas cancer in 10 (24.4%). The preoperative splenomegaly rate was statistically higher in the PS group than the non-PS group [44 (65.7 %) versus 12 (29.3 %), p = 0.001].

Trauma

The most common pathological diagnosis that was statistically higher in the PS group was hamartoma, whereas the most common diagnosis was a tumoral invasion in the non-PS group (p < 0.01). Of the 41 patients that underwent splenectomy due to concern about cancer invasion, only 8 (19.5%) had pathologically confirmed cancer invasion to the spleen from non-splenic intraabdominal cancers. The deseases pathological diagnosis in in non-PS was found to be statistically higher compared to PS (77.5% vs 45.3% p = 0.001, Table 2).

Congestion

Statistics The NCSS (Number Cruncher Statistical System, 2007, Kaysville, Utah, USA) program was used for statistical analysis. To analyze the data we used definitive statistical methods and calculated the mean ± SD, median, frequency, minimum and maximum values. Normal distribution quantitative values were compared using the Student’s t-test, whereas non-normal distribution values were compared in two groups using the Mann Whitney U test. Nonnormal distributed values in the same group were compared using the Friedman test and Wilcoxon Signed Ranks test. Qualitative values were compared using the Pearson chi-squared test, Fisher’s exact test, and the Fisher Freeman Halton test. A p-value of < 0.05 was used as a cut-off for significance.

No significant differences were found in platelet number between the two groups at 1 week postoperation (464.80 ± 281.99/µL in PS vs. 482.67 ± 283.12/µL in non-PS, p = 0.76) and 1 month postoperation (483.61 ± 570.58/µL vs. 475.60 ± 247.16/µL, p = 0.23). The preoperative platelets rate was statistically lower in the PS group (250.4 ± 279/µL vs. 323.9 ± 129/µL, p = 0.001). To

16 (23.9 %)

Colon cancer

3 (7.3 %)

Endometrium cancer

1 (2.4 %)

Gastric cancer

16 (39 %)

Lung cancer

2 (4.9 %)

Over cancer

8 (19.5 %)

Pancreas Cyst

1 (2.4 %)

Pancreas cancer

10 (24.4 %)

Pancreas Trauma

3 (7.3 %)

Table 2. Pathological Diagnosis in Groups Groups Non-PS (n=41)

PS (n=67)

5 (7.5%)

χ2:40,417

33 (80.5%)

29 (43.3%)

d0,001**

Cyst

1 (1.5%)

Cystic Malignancy

3 (4.5%)

Hamartom

16 (23.9%)

Hydatic Cyst

1 (1.5%)

Hypersplenism

4 (6%)

Inflamation

3 (4.5%)

Infarction

3 (4.5%)

Lymphoma

1 (1.5%)

Nodular Lesion

1 (1.5%)

8 (19.5%)

0 (0)

Abcess

Tumoral Invasion

Fisher Freeman Halton Test

**p<0,01

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postoperation was statistically significant (12.55 ± 4.67 x109/L vs. 10.30 ± 3.86 x109/L, p = 0.001). The increase in WBC from the day of splenectomy to 1-week postoperation was significant in the non-PS group (11.05 ± 43.17 x109/L vs. 16.93 ± 20.93 x109/L, p = 0.001), and the decrease of WBC from 1-week postoperation to 1-month postoperation was statistically significant (16.93 ± 20.93 x109/L vs. 11.77 ± 3.47 x109/L, p = 0.001).

Figure 1. Changes in platelet number following splenectomy

No differences were found in preoperative WBC in the two groups (9.13 ± 3.69x109/L in PS vs. 11.05 ± 43.17 x109/L, p = 0.212). The increase of WBC from the day of splenectomy to 1 week postoperation was found to be significant in the non-PS group (9.13 ± 3.69 x109/L vs. 12.55 ± 4.67 x109/L, p = 0.001), and the decrease of WBC from 1 week postoperation to 1 month

Patients in the PS group had significantly lower postoperative hospital stay day compared to the non-PS group (11.2 ± 7.3 vs. 6.4 ± 4.2 day, p = 0.001). The mean stay in the ICU period was statistically longer in patients with non-PS (1.8 ± 1.2 vs. 0.6 ± 0.8 day, p = 0.014, Table 3). The total complication rate was statistically higher in the non-PS patients (31.7% vs. 10.4%, p = 0.012, Table 3). However, no significant differences were found in the postoperative infection rates of the two groups (17% in nonPS versus 7.5% in PS, p = 0.22, Table 3). The complications in PS were Clavien-Dindo classification class-1 [5 of 7 (71.4%)] and class-2 [2 of 7, 28.6%]. In the non-PS groups, the complications were Clavien-Dindo classification class-1 [6 of 13 (46.1%)], class-2 [5 of 13(38.5%)], and class-3 [2 of 13 (15.4%)].

Table 3. The complications rate and hospital and ICU stay times

Postoperative Hospital Stay (day)

Min-max (Median) Mean±SD

Postoperative ICU Stay (day)

Min-Max (Median) Mean±SD

Total Complications (rate)

Non- PS (n=41)

PS (n=67)

3-34 (8)

1-30 (5)

11,22±7,28

6,37±4,20

0-4 (2)

0-2 (0)

1,79±1,19

0,64±0,81

13 (31.7%)

7 (10.4%)

p Z:-4,128 0,001**

Z:-2,448 0,014*

0,012

Infections (rate) Fisher’s Exact Test

Mann Whitney U Test

*p<0,05

The rate of patients that received a post-splenectomy vaccine was not statistically different between the two groups (62.5% in PS vs. 45.5% in non-PS, p = 0.08). Post-splenectomy vaccination did not affect the infection rate in either of the two groups (10% in vaccinated patients vs. 4.2% in non-vaccinated patients, p = 0.30). Post-splenectomy vaccination did not affect the total complications rate in the two groups (11.6% in vaccinated patients vs. 10.4 % in non-vaccinated patients, p = 0.83). No differences were detected in the total complications rate in patients with splenectomy and pancreatectomy versus splenectomy and gastrectomy (8.2% vs. 6.3%, p = 0.655). Two (4.9%) patients died in the non-PS group due to cardiopulmonary causes, whereas no deaths were reported in the PS group during the 1 month follow-up period. The variables that were significant in the univariant analysis were analyzed using backward stepwise logistic regression analysis. In the logistic regression analysis, we detected increased risk for a longer hospital stay [OR: 1.148 (%95 CI: 1.028-1.283), p = 0.014] and higher chance to have congestion (OR: 5.111 (%95 CI: 1.32919.646), p = 0.018) in spleen pathological reports in the non-PS group. However, having preoperative splenomegaly is most likely in the patients in the PS group [OR: 6.870 (%95 CI: 2.025-23.30), p = 0.002].

**p<0,01

Discussion As reported in the literature, prophylactic splenectomy does not provide survival advantages in proximal gastric cancer surgeries but can cause unnecessary postoperative complications [8,9]. However, not doing splenectomy in non-splenic intraabdominal cancer surgery can cause insufficient oncological surgery due to missing metastatic splenic hilar lymph nodes or invasions of neighboring organs, such as in gastric, pancreas or colon cancers. It remains unclear whether the intraoperative decision to perform splenectomy is sufficiently safe. In this study, we analyzed our records to determine how many splenectomies were unnecessary, as well as the rate of splenectomy-related early complications in non-predictive splenectomy. We also compared early results of patients with predictive and non-predictive splenectomy. Previously, in patients with proximal gastric cancer, splenectomy was performed routinely to clear metastatic lymph node or tumoral invasion in splenic hilum. However, it was reported that this does not have a survival benefit but increases postoperative complications [10]. Nevertheless, splenectomy must be done if there is tumor invasion in spleen hilum [10]. However, other studies have recommended spleen hilar lymph nodes dissection even if 205

doi: 10.5455/medscience.2019.08.9011

laparoscopically can be safely done without doing splenectomy [11,12]. Some studies have reported that, for neuroendocrine pancreas tumor in the left side of the pancreas, it is not necessary to perform splenectomy because it does not affect the outcome and no tumor invaded the lymph node retrieved in their series [13]. A meta-analysis comparing distal pancreatectomy spleen preservation (SPDP) to distal pancreatectomy with splenectomy (DPS) showed that SDPS has more benefits in borderline pancreas malignants [14,15]. However, a study reported and claimed that spleen preservation is time-consuming and causes more blood transfusion, which increases the risk of postoperative complications [16]. Another study detected no difference in long-term complication rate when comparing performing colectomy with or without splenectomy in patients with colon cancer and inadvertent splenectomy [17]. This study related complications in colectomy and splenectomy to non-splenectomy causes [17]. Splenectomy is recommended for cytoreductive surgery for stage-4 ovarian cancers, and it is reported that splenectomy improves survival rate [18]. Of the 41 patients who underwent non-predictive splenectomy based on the surgeon’s intraoperative decision, 19.5% had a malignant invasion in splenic hilum. However, in this study, about 80% of splenectomies was unnecessary. It is noteworthy that some of the splenectomies were performed due to the previously accepted protocol, which recommended a splenectomy in case of proximal gastric cancer. Therefore, this might account for why the unnecessary splenectomy rate might is higher than expected. Although we cannot provide the information in this study, how many metastasis or tumoral invasion were missed by not doing splenectomy in gastric and other intraabdominal cancers is unknown . Unfortunately, the information about the risk of missing metastatic lymph nodes by not doing splenectomy is scarce in the literature. Therefore, more studies are needed to determine the risks and benefits of performing (or not performing) splenectomy in non-splenic intraabdominal cancers. We also accept that some of the tumor invasion to the spleen might have occurred preoperatively, but been missed in the operative evaluation. In this study, the complications were higher in non-predictive splenectomy, most likely due to concurrent organ surgery-related complications, such as a pancreatic leak from pancreas resection or anastomosis complications in gastric and colon surgeries. We also did not determine the differences in infections rate in patients who underwent predictive versus non-predictive splenectomy. Since we only included early complications in the first month after splenectomy, the long-term follow-up findings might differ. Postsplenectomy hematologic changes in platelets and WBC were similar in the two groups. In this study, platelets increased after splenectomy, which is consistent with the literature. The increase of WBC after splenectomy was consistent with the findings of a previous study, and this is most likely a physiological reaction to splenectomy [19]. Although we did not include longterm complications of splenectomy in this study, the fatal longterm complication of splenectomy is an overwhelming postsplenectomy infection (OPSI) which has a high mortality rate [20]. Even if the early morbidity and mortality have decreased in recent years, the long-term complications rate remains high [21]. Although a study reported that non-vaccinated patients have more

Med Science 2019;8(1):203-7

complications compared to the unvaccinated [22], in this study, the vaccinated rate did not affect the infection rate in patients, and this might be due to the shorter follow-up period. Conclusions Overall, although splenectomy can increase the risk of postoperative complications (some of which are fatal), not performing these splenectomies might result in non-optimal oncological surgery and thus affect patient survival. We recommend thorough preoperative investigations to determine whether lymph node metastasis or invasion to spleen have occurred, thus increasing the accuracy of the surgical plan. However, even if the preoperative investigation does not show any indication for splenectomy, but the surgeon has intraoperative concerns about sub-optimal oncological surgery without splenectomy, we recommend that the surgeon should perform the splenectomy. More randomized studies are needed to address long-term complications in patients with predictive and non-predictive splenectomy and the necessity of splenectomy in non-splenic intraabdominal centers surgery. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support. Ethical approval Consent of ethics was approved by the local ethics committee. Yusuf Gunay ORCID: 0000-0002-6518-9997 Ilhan Tasdoven ORCID: 0000-0002-3231-3189

References 1.

Brunicardi FC, Anderson DK, Billiar TR, et al. Schwartz’s Principles of Surgery, Tent Editon, 34th Chapter. 2015, p. 1420-39.

Katz SC1, Pachter HL. Indications for splenectomy. Am Surg. 2006 ;72:565-80.

Rodeghiero F, Ruggeri M. Short- and long-term risks of splenectomy for benign haematological disorders: should we revisit the indications? Br J Haematol. 2012;158:16-29.

Bagrodia N, Button AM, Spanheimer PM, et al. Morbidity and mortality following elective splenectomy for benign and malignant hematologic conditions: analysis of the american college ofsurgeons national surgical quality improvement program data. JAMA Surgery.2014;149:1022-29.

Edgren G, Almqvist R, Hartman M, et al. Splenectomy and the risk of sepsis: a population-based cohort study. Ann Surg 2014;260:1081–87.

Sinwar PD. Overwhelming post splenectomy infection syndrome review study. Int J Surg. 2014;12:1314-16.

Xiang L, Tu Y, He T, et al. Distal pancreatectomy with splenectomy for the management of splenic hilum metastasis in cytoreductive surgery of epithelial ovarian cancer. J Gynecol. Oncol. 2016;27:62-3.

Weitz J, Jaques DP, Brennan M, et al. Association of splenectomy with postoperative complications in patients with proximal gastric and gastroesophageal junction cancer. Ann Surg Oncol. 2004;11:682–89

Yu W, Choi GS, Chung HY. Randomized clinical trial of splenectomy versus splenic preservation in patients with proximal gastric cancer. Br J Surg. 2006;93:559–63.

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doi: 10.5455/medscience.2019.08.9011 10. Sano T, Sasako M, Mizusawa J, et al. Randomized controlled trial to evaluate splenectomy in total gastrectomy for proximal gastric carcinoma. Ann Surg. 2017;265:277-83. 11. Usui S, Tashiro M, Haruki S, et al. Spleen preservation versus splenectomy in laparoscopic total gastrectomy with D2 lymphadenectomy for gastric cancer: A comparison of short-term outcomes. Asian J Endosc Surg. 2016;9:5-13. 12. Son SY, Shin DJ, Park YS, et al. Spleen-preserving lymphadenectomy versus splenectomy in laparoscopic total gastrectomy for advanced gastric cancer. Surg Oncol. 2017;26:207-211. 13. Yoo YJ, Yang SJ, Hwang HK, et al. Overestimated oncologic significance of lymph node metastasis in g1 nonfunctioning neuroendocrine tumor in the left side of the pancreas. Medicine (Baltimore). 2015 ;94:1404. 14. He Z, Qian D, Hua J, et al. Clinical comparison of distal pancreatectomy with or without splenectomy: A meta-analysis. PLoS One. 2014;9:91593. 15. Tang CW, Feng WM, Bao Y, et al. Spleen-preserving distal pancreatectomy or distal pancreatectomy with splenectomy?: Perioperative and patientreported outcome analysis. J Clin Gastroenterol. 2014;48:62-6 16. Shoup M, Brennan MF, McWhite K, et al. The value of splenic

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preservation with distal pancreatectomy. Arch Surg. 2002;137:164-8. 17. Lolle I, Pommergaard HC, Schefte DF, et al. Inadvertent splenectomy during resection for colorectal cancer does not Äąncrease long-term mortality in a propensity score model: a nationwide cohort study. Dis Colon Rectum. 2016;59:1150-59. 18. Sun H, Bi X, Cao D, et al. Splenectomy during cytoreductive surgery in epithelial ovarian cancer. Cancer Manag Res. 2018;10:3473-82. 19. Djaldetti M, Bergman M, Salman H, et al. On the mechanism of postsplenectomy leukocytosis in mice. Eur J Clin Invest. 2003;33:811-17. 20. Morgan TL, Tomich EB. Overwhelming post-splenectomy infection (OPSI): a case report and review of the literature. J Emerg Med. 2012;43:758-63. 21. Yong M, Thomsen RW, Schoonen WM, et al. Mortality risk in splenectomised patients: a Danish population-based cohort study. Eur J Intern Med. 2010;21:12-6. 22. Di Sabatino A, Lenti MV, Tinozzi FP, et al Vaccination coverage and mortality after splenectomy: results from an Italian single-centre study. Intern Emerg Med. 2017;12:1139-47.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):208-10

Effect of different positive end-expiratory pressures in donor liver transplantation patients on hemodynamics and ICU admission period: A Prospective, randomized, double-blind study Muharrem Ucar, Mustafa Said Aydogan Inonu University Faculty of Medicine, Department of Anesthesiology, Malatya, Turkey Received 11 January 2019; Accepted 11 February 2019 Available online 21.02.2019 with doi:10.5455/medscience.2019.08.9007 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Donors are generally volunteers without any sanitary problems. For this reason, security of the anesthesia practice and ICU admission period is significant. The goal of present study was to determine whether there was any important coalition among different positive end-expiratory pressure (PEEP) level hemodynamics and ICU admission in donor patients. This study was performed with40 patients who underwent general anesthesia. Patients were divided into two groups by their PEEP as0 cm H20 in the first group (group Z), and 10 H20 in the second group (group H). We investigated the data concerning demographical data, perioperative values, hemodynamic parameters, intraoperative blood loss, andICU admission. Patient characteristic,characteristicsand perioperative values were similar among the groups. Mean arterial pressure, and central venous pressure were importantly different among the groups (P<.05). Intraoperative bleeding remained statistically unchanged in both groups. The median ICU admission after surgery was longer in group Z versus the group H (2 and 1 days per patient, respectively; P>.05). We have concluded that our data pool is low and single-centered,we determined that PEEP values (10 cm H2O) may be a decisive element for the ICU admission after donor patients. Keywords: Positive end-expiratory pressure, donors, liver transplantation, ICU admission

Introduction

Material and Methods

Donor patients are generally volunteers without any sanitary problems. For this reason, safety of the patients is the foremost topic in anesthesia practice [1]. The intensive care unit (ICU) shows a crucial act in the application of donor liver transplantation. AnextendedICU admission increases health expenses.

Institutional ethics board of the Inonu University Medical School (2013/19) approved the study, and written informed permissionswere receivedfrom each patient before the study. We prospectively examined 40 patients whose ages ranged from 18 to 65 years andwho passed right hepatectomy surgery between August 2013 and January 2014.

Gas replacement inconvenience are extensive in patients with donors surgery [2]. Therefore, ventilatory assistance with positive end-expiratory pressure (PEEP) is frequently performed and increasesfunctional residual capacity and decreases intrapulmonary shunt [3]. The aim of thepresent studywas todetermine the impact of different PEEP levels on ICU admission period in donors with hemodynamics.

*Coresponding Author: Mustafa Said Aydogan, Inonu University Faculty of Medicine, Department of Anesthesiology, Malatya, Turkey E-mail: dr_mustafasaid@hotmail.com

In the surgery room,the hemodynamic levels of thepatients were recorded. BIS was used to definethedepth of anesthesia. Patients received 100% oxygenfor 3 minutes before initiation of anesthesia. Anesthesia was induced 2 mg/kg propofol (1% propofol;Fresenius) and 1µg/kg remifentanil with 0.6 mg/kg atracurium. Anesthesia maintenance was continued to ensure an isoflurane concentrationof 0.5%–1.5% that the BIS value remained between 40 and 60.Ventilation was controlled with a tidal volume of 7–10 mL/kg andventilator rate adjusted to maintain an end-tidal CO2of 35– 40 mmHg. Concentrations of isoflurane were measured with the use of ananesthesia device (Dräger Primus, Germany). A constant fresh gasflow of 3 L/min (60% air and 40% oxygen) was used during themaintenance of anesthesia.Both groups received remifentanil (0.25µg/kg/min) and atracurium (0.5 mg/kg/h) infusions (Life Care5000 Infusion System; Abbott, Sligo, Ireland).A radial arterial 208

doi: 10.5455/medscience.2019.08.9007

cannula was inserted into the patient’s nondominant hand. Threeway 7.5-Fr Central venous pressure (CVP) was monitoredfrom the internal jugular vein via a central catheter. In addition, weinserted nasogastric tube and a nasopharyngeal heat probe. Neuromuscular conduction was monitored via a train-of-four device.All patients weremonitored to maintain normothermia during surgery and bodytemperature was monitored. Patients were followed in supine position during surgery. The patients were randomly divided into 2groups with the use of a computer-generated random number table. Forty patients were included in the studyand randomly divided into two groups considering their PEEP as 0 cm H20 in the first group (group Z) and 10 H20 in the second group (group H). The anesthesia was ensuredwith BIS levels between 45 - 60. The same surgical team performed all operations usingthe Pringle maneuver routinely. Pringle maneuver was recorded. The centers’ protocol for total portal occlusion is 15-minute occlusion alternated with5minute reperfusion for patients with normal liver parenchyma.All donors were extubated at theend of the operation and subsequently transferred to the intensive care unit. Observed complications were recorded during the operation. We investigated the demographical data, hemodynamics (mean arterial pressure [MAP], central venous pressure [CVP], and heart rate [HR]), intraoperative blood loss, ICU admission period. Statistical Analyses SPSS 16.0 package program was used in the statistical analyses of the characteristics. With Kolmogorov-Smirnov normality test, characteristicsconcerning the quantitative variables were defined to demonstrate normal distribution (P>.05). Paired t-test was used to test the change in characteristicsthroughout the process. Independent t-test was used in the intergroup comparisons. A point of P<.05 was considered statistically significant. The scoresare shown as mean values, standard deviation (SD), or numbers and percentages. Results No differences weredetected among the groups in respect to demographical data(P>.05; Table 1). We detected no differences in terms of surgery period, percentage of liver remnant, graft gravity and quantity of blood loss among groups (Table 2). Important variables in the MAP and CVP values were monitored in cases aerated with PEEP 0 or 10 cm H2O (P<.05; Table 3). When groups were checked for ICU admission,itwas longer in group Z versus group H (P >.05; Table 3). Table 1 Demographic Characteristics Range Mean ± std n Age (years) 7 – 61 38.90 ± 13.75 Sex (male/female) 29/11 Weight (kg) 23 – 104 64.80 ± 17.25 Cadaveric/living 8/32 ASA III/IV 21 – 30 24.95 ± 2.85 38/2 Hemoglobin(mg/dL) 6.3 – 10.3 8.02 ± 1.06 Need for additional analgesics 8 Comorbidity None 22 Hypertension 12 Diabetes +Hypertension 3 Diabetes 2 FVII Deficiency 1 Sleep Apnea 1 Complications none 36 hemorrhage 1 thrombosis 1 mortality 1 ASA; American Society of Anesthesiology, n: number of cases, Range: minmax

Med Science 2019;8(1):208-10

Table 2. Procedure Datas Range

Mean ± std

Duration of anesthesia (min)

180-360

298.50±32.22

Duration of surgery (min)

170-320

253.50±30.93

Total crystalloid (mL)

600-4000

3062.50±833.80

Mannitol (mL)

30-150

93.75±26.57

Furocemid (mg)

80-180

131.50±18.05

Bupivacain (mg)

15-25

24.5±0.44

Blood Transfusions

Duration of cold ischemia (min)

67-1116

275.82±379.14

Duration of hot ischemia (min)

1.11-4

2.27±0.78

Duration of urinary flow (min)

3-34

7.96±8.81

Length of hospital stay (day)

5-35

10.95 ±10.38

Discussion The key point of the present study was that 10 H20 PEEP was associated with reduced median ICU admission in postoperative period. In this trial, a PEEP of 0 or 10 during donor transplantation did not affect intraoperative bleeding. We have monitored that MAP and CVP levels were significantly different in ventilated 10 H20 PEEP donors. In former trials, PEEP at physiologic values didnot have a practical impact until 10-15 cm H2O; also, it disturbed hepatic function (4). Established affinity of 5 to the physiologic PEEP value, we select 10 cmH2O for the high level of PEEP- at 15 cm H2O- disturbed hepatic missions. Saner et al. (5) showed that dissimilar PEEP values on MAP, and CVP in hepatic transplant patients; CVP levels were showed to be highat a significant levelat PEEP levels of 5 and 10 cm H2O checked with a PEEP of 0 cm H2O. We have showed that there were no differences among patients for HR; however, there were significant differences for CVP, and MAP. In a prior trial of dissimilar PEEP levels in cases with hepatic resection, cardiac flow was showed to be decreased at a significant levelat a PEEP of 10 cm H2O and venous pressures were showed to be high at a significant levelin these locations, checked with a supine location (6). In previous trials by Saner et al. (7) in hepatic transplant patients, they showed differences at a significant levelat a PEEP of 15 cm H2O in CVP. In thepresent trial, we showed that there were no differences at a significant level among MAP (low in group Z). Also, we built our trial in fully healthy patients. Moreover, decreases in MAP are harmonious with former trials. Further, there were minimal differences in blood losswith rises in CVP andPEEP value. This is more prominent in situations in which PEEP level is ≥10 cm H2O. There are a few limitations to thepresent trial. The present trial included a smallsampling. Further trials with a huge size of donors can be built to confirm present outcomes. Finally, the present data showed that different PEEP values might be definitive incases who are probably to demand an extended median ICU admission. Present results might have inclusions for both intraoperative PEEP administration strategies in donor patients. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support. Ethical approval Consent of ethics was approved by the local ethics committee.

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Med Science 2019;8(1):208-10

Muharrem Ucar ORCID: 0000-0002-1232-9829 Mustafa Said Aydogan ORCID: 0000-0002-7106-1156

Hess DR, Thompson BT. Ventilatory strategies in patients with sepsis and respiratory failure. Curr Infect Dis Rep. 2005;7:342.

References

Saner FH, Pavlakovic G, Gu Y, et al. Effects of positive endexpiratory pressure on systemic haemodynamics, with special interest to central venous and common iliac venous pressure in Liver transplanted patients. Eur J Anaesthesiol. 2006;23:766.

Sand L, Rizell M, Houltz E, et al. Effect of patient position and PEEP on hepatic, portal and central venous pressures during liver resection. Acta Anaesthesiol Scand. 2011;55:1106.

Saner FH, Damink SWM, Pavlakovic G, et al. How far can we go with positive end-expiratory pressure (PEEP) in liver transplant patients? J Clin Anesthes. 2010;22:104.

Ayanoglu HO, Ulukaya S, YĂźzer Y, et al. Anesthetic management and complications in living donor hepatectomy. Transplant Proc. 2003;35:2970.

Saner FH, Pavlakovic G, Gu Y, et al. Does PEEP impair the hepatic outflow in patients following liver transplantation? Intensive Care Med. 2006;32:1584.

Saner FH, Damink SWM, Pavlakovic G, et al. Positive endexpiratory pressure induces liver congestion in living donor Liver transplant patients: myth or fact. Transplantation. 2008;85:1863

210

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):211-7

Evaluation of concordance between histopathological prognostic findings from prostate needle biopsy samples and serum prostate-specific antigen levels Cengiz Kocak Usak University Faculty of Medicine, Department of Pathology, Usak, Turkey Received 05 Febuary 2019; Accepted 12 Febuary 2019 Available online 04.03.2019 with doi:10.5455/medscience.2019.08.9016 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Prostate cancer is the most common cancer in men. Although the prostate-specific antigen (PSA) is still used as a diagnostic and screening test, there are some controversies about its performance for the differentiation of high-risk cancer from low-risk cancer at an early stage. The Gleason grading system for the pathological grading of prostatic adenocarcinoma is based on the architectural patterns of prostatic glands and it is one of the major predictors of prostate cancer prognosis and clinical management. This study aimed to investigate the concordance between histopathological prognostic findings from prostate needle biopsy samples and serum PSA levels. This retrospective study included data from 150 patients with histopathologically diagnosed as prostatic adenocarcinoma. All patients underwent multi-core transrectal ultrasound-guided prostate needle biopsy because of elevated PSA. Pathological data were classified as high-grade (≥7, 4+3) and low-grade (≤7, 3+4) based on the Gleason score values. Laboratory data were classified as high-risk (>10 ng/mL) and low-risk (≤10 ng/mL) based on the PSA levels. Ninety three (62%) patients had PSA >10 ng/mL. Seventy patients (46.7%) had Gleason score ≥7 (4+3). Age, tumor volume, PSA levels, and the number of tumor-positive cores were significantly higher in the tumors with Gleason score ≥7 (4+3). Tumor volume, Gleason score, and the number of tumor-positive cores were significantly higher in the tumors with PSA >10 ng/mL. Lymphovascular invasion (LVI) and perineural invasion (PNI) positivity were more often in the high-grade and high-risk tumors. Age, tumor volume, PSA, and the number of tumorpositive cores showed a significant positive correlation with the Gleason score and tumor volume. The cut-off values of PSA (Gleason score ≤7 vs ≥7) was 15.45 ng/mL with AUC=0.882 (95% confidence interval, CI: 0.82 to 0.94), sensitivity was 87% (95% CI: 0.76 to 0.94), specificity was 81% (95% CI: 0.69 to 0.88), and likelihood ratio was 4.4. Keywords: Biopsy, needle, neoplasm grading, pathology, prostatic neoplasms, prostate-specific antigen

Introduction Prostate cancer is the most common cancer in men and the second leading cause of cancer death [1]. With the introduction of prostatespecific antigen (PSA) screening programs, prostate cancer incidence increased in recent years. Age, PSA testing, and family history are the most important risk factors for prostate cancer [2]. PSA is a kallikrein-like serine proteinase and an esterase produced by prostatic ductal and acinar epithelial cells. PSA liquefies semen, enhances sperm motility, and dissolves cervical mucus. In the blood, PSA is present in very low concentrations. Serum PSA level increases in prostate cancer, but many benign conditions, including prostate irritation, prostatic infection, and benign prostatic hyperplasia, also cause the elevation in PSA levels [3,4].

*Coresponding Author: Cengiz Kocak, Usak University Faculty of Medicine, Department of Pathology, Usak, Turkey, E-mail:drcengizkocak@hotmail.com

The Gleason grading system for the pathological grading of prostatic adenocarcinoma is based on the architectural patterns of prostatic glands. It is a measure of the degree of differentiation and tumor aggression in prostate cancer. The Gleason grading system was first described by Donald Gleason in1966. As most of the tumors typically had two histologic patterns, a score was created that added the two most common grade patterns in a tumor, with scores ranging from 2 to 10 [5]. In this system, the degree of glandular differentiation and the growth pattern of a tumor in relation to the stroma are evaluated. It is only based on cancer architecture and not influenced by cellular morphology. In course of time, It has undergone various modifications. Although these modifications, the Gleason grading system is still one of the major predictors of prostate cancer prognosis and clinical management [6,7]. Although the PSA is still used as diagnostic and screening test, there is some controversies about its performance for differentiation of high-risk cancer from low-risk cancer at an early stage. It has 211

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been reported that PSA has not shown the ability to discriminate high-risk cancer from low-risk cancer [8]. Furthermore, although current modifications have improved the Gleason grading system, there are differences in interpretation among pathologists. Many of the cancers differently interpreted by multiple pathologists represent borderline cases between 3+3=6 and 3+4=7 or between 3+4=7 and 4+3=7 [9]. Thus, the present study was conducted in order to investigate the concordance between histopathological prognostic findings from prostate needle biopsy samples and serum PSA levels. Materials and Methods Data collection This retrospective study included data from 150 patients with histopathologically diagnosed as prostatic adenocarcinoma at the Department of Pathology of the Education and Research Hospital between 2011 and 2017. The clinic, histopathologic, and laboratory records of patients, who underwent prostate needle biopsy because of elevated tPSA, were collected. All patients underwent multi (≤12)-core transrectal ultrasound (TRUS)-guided prostate needle biopsy. The following inclusion criteria were applied: 1. increased serum tPSA was incidentally found from physical examinations; 2. all pathological results of biopsy specimens were prostatic adenocarcinoma. Patients with missing serum PSA data and no sufficient medical records were excluded from this study. The study was in accordance with the principles outlined in the Declaration of Helsinki. Ethical approval was received from the local Human Non-invasive Clinical Research Ethics Committee. The informed consent was not requested since the study was retrospective and the data were analyzed anonymously. Study design The histopathological characteristics of prostate biopsy specimens including tumor volume, Gleason score, total number of core biopsies taken, the number of tumor positive cores, the status of lymphovascular invasion (LVI) and perineural invasion (PNI) were obtained from pathological reports, retrospectively. Pathological data were classified as high (≥7, 4+3) and low (≤7, 3+4) grade tumor based on the Gleason score values [5,10]. Pre-biopsy hematological laboratory data including tPSA were collected from routine laboratory test records. Laboratory data were classified as high-risk (≤10 ng/mL) and low-risk (>10 ng/mL) based on the tPSA levels [11]. Statistical analysis Statistical analyses were performed using GraphPad Prism version 6.05 (GraphPad Software, Inc., CA, USA). All data sets were tested for normality using the Kolmogorov-Smirnov test. Normally distributed data were expressed as mean ± standard deviation (SD). Not normally distributed data were expressed as median and interquartile range (IQRs). Parametric or nonparametric statistical tests were used according to the distribution of data. The comparisons of continuous variables between groups were analyzed with Mann Whitney-U or two-tailed unpaired student-t test according to the normality of data. For categorical variables, two-tailed Fisher’s exact test was used. The correlation analyses were performed using the Spearman’s coefficient of rank correlation analysis since data were not normally distributed. In order to detect the sensitivity and specificity of PSA for discriminating of high-grade tumor from the low-grade tumor, the

Med Science 2019;8(1):211-7

area under the ROC curve was analysed and the cut-off value of tPSA was calculated. A P value <0.05 was considered statistically significant. Results Demographic and laboratory parameters of the patients are represented in Table 1. The mean age of the study population was 70.6 ± 8.5. Ninety three (62%) patients had PSA >10 ng/ mL. Seventy patients (46.7%) had Gleason score ≥7 (4+3). Lymphovascular invasion was positive in 47 patients (31.3%) and PNI was positive in 77 patients (51.3%). Table 1. Demographic, histopathological, and laboratory data of patients. Parameters

n = 150

Age (years)

70.6 ± 8.5

Total Gleason score

7.0 (6.0 – 8.0)

Primary and secondary patterns of Gleason score (n) 2+2

2+3

3+2

3+3

3+4

3+5

4+3

4+4

4+5

5+3

5+4

5+5 Tumor volume (%)

1 40 (17 – 75)

Lymphovascular invasion (n) Positive

Negative

103

Perineural invasion (n) Positive Negative

77 73

Total number of core biopsies taken (n)

12 (10 – 12)

The number of tumor positive cores (n)

5 (2 – 9)

Total PSA (ng/mL)

15.5 (8.1 – 46.4)

*Abbrevations: PSA: Prostate-specific antigen. Normally distributed data are presented as mean ± SD, not normally distributed data are presented as median and interquartile ranges (IQRs).

Significant differences were observed between groups categorized as high and low-grade based on the Gleason score values for age, tumor volume, tPSA, the number of tumor positive cores, LVI, and PNI (P=0.0002, P<0.0001, P<0.0001, P<0.0001, P<0.0001, P < 0.0001, respectively) (Table 2). The results of the study revealed that age, tumor volume, the number of tumor positive cores, and tPSA values were significantly higher in the tumors with Gleason score ≥7 (4+3) compared to the tumors with Gleason score ≤7 (3+4). LVI and PNI positivity were more often in the high-grade tumors (Figure 1). 212

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Figure 1. The distribution of the status of LVI and PNI in low-grade and high-grade tumors Table 2. The comparisons of prognostic variables between low-grade (Gleason Skor ≤7, 3+4) and high-grade (Gleason Skor ≥7, 4+3) tumor groups Gleason Skor ≤ 7 (3+4) (n=80) Age (years)

Gleason Skor ≥ 7 (4+3) (n=70)

68 (62-74)

75 (67-81)

0.0002*

Tumor volume (%)

17 (9.5 - 30)

75 (48.8 - 90)

< 0.0001*

Total PSA (ng/mL)

9.4 (6.9 - 14.4)

47.5 (19.4 - 100)

< 0.0001*

3 (2 – 5)

8 (6 – 10)

< 0.0001*

The number of tumor positive cores (n) Lymphovascular invasion (n)

< 0.0001*

Positive

Negative

Perineural invasion (n)

< 0.0001*

Positive

Negative

*Abbrevations: PSA: Prostate-specific antigen. Normally distributed data are presented as mean ± SD, not normally distributed data are presented as median and interquartile ranges (IQRs). Normally distributed data were tested using the two-tailed Student-t test. Not normally distributed data were tested using the Mann–Whitney U-test. A P-value < 0.05 was considered statistically significant.

Significant differences were found for tumor volume, Gleason score, the number of tumor positive cores, LVI, and PNI between groups categorized as high and low risk based on tPSA levels (P <0.0001, P <0.0001, P <0.0001, P=0.046, P <0.0001, respectively) (Table 3). As illustrated in Figure 2, LVI and PNI positivity were significantly higher in the tumors with tPSA >10 ng/mL. The data were analyzed using Spearman’s coefficient of rank correlation to evaluate the possible association of prognostic variables with Gleason score and tumor volume in 150 patients

(Table 4). Age, tumor volume, tPSA, and the number of tumor positive cores showed significant positive correlation with the Gleason score (r=0.336, P <0.0001; r=0.787, P <0.0001; r=0.667, P <0.0001; r=0.716, P <0.0001, respectively). Correlations between tumor volume, age, tPSA, and the number of tumor positive cores were also analyzed (Table 4). Age, tPSA, and the number of tumor positive cores showed significant positive correlation with the tumor volume (r=0.254, P=0.0017; r=0.736, P <0.0001; r=0.786, P <0.0001, respectively).

Figure 2. The distribution of the status of LVI and PNI in low-risk and high-risk

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Table 3. The comparisons of prognostic variables between low-risk (tPSA ≤10.0 ng/mL) and high-risk (tPSA >10.0 ng/mL) tumor groups tPSA ≤ 10.0 ng/mL (n=57)

tPSA > 10.0 ng/mL (n=93)

Age (years)

70 (62-74)

71 (65-79)

0.154

Tumor volume (%)

15 (8 - 25)

60 (25 – 81.5)

< 0.0001*

Gleason Score

6 (6 - 6)

7 (6 - 8)

< 0.0001*

The number of tumor positive cores (n)

3 (1 – 4)

6 (3 – 9)

< 0.0001*

Lymphovascular invasion (n)

0.046*

Positive

Negative

Perineural invasion (n)

< 0.0001*

Positive

Negative

Table 4. The associations of prognostic variables with Gleason score and tumor volume n = 150

Gleason Score r

Age (years)

0.336

< 0.0001*

Tumor volume (%)

0.787

< 0.0001*

tPSA (ng/mL)

0.667

< 0.0001*

The number of tumor positive cores (n)

0.716

< 0.0001*

n = 150

Tumor Volume r

Age (years)

0.254

0.0017*

Gleason Score

0.787

< 0.0001*

tPSA (ng/mL)

0.736

< 0.0001*

The number of tumor positive cores (n)

0.786

< 0.0001*

*Abbrevations: PSA: Prostate-specific antigen. Data were tested using the Spearman’s coefficient of rank correlation analysis since data were not normally distributed.. A P value less than 0.05 was considered statistically significant.

Diagnostic value and clinical usefulness of tPSA for discrimination of a high-grade tumor (GS ≥7, 4+3) from the low-grade tumor (GS ≤7, 3+4) were evaluated by analysing area under the ROC curve. The cut-off values of tPSA was 15.45 ng/mL with AUC=0.882 (95% confidence interval, CI: 0.82 to 0.94; standard error, SE: 0.03, P <0.0001), sensitivity was 87% (95% CI: 0.76 to 0.94), specificity was 81% (95% CI: 0.69 to 0.88), and likelihood ratio was 4.4 (Figure 3).

Figure 3. The area under the ROC curve analysis of PSA as diagnostic test for discriminating of high-grade tumor from the low-grade tumor (Gleason score ≤7 vs ≥7)

Discussion Current screening and diagnostic procedures in prostate cancer recommended by European Association of Urology (EAU) - European Society for Radiotherapy & Oncology (ESTRO) International Society of Geriatric Oncology (SIOG) Guidelines are based on PSA measurements and digital rectal examination (DRE) or TRUS. For pathological analysis, the Gleason score is recommended to evaluate tumor grade [12]. The Gleason score and other clinical variables are commonly used to create risk stratification for patient management. The most common risk stratification procedures for prostate cancer is the National Comprehensive Cancer Network (NCCN) and D’Amico classification system. It classifies prostate cancer as low risk (Gleason score: 2–6, PSA ≤10), intermediate risk (Gleason score: 7, PSA >10–20), and high risk (Gleason score: 8–10, PSA >20) 214

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according to the serum PSA level and the Gleason score both 3 + 4 = 7 and 4 + 3 = 7 is considered the same within the intermediate risk group [13,14]. There is considerable disagreement in the literature regarding Gleason score grouping. Some studies have reported that Gleason 7 tumors should be further subdivided, with most of them suggesting a categorization into Gleason 3+4 and Gleason 4+3 tumors depending on the predominant Gleason pattern seen in cancer [15-17]. Despite the confirmed prognostic value of Gleason score in prostate cancer, Gleason score 7 tumors exhibit a heterogeneous clinical outcome. Several studies have shown that Gleason score 4 + 3=7 demonstrates worse pathological stage and biochemical recurrence rates than 3 + 4=7. This could be explained by the presence of both moderately (Gleason pattern 3) and moderately to poorly (Gleason pattern 4) differentiated elements with various proportions in GS 7 tumors. [15,18,19]. In this study, prostatic adenocarcinomas with Gleason 7 score were grouped as 3+4 and 4+3 based on the modified International Society of Urological Pathology (ISUP) 2014 Gleason grading system [10]. The high sensitivity and low specificity of PSA testing in the diagnosis of prostate cancer is a problem in clinical practice. Despite this disadvantage, PSA is still a clinically useful tumor marker for the early detection of prostate cancer. In general, an increased PSA may indicate the presence of prostate carcinoma and higher PSA levels may reflect the greater risk of prostate cancer. However, data from several studies have shown that this relationship is not valid as previously thought [2,20,21]. Thus, diagnostic performance and clinical usefulness of tPSA for distinction of a high-grade tumor from the low-grade tumor were investigated in this study. In addition, it was examined whether an agreement between serum tPSA levels and histopathological prognostic parameters. Several factors were assessed for potential association with prostatic adenocarcinoma in the present study. It was observed that advanced age and increased tPSA levels had a significant association with prostatic adenocarcinoma. Age and tPSA levels showed a significant positive correlation with the Gleason score. When data were grouped as high and low-grade tumor based on the Gleason score values, tPSA levels were significantly higher in the tumor with the Gleason score ≥7. Furthermore, when data were classified as low and high risk based on tPSA levels, the Gleason scores were higher in the group with tPSA >10 ng/mL. These findings are consistent with several studies in the literature [22-25]. Bright and colleagues reported that advanced age and elevated serum PSA levels were found to be predictive of incidentally diagnosed prostatic carcinoma [22]. Gunda et al. found that incidental prostatic carcinoma was independently associated with age of 70– 80 years and PSA levels >10ng/mL [23]. In another study, PSA level and Gleason score contributed significantly to the prediction of pathological stage [24]. Guimaraes and colleagues also found a positive correlation between high-grade Gleason score and higher preoperative PSA [25]. On the other hand, contrary results were obtained by Antunes et al. In their study, while advanced age was significantly associated with the finding of prostatic carcinoma, the PSA levels did not have any significant association with incidental prostatic carcinoma [26]. Pai et al. found no significant correlation between tumor grade by Gleason score and pre-operative levels of PSA [27]. In another study, PSA and age were not found to

Med Science 2019;8(1):211-7

significantly correlate with the Gleason score [28]. In this study, increased tPSA levels were also significantly associated with tumor volume. Tumor volume values were higher in the group with tPSA levels >10 ng/mL. At the same time, tumor volume values were positively correlated with Gleason score values. Consistent with the findings of this study, Kato et al. found positive correlations between the serum PSA levels and the tumor volume [29]. In a study by Carvalhal et al, it has been found that PSA had a significant correlation with prostate size only at a prostate weight ≥ 54.6 gm (P=0.01). Regardless of prostate size, PSA had a more strong correlation with tumor volume than with prostate size (P<0.0001). Authors suggested that PSA was significantly correlated with prostate size only in the largest prostate glands, but was significantly associated with tumor volume in small, medium, or large prostates. Thus, PSA continues to be a better marker for tumor volume than for prostate size [30]. Although higher grade and larger volume tumors produce less PSA per cell as compared to lower grade tumors, poorly differentiated tumors are associated with higher PSA levels as these tumors tend to be larger and of more advanced stage [31]. In contrast to findings of the present study, Stamey and colleagues reported a decrease in the association of PSA with tumor volume. In a series of 1300 radical prostatectomies performed from 1993 to 2003, Stamey et al. divided the cases into four 5-year time intervals. The association between PSA and tumor volume decreased over time. The authors suggested that the loss of correlation with tumor volume may compromise the current usefulness of PSA for early prostate cancer detection [32]. It was found that LVI and PNI were prognostic factors in prostatic adenocarcinoma in this study. Lymphovascular invasion and PNI positivity were more often in high grade and high-risk groups. This is similar to the findings of Miyake et al. Their study included 959 patients diagnosed as GS 7 prostate cancer. They grouped patients as Gleason score 3+4 and 4+3. They found significant differences in the PSA level, LVI, and PNI between these 2 groups [33]. Cheng et al. found a significant association between LVI and higher serum PSA, advanced pathological stage, higher Gleason score, and PNI [34]. Liu et al. reported that LVI and PNI indicated a worse prognosis in patients with prostate cancer [35]. Jiang et al. observed that LVI was correlated with Gleason score, higher pathological stage, positive surgical margin, and seminal vesicle invasion. Authors suggested that LVI in histopathology is associated with advanced clinicopathological features in prostate cancer patients and could serve as a poor prognostic factor in patients who underwent radical prostatectomy [36]. In a study by Kang et al., it has been found that patients with PNI or LVI had higher rates of advanced biopsy and pathological Gleason score (≥7), and higher proportions of advanced clinical and pathological T stage ≥3. Researchers suggested that PNI and LVI are adverse pathologic parameters and independent predictors for prostate cancer, and the concurrent presence of PNI and LVI resulted in poorer outcomes in prostate cancer patients who underwent radical prostatectomy [37]. Early reports by Partin et al. and D’Amico et al. defined important PSA cut-off points of <10, 10.1–20, and >20 ng/mL that are still used to define prostate cancer risk stratification groups [13,14,24]. In a study by Catalona et al., cancer was found in 26% of the men 215

doi: 10.5455/medscience.2019.08.9016

with a PSA level of 4.0 to 10.0 ng/mL. 72% of these tumors were confined to the prostate. Cancer was found in 66% of patients with a serum level >10.0 ng/mL. While 77% of these cancers were clinically localized, only 33% of the patients had a prostateconfined cancer. Thus, PSA levels of 4 to 10 ng/mL will detect cancer pathologically confined to the prostate, but if the level is >10 ng/mL, patients will have locally advanced cancer according to the findings of the study by Catalona et al [38]. In the present study, ROC curve was analysed and the cut-off value of tPSA was calculated to detect the sensitivity, specificity, and diagnostic performance of PSA for distinction of a high grade (Gleason score ≥7, 4+3) tumor from the low grade (Gleason score ≤7, 3+4) tumor. It was found that the cut-off values of tPSA was 15.45 ng/mL with AUC = 0.882 (95% CI: 0.82 to 0.94), sensitivity was 87% (95% CI: 0.76 to 0.94), specificity was 81% (95% CI: 0.69 to 0.88), and likelihood ratio was 4.4. According to these findings, tPSA values higher than 15.45 ng/mL indicated poorly differentiated and high graded tumors. Lojanapiwat et al. found similar results with the present study. They studied the correlation and diagnostic performance of the PSA level with cancer diagnosis and aggressiveness of prostate cancer (Gleason score >7) in 1.116 patients who underwent TRUS and prostate biopsy. A positive biopsy result was found in 395 patients and these patients were grouped based on baseline PSA level. A significant correlation was found between the PSA level and tumor diagnosis and tumor aggressiveness. AUC was 0.82 for the diagnosis of prostate cancer and 0.78 for Gleason score >7. The sensitivity and specificity of PSA level of 4.1–10, 10.1–20, 21.1–50, 50.1–100, and >100 ng/mL in the diagnosis prostate cancer was 98.0% and 9.3%, 81.5% and 55.5%, 65.8% and 87.5%, 47.8% and 98.2%, 34.4% and 99.7%, respectively. Lower sensitivity was found at higher PSA levels, whereas the specificity was elevated when the PSA level was higher. The sensitivity and specificity of PSA level of 4.1–10, 10.1–20, 21.1–50, 50.1–100, and >100 ng/ for tumor aggressiveness (tumor with Gleason score >7) was 97.8% and 1.99%, 91.6% and 36.4%, 83.2% and 62.8%, 66.5% and 79.3%, 52% and 87.8%, respectively. Authors suggested that the chance of prostate cancer diagnosis was more than that of benign prostatic hyperplasia and the chance of detection of prostate cancer was about 50% when the biopsy was performed when the PSA level was higher than 20 ng/mL [39]. Conclusion The correct diagnosis and grading of prostate cancer are very important for a patient’s prognosis, clinical management, and therapeutic options. The findings of this study reveal that there is a well correlation between serum PSA levels and Gleason score, tumor volume, the number of tumor positive cores, LVI, and PNI. Tumors with high-grade Gleason score show an associaton with more increased PSA level, more extensive tumor volume, more often LVI, PNI positivity, and advanced age. As mentioned above, although PSA has relatively a low specificity, with high sensitivity, it can be used in urologic practice for discrimination of a lowgrade tumor from the high-grade tumor. Consequently, both PSA and Gleason grading system is a clinically useful diagnostic and prognostic tool for the management of prostate cancer. Financial Disclosure All authors declare no financial support.

Med Science 2019;8(1):211-7

Ethical approval Ethical approval was received from the local Human Non-invasive Clinical Research Ethics Committee.

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Arneth BM. Clinical significance of measuring prostate-specific antigen. Lab Med. 2009;40:487–91.

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10. Epstein JI, Amin MB, Reuter VE, et al. Contemporary Gleason grading of prostatic carcinoma: An update with discussion on practical issues to implement the 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma. Am J Surg Pathol. 2017;41:1-7. 11. Rodrigues G, Warde P, Pickles T, et al. Pre-treatment risk stratification of prostate cancer patients: A critical review. Can Urol Assoc J. 2012;6:121-7. 12. Mottet N, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG Guidelines on prostate cancer. Part 1: Screening, diagnosis, and local treatment with curative intent. Eur Urol. 2017;71:618-29. 13. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969-74. 14. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy or external beam radiation therapy for patients with clinically localized prostate carcinoma in the prostate specific antigen era. Cancer. 2002;95:281-6. 15. Chan TY, Partin AW, Walsh PC, et al. Prognostic signiﬁcance of Gleason score 3+4 versus Gleason score 4+3 tumor at radical prostatectomy. Urology. 2000;56:823–7. 16. Koontz BF, Tsivian M, Mouraviev V, et al. Impact of primary Gleason grade on risk stratiﬁcation for Gleason score 7 prostate cancers. Int J Radiat Oncol Biol Phys. 2012;82:200–3. 17. Makarov DV, Sanderson H, Partin AW, et al. Gleason score 7 prostate cancer on needle biopsy: is the prognostic difference in Gleason scores 4+3 and 3+4 independent of the number of involved cores? J Urol. 2002;167:2440–2. 18. Burdick MJ, Reddy CA, Ulchaker J, et al. Comparison of biochemical

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relapse-free survival between primary Gleason score 3 and primary Gleason score 4 for biopsy Gleason score 7 prostate cancer. Int J Radiat Oncol Biol Phys. 2009;73:1439â&#x20AC;&#x201C;45.

29. Kato RB, Srougi V, Salvadori FA, et al. Pretreatment tumor volume estimation based on total serum psa in patients with localized prostate cancer. Clinics (Sao Paulo). 2008;63:759-62.

19. Kang DE, Fitzsimons NJ, Presti JC, Jr, et al. Risk stratification of men with Gleason score 7 to 10 tumors by primary and secondary Gleason score: results from the SEARCH database. Urology. 2007;70:277â&#x20AC;&#x201C;82.

30. Carvalhal GF, Daudi SN, Kan D, et al. Correlation between serum prostatespecific antigen and cancer volume in prostate glands of different sizes. Urology. 2010;76:1072-6.

20. Vickers AJ, Sjoberg DD, Ankerst DP, et al. The Prostate Cancer Prevention Trial risk calculator and the relationship between prostate-specific antigen and biopsy outcome. Cancer. 2013;119:3007-11.

31. Partin AW, Carter HB, Chan DW, et al. Prostate specific antigen in the staging of localized prostate cancer: influence of tumor differentiation, tumor volume and benign hyperplasia. J Urol. 1990;143:747-52.

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32. Stamey TA, Caldwell M, McNeal JE, et al. The prostate specific antigen era in the United States is over for prostate cancer: what happened in the last 20 years? J Urol. 2004;172:1297-301.

22. Bright EA, Manuel C, Goddard JC, et al. Incidence and factors predicting the detection of prostate cancer after transurethral resection of the prostate for clinically benign disease. Urol Int. 2009;83:171-4.

33. Miyake H, Muramaki M, Furukawa J, et al. Prognostic significance of primary Gleason pattern in Japanese men with Gleason score 7 prostate cancer treated with radical prostatectomy. Urol Oncol. 2013;31:1511-6.

23. Gunda D, Kido I, Kilonzo S, et al. Prevalence and associated factors of incidentally diagnosed prostatic carcinoma among patients who had transurethral prostatectomy in Tanzania: A retrospective study. Ethiop J Health Sci. 2018;28:11-8.

34. Cheng L, Jones TD, Lin H, et al. Lymphovascular invasion is an independent prognostic factor in prostatic adenocarcinoma. J Urol. 2005;174:2181-5.

24. Partin AW, Kattan MW, Subong EN, et al. Combination of prostatespecific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA. 1997;277:1445-51. 25. Guimaraes MS, Quintal MM, Meirelles LR, et al. Gleason score as predictor of clinicopathologic findings and biochemical (PSA) progression following radical prostatectomy. Int Braz J Urol. 2008;34:23-9. 26. Antunes AA, Freire Gde C, Aiello Filho D, et al. Analysis of the risk factors for incidental carcinoma of the prostate in patients with benign prostatic hyperplasia. Clinics (Sao Paulo). 2006;61:545-50. 27. Pai K, Salgaonkar GA, Kudva R, et al. Diagnostic correlation between serum PSA, Gleason score and bone scan results in prostatic cancer patients with bone metastasis. British Biomedical Bulletin. 2015;3:1-7. 28. Nnabugwu II, Udeh EI, Ugwumba FO, et al. Predicting Gleason score using the initial serum total prostate-specific antigen in Black men with symptomatic prostate adenocarcinoma in Nigeria. Clin Interv Aging. 2016;11:961-6.

35. Liu H, Zhou H, Yan L, et al. Prognostic significance of six clinicopathological features for biochemical recurrence after radical prostatectomy: a systematic review and meta-analysis. Oncotarget. 2017;9:32238-32249. 36. Jiang W, Zhang L, Wu B, et al. The impact of lymphovascular invasion in patients with prostate cancer following radical prostatectomy and its association with their clinicopathological features: An updated PRISMAcompliant systematic review and meta-analysis. Medicine (Baltimore). 2018;97(49):e13537. 37. Kang M, Oh JJ, Lee S, et al. Perineural invasion and lymphovascular invasion are associated with increased risk of biochemical recurrence in patients undergoing radical prostatectomy. Ann Surg Oncol. 2016;23:2699-706. 38. Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med. 1991;324:1156-61. 39. Lojanapiwat B, Anutrakulchai W, Chongruksut W, et al. Correlation and diagnostic performance of the prostate-specific antigen level with the diagnosis, aggressiveness, and bone metastasis of prostate cancer in clinical practice. Prostate Int. 2014;2:133-9.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):218-20

Comparison of alternative nutrition practices in intensive care patients in terms of mortality and malnutrition Yahya Atayan1, Aysegul Ertinmaz Ozkan2, Gokhan Aksakal2, Ali Ramazan Benli2, Nurhayat Ozkan Sevencan2, Mehmet Ali Erdogan1 1 Malatya Education and Researche Hospital, Malatya, Turkey Karabuk University Education and Researches Hospital, Karabuk, Turkey 3 Inonu University Medical Faculty, Department of Gastroenterology, Manisa, Turkey 2

Received 03 January 2019; Accepted 28 January 2019 Available online 06.03.2019 with doi:10.5455/medscience.2019.08.9019 Copyright ÂŠ 2019 by authors and Medicine Science Publishing Inc. Abstract It is important to ensure proper nutrition to prevent malnutrition, mortality and the development of metabolic disorders in followed up patients in the intensive care unit. In case the patients gastrointestinal tract starts functioning, enteral feeding should be started in the early period. Patients should be given parenteral support when the gastrointestinal tract does not work. In this study, we compared the mortality, malnutrition and metabolic parameters of patients who received nutritional support via nasogastric catheter, percutaneous endoscopic gastrostomy and total parenteral nutrition. We retrospectively analyzed 117 patientsâ&#x20AC;&#x2122; data with no oral intake in the intensive care unit. Patients were divided into 3 groups according to nutritional practices. Group 1included 62 patients with PEG, group 2 included 28 patients with NG and group 3 had 27 patients with TPN support. In the comparison of mortality between groups, there was a significant decrease in PEG fed patients (p <0.001). There was also a significant decrease in mortality of NG group when compared to TPN group (p<0.01, Table2). In malnutrition comparison, serum albumin levels were significantly higher in PEG fed patients than in other groups (Table 3, p <0.03). There were significant improvements in metabolic parameters in the PEG group patients. We suggest that nutritional support should be provided to serious patients in intensive care unit as soon as possible in order to reduce morbidity, mortality and malnutrition, and we think that PEG procedure is safer and more effective nutritional practice than other procedures. Keywords: Nasogastric catheter, percutaneous endoscopic gastrostomy and total parenteral nutrition

Introduction It is important to ensure proper nutrition to prevent malnutrition, mortality and the development of metabolic disorders in followed up patients in intensive care. Enteral feeding should be started in an early period in the patients in order to protect the gastrointestinal tract, and the nasogastric catheter (NG) is one of the first procedures to be selected. However, it has some side effects such as acute sinusitis, pharyngeal irritation and aspiration risk [1]. One of the easiest ways of feeding patients, who are not fed orally, enterally is to feed them through percutaneous endoscopic gastrostomy (PEG) [2]. PEG has two main indications; one is to provide enteral feeding and the other is gastrointestinal decompression [3]. In cases where nutritional support is not possible for nonfunctional gastrointestinal tract or when enteral feeding can not *Coresponding Author: Yahya Atayan, Malatya Education and Researche Hospital, Malatya, Turkey E-mail: yahyaatayan@hotmail.com

be administered, the total parenteral nutrition (TPN) option for parenteral nutrition should be considered. In this study, we compared the mortality, malnutrition and metabolic parameters of the patients who were fed with NG, PEG and TPN procedures in the early period. Material and Methods Between January 2015 and January 2018, data of 117 patients who received nutritional support in a short period of time during their hospitalization due to lack of oral nutrition in intensive care units, were retrospectively evaluated. The patients were divided into 3 groups according to their nutritional practices. Within the first 10 days in intensive care unit, study groups were formed which included 62 patients with PEG as group 1, 28 patients with NG as group 2 and 27 patients with TPN support as group 3. Calorie needs of patients were calculated (average 2000-2700 kilocalories / day) for nutritional purposes according to their weight, and nutritional support was provided. In order to examine mortality rates, malnutrition and metabolic status, serum albumin, urea, 218

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creatinine, hemoglobin, AST, ALT, hospitalization periods and hospitalization costs of the groups, were compared. Results Of the 117 patients included in the study, 54 (46.2%) were male and 63 (53.8%) were female. No significant difference between patient groups was found in terms of age and gender (Table 1). In the first 3 months, 13 (11.1%) of the patients fed with PEG were dead and 49 (41.9%) patients were discharged. 18 patients (12.2%) fed with TPN died in the first 3 months. 5 (4.2%) patients were dministered PEG before discharge and 3 had oral feeding. 15 (12.8%) of NG fed patients were dead in first 3 months and 10 patients (8.5%) were administered PEG and 2 (1.7%) patients were orally fed before being discharged. When the groups were compared in terms of mortality, there was a significant decrease in PEG fed patients (p<0.001), and also there was a significant decrease in NG fed patients among NG and TPN groups (p <0.01, Table2). Serum albumin levels were significantly higher in patients fed with PEG compared to NG and TPN groups when investigated in terms of malnutrition (Table 3, p <0.03). The discharge rates were significantly higher in patients with PEG. When compared with respect to metabolic parameters of patients, urea, creatine, hemoglobin, AST, ALT values were found to be significantly

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improved in PEG group (Table 3). Even though the hospitalization duration was longer in PEG patients, there was no significant difference in cost of hospitalization of PEG patients with other groups (Table 3). Table 1. Groups and patient distribution Groups

Age Median (min-max)

Male n (%)

Female n (%)

Total n (%)

PEG

78 (20-96)

32 (27.3)

30 (25.6)

62 (53)

TPN

77 (53-94)

13 (11.1)

15 (12.8)

28 (24)

76 (51-93)

9 (7.7)

18 (15.3)

27(23)

54 (46.1)

63 (53.9)

117 (100)

Total

Results are expressed as number of patients and percent Table 2. Mortality comparison of groups Patients groups

Deatn(%)

Discharged n(%)

Total n(%)

P value

PEG

13 (20.9)

49 (79.1)

62 (100)

<0.001*

15 (55.5)

12 (44.5)

27 (100)

<0.01**

TPN

18 (64.2)

10 (35.8)

28 (100)

Results are expressed as number of patients and percent *P < 0.05 versus group PEG,TPN and NG; **P < 0.05 versus group NG and TPN

Table 3. Comparison of groups in terms of malnutrition and metabolic parameters Variables

Age Median (min-max)

TPN Median (min-max)

NG Median (min-max)

P value<

Albumin(gr/Dl)

2.9 (1.7-4.2)

2.3 (2-3.1)

2.5 (2.2-3.7)

0.03

AST(U/L)

25 (10-1314)

37.5 (11-799)

32 (13-139)

0.04

ALT(U/L)

19 (5-716)

21.5 (4-681)

22 (6-82)

0.5

Urea (mg/dL)

57 (13-307)

135 (37-337)

98 (17-281)

0.001*

Creatine(mg/dL)

0.6 (0.2-4)

2 (0.2-6.9)

1.5 (0.1-3.7)

0.001*

Hgb (gr/dL) Wbc (1000/uL) Cost (TL) Hospitalization Period (day)

11 (7.4-14)

9.5 (7.2-12.8)

10.3 (8.2-13.9)

0.03*

10.8 (4.65-42.3)

14.4 (2.4-38.4)

11.7 (1.8-36.7)

0.2

16.577 (2659-211494)

15.615 (439-89009)

11.771 (439-211494)

0.9

25 (4-160)

20 (4-63)

16 (4-74)

0.3

Mean, minimum and maximum results of metabolic parameters were given *P <0. 05 versus group PEG, TPN and NG;

Discussion One of the most important points of intensive care treatment protocols is the provision of nutritional support and prevention of malnutrition and infection. In studies conducted in developed countries, malnutrition was found to be 50% in the patients who were hospitalized and then treated [4]. If the gastrointestinal tract is working in critical cases, nutrition should be given primarily by using enteral administration (5]. If oral intake is not possible, nutrition should be given by means of gastrostomy or jejunostomy tubes placed using nasogastric catheter endoscopic or surgical techniques [6]. PEG is an acceptable method in terms of comfort which can be applied at patientâ&#x20AC;&#x2122;s bedside and does not require general anesthesia in patients requiring long-term enteral nutrition who cannot take food orally. Because of the low risk of aspiration,

the PEG is accepted to be superior to other enteral feeding pathways [7]. It was introduced in 1980 by Gauderer and in 1981 by Ponsky [8,9]. PEG can be performed by different methods. The Pull-PEG method has been widely used in recent years and is the most preferred method [10]. PEG should be administered in patients who have; no swallowing reflexes, inadequate swallowing, no NG tube tolerance, cases planned for more than 4 weeks of feeding, neurological diseases, tumoral diseases located in the head and neck region, pharyngeal-esophageal obstructions, head-neck trauma and severe debilities [11]. The definite contraindications for PEG are patients with gastric resection, severe ascites, hepatomegaly, obesity and coagulation disorders [12]. Patients with an obstacle to enteral feeding should be given parenteral nutrition. Although the patientâ&#x20AC;&#x2122;s clinical outcome is 219

doi: 10.5455/medscience.2019.08.9019

positively affected when used appropriately, improper use results in increased infectious complications, metabolic abnormalities and increased medical costs. In the absence of contraindication, PEG has been reported to be the exclusive method for nutritional support in trauma patients. Although PEG is a minimally invasive method, it has a complication rate of 8% [13]. In the study of Mc Carter TL et al., it was found that administering PEG in patients reduced both time and cost of hospitalization [14]. In our study, the duration of hospitalization of patients who underwent PEG procedure was not shorter than other procedures, but there wasn’t any additional costs compared to other procedures (Table 3). In a large series of studies by Stockeld D et al. (229 cases), mortality and morbidity were examined, and the success of PEG was found to be 97.0% [15]. In a study conducted by Gençosmanoğlu et al., 30-day mortality was reported as 8.0% and an overall mortality rate was reported as 32.0% [16]. Erdil A et al., reported 30-day mortality as 26.8% and late mortality as 15.7% [17]. In our study, the mortality rate between PEG, NG and TPN patient groups was 20.9%, 55.5% and 64.2% respectively. There was a significant difference between the PEG group and the other groups in terms of mortality (Table 2, p <0.001). In the study of Hamidon BB et al., the safety, efficacy, nutritional status and treatment adequacy of PEG and NG procedures were compared, and nutrition with PEG was found to be more effective than NG in the treatment of dysphagia in stroke patients [18]. Similarly, in our study, the risk of malnutrition was found to be significantly lower in the PEG group. The number of patients who were discharged from intensive care unit was found to be significantly higher in the PEG group (P <0.001, table 2). There was no significant difference in terms of discharge and malnutrition between the TPN and NG groups (Table 3). As a result, PEG is a safe and effective process in patients with planned nutritional support because it does not require general anesthesia, can be applied at the bedside if necessary, has low morbidity, mortality and malnutrition risk. Therefore, in the treatment of critically ill patients, PEG-mediated feeding can reduce the mortality, malnutrition and metabolic disorders. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support. Ethical approval Ethics committee approval was not taken due to retrospective study. Yahya Atayan ORCID:0000-0003-2076-1934 Aysegul Ertinmaz Ozkan ORCID 0000-0002-3273-1305 Gokhan Aksakal ORCID:0000-0002-8787-7790 Ali Ramazan Benli ORCID:0000-0003-0039-1497 Nurhayat Ozkan Sevencan ORCID 0000-0001-9013-3517 Mehmet Ali Erdogan ORCID:0000-0002-1713-5695

References 1.

Beaver ME, Myers JN, Griffenberg L. et al. Percutaneous fluoroscopic gastrostomy tube placement in patients with head and neck cancer. Arch

Med Science 2019;8(1):218-20

Otolaryngol Head Neck Surg. 1998;124:1141-4. 2.

Gauderer M. Twentyyears of percutaneous endoscopic gastrostomy: origin and evolution of a concept and its expanded applications. Gastrointest Endosc. 1999;50:879-83.

Schrag SP, Sharma R, Jaik NP, et al. Complications related to percutaneous endoskopic gastrostomy (PEG) tubes. A comprehensive clinical review. J Gastrointestin Liver Dis. 2007;16:407-18.

Martínez Olmos MA, Martínez Vázquez MJ, Martínez-PugaLópez E, et al. Nutritional status study of inpatients in hospitals of Galicia. Eur J Clin Nutr. 2005 59:938-46.

Kudsk KA, Croce MA, Fabian TC, et al. Enteral versus parenteral feeding: Effects on septic morbidity after blunt and penetrating abdominal trauma. Ann Surg. 1992;215:503-11.

McClave SA, Lukan JK, Slefater JA. Poorvalidity of residual volumes as a marker for risk of aspiration in critically ill patients. Crit Care Med. 2005;33:324-30.

Norton B, HomerWard M, Donelly MT, et al. A randomized comparison of percutaneous gastrostomy and nasogastric feding after acute dysphagic stroke. BMJ. 1996;312:13-6.

Gauderer MW, Ponsky JL, Izant RJ Jr. Gastrostomy without laparotomy: a percutaneous endoscopic technique. J Pediatr Surg. 1980;15:872-5.

Ponsky JL, Gauderer MW. Percutaneous endoscopic gastrostomy: a non-operative technique for feding gastrostomy, Gastrointest Endosc.1981;27:9-11.

10. Hiki N, Maetani I, Suzuki Y, et al. Reduced risk of periostomal infection of direct percutaneous endoscopic gastrostomy in cancer patients: comparison with the pull percutaneous endoscopic gastrostomy procedure. J Am Coll Surg. 2008;4:737-44. 11. Nicholson FB, Korman MG, Richardson MA. Percutaneous endoscopic gastrostomy: A review of indications, complications and outcome. J Gastroenterol Hepatol. 2000;15:21-5. 12. Chaer RA, RekkasD, Trevino J, et al. Intrahepatic placement of a PEG tube. Gastrointest Endosc. 2003;57:763-5. 13. Gauderer MW. Percutaneous endoscopic gastrostomy: a 10-year experience with 220 children. J Pediatr Surg. 1991;26:288-94. 14. Mc Carter TL, Condon SC, Aguilar RC, et al. Randomized prospective trial of early versus delayed feding after percutaneous gastrostomy placement. Am J Gastroenterol. 1999;94:1107-8. 15. Stockeld D, Faberberg J, Granstrom L. et al.Percutaneous endoscopic gastrostomy for nutrition in patients with oesophageal cancer. Eur J Surg. 2001;167:839-44. 16. Şit M, Kahramansoy N, Tekelioğlu ÜY, Perkütan Endoskopik Gastrostomi Uygulamalarındaki Deneyimlerimiz. J Academic Res Med. 2013:3. 17. Erdil A, Saka M, Ateş Y. ve ark. Enteral nutrition via percutaneous endoscopic gastrostomy and nutritional status of patients: five-year prospective study. Gastroenterol Hepatol. 2005;20:1002–7. 18. Hamidon BB, Abdullah SA, Zawawi MF. et al. A prospective comparison of percutaneous endoscopic gastrostomy and nasogastric tube feeding in patients with acute dysphagic stroke. Med J Malaysia. 2006;61:59–66.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):221-4

Evaluation of the association between gross motor function classification system levels and implementation of home programs in children with cerebral palsy Filiz Ciledag Ozdemir Inonu University Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation, Malatya, Turkey Received 18 December 2018; Accepted 27 December 2018 Available online 08.02.2019 with doi:10.5455/medscience.2018.07.8978 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The aim of this study is to evaluate the association between gross motor function classification system levels and implementation of home programs in children with cerebral palsy. Material-Method: This study is a cross-sectional study. The study group consists of 247 cerebral palsy patients who referred to rehabilitation centers and who agreed to participate in the study and their relatives. Gross Motor Function Classification System was used to find out the severity of cerebral palsy. The state of implementing home program was questioned through the parents of the children within the rehabilitation program. 51.6% of the children in the study were male, while 48.4% were female. Average age of the participants was 9.5±0.5 years (min.:0, max.:21). When the reasons for cerebral palsy were examined, 17.5% were found to be prenatal, 54.2% were found to be natal and 27.3% were found to be postnatal. Distribution of the children in terms of Gross Motor Function Classification System levels was found as 4.9% in level 1, as 21.9% in level 2, 34.4% in level 3, 25.1% in level 4, and 13.8% in level 5. Average age of the participant parents was found as 36.4±12.4 years (min.:18, max.:73). 93.8% of the parents were mothers, while 6.2% were fathers. Home program given by physiotherapist was applied to only 35.6% of the children by the parent. In this study, statistically significant difference was found between Gross Motor Function Classification System levels and application of home programs (p<0.05). We believe that families need to be informed about the efficiency of home programs. Families should be stated that home programs are effective in all motor function levels. Necessary arrangements should be made to increase the efficiency of home programs. Keywords: Home programs, gross motor function classification system, cerebral palsy

Introduction Cerebral palsy (CP) is a group of motor disorders which develop secondary to brain anomalies or lesions that occur in early periods of development; they are not progressive, but they change frequently. In children with CP, a great number of physical, sensory, cognitive and emotional problems are seen together [1,2]. CP is the most common disorder causing a severe deterioration in motor function in children. While the CP prevalence in developed countries is 1-2 in each 1000 live births, this rate was found to be 4,4 in each 1000 live births in a study conducted in Turkey [3,4]. Neuroplasticity is the brain’s ability to reshape itself. It can be explained with a great number of mechanisms. Since too many synapses are formed in childhood due to repetition and learning, recovery is much better after brain injury when compared with adults. Neuroplasticity development increases with the practice and repetition of applications [5].

*Coresponding Author: Filiz Ciledag Ozdemir, Inonu University Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation, Malatya, Turkey E-mail: fciledag@gmail.com

Home programs are used to increase the intensity of physiotherapy and to increase the success of rehabilitation during the time left from physiotherapy sessions. In terms of content, home program consists of therapeutic activities which can be performed at home with the help of parent and which are designated to reach successful results about the child’s health. Home programs are applied at home by the family with the guidance and support of a therapist [6,7]. There is high quality evidence that goal oriented and task based home programs develop motor skills of children with CP. In addition to their positive effects on motor skills and functional development, home programs are also reported to increase the child’s and the family’s motivation [8,9]. Gross Motor Function Classification System (GMFCS), which defines both the severity and the course of the disease, is used to classify motor disorder in children with CP. This system is a system which is used in informing the family about the instantaneous performance of the child. In addition, the classification in terms of GMFCS can also be used during the process of deciding on which treatment intervention is suitable within time [10]. Participation of families to home program and the factors 221

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influencing this participation are not fully known. The aim of our study is to evaluate the association between GMFCS levels of children with CP and the participation of families to home programs. Material and Methods This study is a cross-sectional study which was conducted in eight private education and rehabilitation centers in the city center of Malatya province. The study group consists of 247 children with CP and their parents who accepted to participate in the study. The inclusion criteria in children was being younger than 21 years old, having met the definition of CP and having been given a home program specially planned by a physiotherapist, while the inclusion criteria for parents was being the person who undertook the implementation of the home program. The study protocol was approved by Inonu University Scientific Research and Publication Ethics Board. The parents who were primarily responsible for the care of children were informed about the study and they signed a consent form that they volunteered to participate and thus the study was performed in compliance with the Declaration of Helsinki. The study form was structured in three parts. In the first part, the parents’ and children’s sociodemographic characteristics and general health were assessed. In the second part, parents’ participation in the home program was analyzed, while in the third part gross motor function levels of children with CP were evaluated. Parents’ participation in the home program was analyzed by questioning “the state of implementing the home program planned specifically for the child by the physiotherapist every day during the last week”. GMFCS was used to classify the severity of the disorder in gross motor functions of children with CP. GMFCS is a valid and reliable standardized system which classifies in five levels the gross motor functions of children with CP between 0-12 years of age. Children with CP are least dependent in level 1 and most dependent in level 5 in motor functions (Table 1) [11]. Statistical Analysis Study data were uploaded to a computing environment and were evaluated using Statistical Package for Social Sciences (SPSS) for Windows version 22.0 (SPSS Inc, Chicago, IL). The suitability of the variables for normal distribution were assessed using Kolmogorov Smirnov Test. Arithmetic averages are expressed with standard errors. Chi-square and Spearman correlation analysis were used for the analysis of data. Total type-1 error level was used as 5% for statistical significance. Results In our study, 51.6% of the children were male, while 48.4% were female. Average age of the participants was 9.5±0.5 years (min.:0, max.:21). 60% of the children were younger than 10, while 40% were older than 10. 65.9% of the cases were spastic (n:163), 5.6% were dyskinetic (n:14), 14,1% were hypotonic (n:35), 4.4% ataxic (n:11) and 9.7 % were mixed type. 71.6% of the children were found to live in cities, while 28.4% were found to live in rural area. Average age of the participant parents was found as 36.4±12.4 years (min.:18, max.:73). 93.8% of the parents were mothers, while 6.2% were fathers. Table 2 shows the education levels, income levels and occupations of the parents (Table 2).

Med Science 2019;8(1):221-4

In our study, it was found that while the home program given to the child by physiotherapist was applied to 35.6% of the children, it was not applied to 64.4%. Distribution of the children in terms of GMFCS levels was found as 13 patients (4.9%) in level 1, 54 patients (21.9%) in level 2, 854 patients (34.4%) in level 3, 62 patients (25.1%) in level 4, and 34 patients (13.8%) in level 5. Distribution of home program participation levels according to GMFCS levels is given in Figure 1.

Figure 1. Distribution of participation levels in home programs in terms of GMFCS

Statistically significant difference was found between GMFCS levels and application of home programs (p<0.05) (Table 3). It was found that as motor function deficits of children with CP increased, parents’ habits of making their children do exercise decreased. Table 1. Gross motor function classification system Level

Description

Level I

Can walk without limitation, limitation in more advanced gross motor skills

Level I

Can walk without assisting device, limitation in walking outside the house and in public

Level III

Can walk with devices helping mobility, limitation in walking outside the house and in public

Level IV

Limited self-movement, children are carried or they use energized mobility devices outside the house and in public

Level V

Self-movement is limited even with assisting technology

Table 2. Education, Income and Occupation status of parents within the study Socio-Demographic Characteristics

Number

Low

25.5

Moderate

141

57.08

High

24.4

Secondary school and lower

205

83.0

High school and upper

17.0

Housewife

213

85.7

Employee with social security

10.9

Income

Level of Education

Occupation

Other

3.4

Total

247

100.0

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Table 3. Distribution of implementation of home programs in terms of gross motor function classification system GMFCS levels

Implementation of home programs

Total

Yes

Level I-III

67 (44,4%)

84 (55,6%)

151 (61,1%)

Level IV-V

21 (21,9%)

71 (78,1%)

96 (38,9%)

Total

88 (35,6%)

159 (64,4%)

247 (100%)

P= 0.001 X2= 12.950 SD= 2

Discussion The aim of this study is to analyze the association between motor function performance levels of children with CP and parents’ participation in the implementation of home programs. The most important result found in the study is the finding that as motor function deficits of children with CP increased, parents’ habits of making their children do exercise decreased. Average age of the participant parents was found as 36.4±12.4 years (min.:18, max.:73). 93.8% of the parents were mothers, while 6.2% were fathers. In our culture, as in many cultures, generally fathers undertake the responsibility of make a living, while mothers stay at home and look after the children during the day. 88.2% of the participants reported that they had another child. For this reason, the mothers who take care of their child all day and do the housework also want to take care of their other children, too. This situation negatively affects their application of the home program. In planning the treatment program and in the assessment of treatment efficiency, a great number of assessment methods specific for children are used. Functional states of children with CP are also assessed with various classification systems. GMFCS is generally used in clinic to classify the motor disorders of children with CP [12]. Similarly, GMFCS was used in this study to classify the motor disorders of children with CP. When the distribution of the patients was evaulated in terms of their GMFCS levels, it can be seen that the highest number of patients were in level 3 (n=85, 34.4%) and level 4 (n=62, 25. 1%). In another study conducted in our country which researched the risk factors and clinical profiles of 625 CP patients, a great majority of the patients were in level 3 and 4. In other studies in literature which assessed the motor functions of children with CP, most of the patients were found to be in level 3 and 4 [13,14]. This can be explained with the number of children with moderate and severe motor performance disorder who refer to rehabilitation centre being higher. Literature review conducted showed that home programs and participation in these programs has positive effects on the developmental achievements of children with CP [7, 15]. Repetitive and experimental application of home program was found to be as important as other therapeutical approaches [16,17]. It can be thought that regular application of home programs can increase the efficiency of the treatment by maximizing the motivation of children and families. In this study, it was found that home program given to children by physiotherapist was applied only in 35.6% of the children.

In literature, not following home exercise programs has been assessed as one of the factors influencing treatment results [18,19]. In spite of this, the participation of families in home programs is low. In their study, Rone-Adams found that home program given by physiotherapist was not followed in 66% of the children. In a study conducted by Başaran et al., it was found that home program was not followed in 64.4% of the children. With this study, it was found that parents’ habits of making their children do exercise decreased as motor function disorders of children with CP increased (p<0.05). In a study conducted by Başaran et al. on 147 children with CP, it was found that as motor function disorders of children increased, parents became more compatible with home programs [19]. The reason for this can be the differences in sample size, families’ sociodemographic characteristics and individual changes of children within the context of the study. The number of studies in current literature about compliance with home exercise programs and the factors influencing this compliance is limited. In existing studies, negative factors influencing the implementation of the home program were found as the child’s age, families’ sociodemographic characteristics, motivation loss in children and parents during the implementation of the program, parents’ jobs and their productive activities, other programs children participated in, children’s mood and their characteristic features during the day [17,20]. Limitations of the Study The limitation of this study is the fact that of the factors that are thought to influence compliance to home programs, only motor function performance levels were assessed. Multicenter monitoring studies which assess compliance and the factors that influence compliance more detailed can be conducted. Conclusion Home program implementation to increase rehabilitation programs of children with CP are an indispensable part of rehabilitation programs. As a result of this study, it was found that families required to be informed about the efficiency of home programs. Families should be told that home programs are effective in all motor function levels. Competing interests The authors declare that they have no competing interest Financial Disclosure The author declared that this study has received no financial support. Ethical approval The study protocol was approved by Inonu University Scientific Research and Publication Ethics Board. Filiz Ciledag Ozdemir ORCID: 0000-0001-9421-0233

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References 1.

Elbasan B, Türker D. Serebral palside fizyoterapi rehabilitasyon. pediatrik fizyoterapi rehabilitasyon. Elbasan B, edition. İstanbul Tip Kitabevleri. İstanbul, 2016;87-123.

Günel MK. Rehabilitation of children with cerebral palsy from a physiotherapist’s perspective. Acta Orthop Traumatol Turc. 2009; 43:173-80.

O’Shea TM. Diagnosis treatment and prevention of cerebral palsy in nearterm/ term infants. Clin Obstet Gynecol. 2008;51:816-28.

Serdaroğlu A, Cansu A, Özkan S, et al. Prevalance of cerebral palsy in Turkish children between the ages of 2 and 16 years. Dev Med Child Neurol. 2006;48:413-6.

Young JA, Tolentino M. Neuroplasticity and Its applications for rehabilitation. Am J Ther. 2011;18:70-80.

Novak I, Cusick A. Home programs in pediatric occupational therapy for children with cerebral palsy: Where to start? Aust J of Occup Ther. 2006;53:251-64.

Kaya Z, Akel BS. Investigation of factors effecting the applicability of home program in children with special needs. Ergoterapi ve Rehabilitasyon Dergisi. 2017;5:179-88.

Katz-Leurer M, Rotem H, Keren O, et al. The effects of a home-based taskoriented exercise programme on motor and balance performance in children with spastic cerebral palsy and severe traumatic brain injury. Clin Rehabil. 2009;23:714-24.

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11. Palisano R, Rosenbaum P, Walter S, et al. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol. 1997;39:214-23. 12. Huang C, Tseng, M, Chen K, et al. Determinants of school activity performance in children with cerebral palsy: multi-dimensional approach using the ICF-CY as a framework. Res Dev Disabil. 2013;34:4025-33. 13. Himmelmann K, Beckung E, Hagberg G, et al. Gross and fine motor function and accompanying impairments in cerebral palsy. Dev Med Child Neurol. 2006;48:417-23. 14. Erkin G, Delialioglu SU, Ozel S, et al. Risk factors and clinical profiles in Turkish children with cerebral palsy: analysis of 625 cases. Int J Rehabil Res. 2008;31:89-9. 15. Johnson RW, Williams SA, Gucciardi DF. Evaluating the effectiveness of home exercise programs using an online exercise prescription tool in children with cerebral palsy: protocol for a randomized controlled trial. BMJ Open 2018;8:e018316. 16. Straus SE, Richardson WS, Glasziou P, et al. Evidence-based medicine: how to practice and teach. EBM. 2005;353-44. 17. Novak I. Parent experience of implementing effective home programs. Phys Occup Ther Pediatr. 2011;31:198-213. 18. Rone-Adams SA, Stern DF, Walker V. Stress and compliance with a home exercise program among caregivers of children with disabilities. Pediatr Phys Ther. 2004;16:140-8.

Schnackers M, Beckers L, Janssen PY. Home-based bimanual training based on motor learning principles in children with unilateral cerebral palsy and their parents (the COAD-study): rationale and protocols. BMC Pediatrics. 2018;18:139-42.

19. Basaran A, Karadavut KI, Uneri SO. Adherence to home exercise program among caregivers of children with cerebral palsy. Turk J Phys Med Rehabil. 2014;60:85-91.

10. Ozel S, Çulha C, Delialioglu S, et al. The relationship between the gross motor function classification system and treatment modalities in children with cerebral palsy. Turk J Phys Med Rehab. 2016;62:116-22.

20. Mutlu A, Tarsuslu T, Günel MK, et al. The evaluation of home exercise program efficiency in children with cerebral palsy. Turk Arch Ped. 2007;42:112-6.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1): 225-8

Pancreatic injury due to blunt abdominal trauma in children Burhan Beger1, Baran Serdar Kizilyildiz2, Metin Simsek3, Huseyin Akdeniz4, Bulent Sonmez5 Van Yuzuncuyil University Medicine Faculty, Department of Pediatric Surgery, Van, Turkey 2 Van Training and Research Hospital, Clinic of Pediatry, Van, Turkey 3 Van Training and Research Hospital, Clinic of Pediatric Surgery, Van, Turkey 4 Van Yuzuncuyil University Medicine Faculty, Department of Radiology, Van, Turkey 5 Van Yuzuncuyil University Medicine Faculty, Department of Pediatric, Van, Turkey

Received 17 January 2019; Accepted 14 Febuary 2019 Available online 27.02.2019 with doi:10.5455/medscience.2019.08.9010 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The diagnosis and management of pediatric pancreatitis is often difficult. Blunt abdominal trauma is one of the most common causes of pancreatitis in childhood. This is a review of patients with blunt pancreatic trauma. Medical records of all children with blunt pancreatic trauma who were admitted to our clinic between July 2007 and December 2017 were analyzed retrospectively. There were 17 patients (7 girls, 10 boys) with a mean age of of 9.89±2.57 years (range, 3-14 years). The time from trauma to admittance to the clinic was mean 17±21.43 days (range, 0-63 days). The mechanism of injury was bicycle injuries in 7 (41.66%), a fall from height in 6 (35.29%), motor vehicle accidents in 3 (17.64%), and a fall from a horse in 1 (5.88%). All patients had serum pancreatic amylase elevation on admission (average, 1002.71±966.36 IU/L; range, 116-3163 IU/L). All the childen were initially managed non-operatively. In 8 patients (52.94%) the traumatic pancreatitis was complicated by development of a pseudocyst. The average diameter of the pseudocyst was 11.5±3.45 cm. The pseudocysts were resolved in 5 cases with percutaneous ultrasonography-guided fluid drainage and the remaining 3 required open surgery (2 cystogastrostomy, 1 surgical drainage). The average length of hospital stay was 18±15.91 days (range, 2–48 days). There were no deaths and no complications in any patients. Non-operative management of traumatic pancreatitis in the absence of complete duct transection is safe in children. Percutaneous drainage of traumatic pancreatic pseudocysts can be used as an effective and useful treatment option. Keywords: Pancreas, blunt abdominal trauma, pediatric, pseudocyst

Introduction Pancreatitis is characterized by tissue edema, infiltration by leukocytes, necrosis, and hemorrhage within the pancreatic parenchyma [1]. The leading causes of pancreatitis in childhood are drugs, systemic diseases, biliary infections, idiopathic, trauma and anatomic anomalies such as choledochal cysts and abnormal union of the pancreatobiliary junction [1,2]. Blunt abdominal trauma accounts for approximately 85% of the abdominal injuries in children [3]. In addition, it is one of the most common causes of pancreatitis, reported as 10%-40% of all cases in different studies [1,4]. Pancreatic injury secondary to trauma is the fourth most common solid organ injury, following the spleen, liver and kidney injury, and is frequently associated with other clinically important injuries (ie, orthopedic, gastrointestinal, and urinary tract) [4,5]. However, *Coresponding Author: Burhan Beger, Van Yuzuncuyil University Medicine Faculty, Department of Pediatric Surgery, Van, Turkey, E-mail: burhanbeger@hotmail.com

great advances have been achieved in the management and imaging of children with blunt abdominal trauma which has led to a sharp decline in laparotomy rates. The diagnosis of pancreatic injury may be difficult, because as a retroperitoneal organ the symptoms and signs can be ambiguous and severe parenchymal or ductal injuries may exist despite normal laboratory or radiographic findings [3,5]. In addition, appropriate treatment of pancreatic injury secondary to blunt trauma in children is still controversial. However, several studies have shown that non-operative management has good clinical outcomes with minimal morbidity and mortality [2,5,6]. The aim of this study was to report our experiences of pancreatic injury secondary to blunt abdominal trauma in children and to discuss the benefits of non-operative management of this clinical condition. Material and Methods Medical records of all children under 15 years old with pancreatic injury due to blunt abdominal trauma who were admitted to our clinic between July 2007 and December 2017 were analyzed retrospectively. They were evaluated in terms of age/ gender, 225

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Med Science 2019;8(1): 226-8

mechanism of ınjury, management, hospitalization and treatment of complications (Table 1). Table 1. The table of patients which shows age, gender, mechanism of the ınjury, hospital stay and complications and managment Case Age/ Mechanism of Hospital Complication Treatment of CompliNo Gender Injury stay (days) cation 1 2 3 4

12,5/M Motor vehicle 9,2/M Bicycle 8,6/M Bicycle 9,8/M Fall off a horse

17 4 3 27

Pseudocyst no no Pseudocyst

Cystogastrostomy Medical Medical Percutaneous drainage

5 6 7 8

12,8/F 6/F 7,7/M 5,8/F

Bicycle Bicycle Bicycle Fall

17 16 48 37

Pseudocyst Pseudocyst Pseudocyst Pseudocyst

Percutaneous drainage Percutaneous drainage Percutaneous drainage Cystogastrostomy

14/M

Fall

Surgical drainage

10 11 12 13 14 15 16 17

10/M Fall 11/M Fall 11/M Motor vehicle 4/M Fall 16/F Bicycle 3/F Fall 9/F Motor vehicle 8/F Fall

Ruptured Pseudocyst no no no no no Pseudocyst no no

2 6 2 8 7 6 11 12

Medical Medical Medical Medical Medical Percutaneous drainage Medical Medical

Figure 1. CT scan shows pseudocyst

In our clinic, patients with blunt abdominal trauma were routinely checked for serum amylase-lipase levels together with other routine laboratory tests. Radiological diagnosis was put with FAST(focused abdominal sonography) and computered tomography after first aid and stabilization of patients. In hemodynamically stable patientes with suspicion of ductal injury, MRI examination was performed. Patients were divided into two groups; as early applied patients (on the day of the trauma) and the delayed applied patients (more than one day after trauma). Explorative laparatomy was planned in the hemodynamically unstable patients or serious suspicion of complete ductal injury. Conservative approach was preferred in all stable patients who were applied following days after trauma. Results There were 17 patients (7 girls, 10 boys) with a mean age of of 9.89±2.57 years (range, 3-14 years). The time from trauma to admittance to the clinic was mean 17±21.43 days (range, 0-63 days). The mechanism of injury was bicycle injuries in 7 (41.66%), a fall from height in 6 (35.29%), motor vehicle accidents in 3 (17.64%), and a fall from a horse in 1 (5.88%). At initial presentation, all patients complained of abdominal pain, and 6 had abdominal tenderness, and abdominal mass in 3 on physical examination. Pancreatic injury was documented by elevated serum amylase level, imaging by computed tomography (CT) and ultrasonography (Figure 1). All patients had serum pancreatic amylase elevation on admission (average, 1002. 71 ± 966. 36 IU/L; range, 116-3163 IU/L). All the childen were initially managed non-operatively. In 8 patients (52.94%) the traumatic pancreatitis was complicated by development of a pseudocyst. The average diameter of the pseudocyst was 11. 5±3.45 cm. The pseudocysts were resolved in 5 cases with percutaneous ultrasonography-guided fluid drainage and the remaining 3 required open surgery (2 cystogastrostomy, 1 surgical drainage). The average length of hospital stay was 18±15.91 days (range, 2–48 days). There were no deaths and no additional complications in any patients.

Figure 1. Handlebar mark on upper quadrant

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Discussion Trauma can be seen in 10%-40% of children with acute pancreatitis. The most common causes in children are motor vehicle crashes, sports injuries, run-overs, accidental falls and sexual abuse [1,7]. In the current study, bicyle-related injuries and falls were the most common causes of pancreatic injury. Bicycling is a good form of sport as well as a means of transportation worldwide but also entails some risks of trauma [8]. Bicycle-related injuries are one of the leading causes of emergency department visits for children with mortality incidence of 900 deaths per year and approximately 1.2 million physician visits per year reported in the United States [8,9]. The main mechanism of injury when cycling is the handlebars striking the body. Namely, after the child has lost control of the bicycle, the front wheel rotates and becomes perpendicular to the body and so the rigid edge of the handlebars can cause serious truncal injury [10]. A review of literature for blunt abdominal trauma related to bicycle accidents revealed that pancreatic injury is a rare condition. Shah reported that fractures (52.9%) were the leading injury pattern followed by traumatic brain injury (33.7%) including skull fractures and intracranial injury in children. Thorax, abdomen, and pelvic injuries were encountered in 15.5% of hospitalized children [9]. Alkan reported 3 pancreatic lacerations after blunt trauma from a bicycle handlebar in a study of 8 children [11]. Similarly, in another study of 32 children with injuries related to handlebars, 3 had traumatic pancreatitis and 2 had transection of the pancreas [12]. The diagnosis of pancreatic injury requires a substantial degree of suspicion [4] as there are no specific physical signs or laboratory findings and therefore diagnosis is often delayed [13]. Elevated amylase levels have low specificity and sensitivity in traumatic pancreatitis but elevated serum amylase levels should still suggest pancreatic injury [14]. In previous reports, repeated serum amylase levels associated with severe injury have been reported to be statistically significant [5] but amylase levels have failed to predict or correlate with the degree of injury or reveal potential ductal disruption, especially when obtained in the early post-trauma period [5,13] Repeated amylase values are important in the absence of emergency laparotomy, when radiographic images are inconclusive, and in children with ongoing abdominal pain. Serum lipase levels after blunt abdominal trauma are non-specific and poor indicators, but they are frequently used clinically for acute pancreatitis [5]. Elevated levels of lipase may provide a clue to a severe injury requiring further investigation [14]. In the diagnosis of pancreatic injury, ultasonography is easy to perform and cost-effective, but its use is limited due to the presence of gastrointestinal gas [13,15]. However, it is useful for the detection of pancreatic ascites and pseudocyst formation, which often occur in cases with traumatic pancreatitis [15]. In hemodynamically stable patients, computed tomography can show pancreatic injuries in detail with 80 % specificity [16]. If the

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CT is performed earlier then 12 hours after the pancreatic trauma, the results can be deceptive because soft tissue changes may be delayed [13,15]. In the past, ERCP was the only method available for evaluating pancreatic duct integrity. More recently MRCP has been used as an alternative, non-invasive diagnostic tool for direct imaging of the pancreatic duct and it is being used more frequently to assess injury to the ductal component [15]. In parallel with the radiological developments, the pathophysiology of blunt abdominal trauma has become better understood and this has reduced the laparatomy rates [3]. Although there are some consensual treatment methods for adults, it is difficult to establish a clear treatment protocol for children [2]. The management of pancreatic injury secondary to blunt abdominal trauma still remains controversial [6,14]. Most authors have accepted that non-operative management should be the first choice of treatment in grade 1 and 2 pancreatic injury. However, in grade 3 and 4 injuries, which show proximal transection or parenchymal injury with probable duct injury or combined pancreatic and duodenal injury, many centres have recommended an aggressive surgical approach to minimize the incidence of later pseudocyst formation and prolonged hospitalization [5,6,14,16]. Non-operative management has become the standard care of most solid organ injuries in hemodynamically stable children but in the treatment of pancreatic injury it is controversial [6]. Nonoperative management of pancreatic trauma has been reported to be associated with minimal morbidity and mortality [4,6,17]. In cases of pancreatic injury, non-operative management consists of fasting, total parental nutrition, octreotide, antibiotherapy for secondary microbial infections and serial radiological imaging and clinical observation to be aware of complications [4]. Octreotide is a synthetic somatostatin analogue that inhibits pancreatic secretions, but its effects are controversial [4]. Nonoperative treatment is the first choice in Grade 1-2 injuries and the main debate concerns grade 3-4 injuries. Authors who have suggested aggressive surgery claim that surgery may reduce complications, morbidity and a long hospital stay [16,17]. Others recommend non-operative treatment in absance of complete duct transection. But; potential complications that can be treated with a minimally invasive approach should be kept in mind. [16]. The most important complication after blunt pancreatic trauma is the development of pseudocysts, for which the reported incidence is high (range,44%-56%) [4,6] and it has been associated with grade 3-4 pancreatic duct injury (6]. Pseudocysts are localised collections of pancreatic secretions, lacking an epithelial lining, which occur secondary to pancreatic inflammation or ductal disruption. [18]. Other complications are abscesses and duct stricture, including peritonitis, intestinal obstruction, gastrointestinal bleeding, endocrine or exocrine insufficiency, splenic artery pseudoaneurysm formation or rupture and splenic vein thrombosis [15]. The size of the pseudocyst is important in respect of the treatment, which can be planned for pseudocysts >6cm that do not resolve spontaneously over 6 weeks. In a previous study all ruptured cysts were reported to be >10 cm in diameter [18]. CT-guided drainage, 227

doi: 10.5455/medscience.2019.08.9010

ultrasonography-guided drainage, and cystogastrostomy are methods performed in the treatment of pseodocyst. To limited of our study; all of the patients who applied to our clinic were hemodynamiclly stable and non of them had complete ductal duct injury. So we could treat them all conservatively. Conclusion In conclusion, the diagnosis of traumatic pancreatitis due to blunt abdominal trauma requires a high level of suspicion. Nonoperative management of traumatic pancreatitis in children is safe in the absence of complete duct transection, with close monitoring for potential complications and there is minimal morbidity. Percutaneous drainage of traumatic pancreatic pseudocysts can be used as an effective and useful treatment option. The use of octreoitide in pseodocysts <6 cm may provide spontaneous resolution. Competing interests The authors declare that they have no competing interest. Financial Disclosure All authors declare no financial support. Ethical approval Van Training and research hospital-03/05/2018/no:9. Burhan Beger ORCID: 0000-0002-1565-8062 Baran Serdar Kizilyildiz ORCID: 0000-0001-7252-3650 Metin Simsek ORCID: 0000-0003-4736-7160 Huseyin Akdeniz ORCID: 0000-0002-7992-4753 Bulent Sonmez ORCID: 0000-0002-5624-8051

References 1.

iBai HX, Lowe ME, Husain SZ. What have we learned about acute pancreatitis in children? J Pediatr Gastroenterol Nutr. 2011;52:262-70.

Suzuki M, Sai JK, Shimizu T. Acute pancreatitis in children andadolescents. World J Gastrointest Pathophysiol. 2014;15;5:416-26.

Rance CH, Singh SJ, Kimble R. Blunt abdominal trauma in children. J pediatr Child Health. 2000;36:2-6.

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Firstenberg MS, Volsko TA, Sivit C, et al. Selective management of pediatric pancreatic injuries. J Pediat. 1999.

Jobst M, Canty T, Lynch F. Management of pancreatic injury in pediatric blunt abdominal trauma. J Pediatr Surg. 1999;34:818-24.

De Blaauw I, Winkelhorst JT, Rieu PN, et al. Pancreatic injury in children: good outcome of nonoperative treatment. J Pediatr Surg 2008;43:1640-3

Mekitarian Filho E, Carvalho WB, Silva FD. Acute pancreatitis in pediatrics: a systematic review of theliterature. J Pediatr. 2012;88:101-14.

Thompson MJ, Rivara FP. Bicycle-related injuries. Am Fam Physician. 2001;15;63:2007-14.

Shah S, Sinclair SA, Smith GA, et al. Pediatric hospitalizations for bicyclerelated injuries. Inj Prev. 2007;13:316-21.

10. Winston FK, Shaw KN, Kreshak AA, et al. Hiddenspears: handlebars as injury hazards to children. Pediatrics. 1998;102:596-601. 11. Alkan M, Iskit SH, Soyupak S, et al. Severe abdominal trauma involving bicycle handlebars in children. Pediatr Emerg Care. 2012;28:357-60. 12. Clarnette TD, Beasley SW. Handlebar injuries in children: patterns and prevention. Aust N Z J Surg. 1997;67:338-9. 13. WY Bao, G She, YF Duan, et al. Sun.Diagnosisandmanagement of highgrade pancreatic trauma: report of 14 cases. 2015;77:1222-6. 14. Holland AJ, Davey RB, Sparnon AL, et al. Traumatic pancreatitis: Longterm review of initial nonoperative management in children. J Paediatr Child Health. 1999;35:78-81. 15. Debi U, Kaur R, Prasad KK, et al. Pancreatic trauma: a concise review. WJG. 2013;19:9003. 16. Wales PW, Shuckett B, Kim PC. Long-term outcome afternon-operative management of complete traumatic pancreatic resection in children. J Pediatr. 2001;36:823-7. 17. ahoti BK, Aggarwal G, Satsangi B, et al. Paediatric pancreatic problems: a five-year experience. Afr J Paediatr Surg. 2010;7:151-5. 18. Cheruvu CV, Clarke MG, Prentice M,et al. Conservative treatment as an option in the management of pancreatic pseudocyst. Ann R Coll Surg Engl. 2003;85:313-6.

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ORIGINAL RESEARCH

Medicine Science International Medical Journal

Medicine Science 2019;8(1):255-9

Does MiRNA gene expression predict gastric cancer stage and localization? Onder Ozcan1, Ahmet Korkut Belli1, Selami Ilgaz Kayilioglu1, Ozgur Ilhan Celik2, Mehmet Kaplan3, Murat Kara4, Murat Polat5 Mugla Sitki Kocman Universty Medical School, Department of General Surgery, Mugla, Turkey . 2 Mugla Sitki Kocman Universty Medical School, Department of Pathology, Mugla, Turkey. 3 NCR International Hospital, Department of General Surgery, Gaziantep, Turkey. 4 Medical Genetics Specialist, Self Employment, Mersin,Turkey. 5 Mugla Sitki Kocman Universty Medical School, Department of General Surgery, Mugla, Turkey

Received 22 January 2019; Accepted 02 February 2019 Available online 03.2019 with doi:10.5455/medscience.2019.08.9012 Copyright ÂŠ 2019 by authors and Medicine Science Publishing Inc. Abstract Gastric cancer comprises 10% of all cancers in the world and is rarely seen before the age of 30. Different genetic interactions or molecular changes like e-cadherin, P16, APC, c-erb B2, c-met, ras, or c-myc have been described in the pathogenesis of the disease. MiRNAs play critical roles in various biological processes such as cell proliferation, cell differentiation, apoptosis, repairing of DNA damage, angiogenesis, stress response, and stem cell division. The aim of this study is to investigate the relationship between miRNA gene expressions and gastric cancer. Method: Sixty-four patients with gastric cancer diagnosed consecutively in our pathology laboratory and 30 consecutive participants with normal gastric tissue, as a control group, were included in our study between 2011 and 2013. Total miRNAs were obtained by using genomic miRNA extraction kit (QIAGEN Sample & Assay Technologies, Hilden, Germany) after the samples had been deparaffinized. MiR-21, 107, 141, 150, 192, 202, 218, 331 gene expressions were evaluated by using real time-PCR (RT-PCR) from the whole miRNA. Results: MiR-331 was downregulated in the stage 2 patients and the rest of the miRNAs were significantly upregulated (p < 0.001). All miRNAs were significantly upregulated in the stage 3a patients (p < 0.001). In the antrum localized tumors, miR-107, -150, -202, -218, and -331 were significantly upregulated, whereas miR-21, -192 were statistically downregulated (p < 0.05). In the cardia localized tumors, miR-21 (p > 0.05) was downregulated and miR-107, -150, -202, -218, and -331 were upregulated (p < 0.05) Different gene expressions of miRNAs according to the different localizations of gastric cancer and different stages suggest that it can be tumor marker to predict the stage and localization of gastric cancer. Keywords: MiRNA, gastric carcinoma, gene, expression

Introduction Gastric cancer comprises 10% of all cancers in the world and is rarely seen before the age of 30. It develops after the age of 50 and in males 2 times more often than females (1). Diet, genetic factors, and bacterial agents such as Helicobacter pylori are some of the risk factors of the disease (2,3). Different genetic interactions or molecular changes like e-cadherin, P16, APC, c-erb B2, c-met, ras, or c-myc have been described in the pathogenesis of the disease (4,5). MiRNAs are members of noncoding small RNA family with a length of 19-25 nucleotides (4). MiRNAs play critical roles in various biological processes such as cell proliferation, cell differentiation, apoptosis, repairing of DNA damage, angiogenesis, stress response, and stem cell division. They also work as tumor *Coresponding Author: Onder Ozcan, Mugla Sitki Kocman Universty Medical School, Department of General Surgery, Mugla, Turkey E-mail: onderozcan@mu.edu.tr

suppressor gene and/or oncogene in the diseases or specific tissues, and function in the regulation of gene expressions during transcription processes. Moreover, genetic alterations of miRNA are associated with development of various human diseases such as cancer, cardiovascular diseases, inflammation, and asthma (6-11). The aim of this study is to investigate the relationship between miRNA gene expressions and gastric cancer. Material and Methods This study was conducted by the coordination of General Surgery, Pathology, and Medical Genetics in Mugla Sitki Kocman University Medical School after obtaining an approval from the clinical research ethics committee (05 August 2013, 13/109). Sixty-four patients with gastric cancer diagnosed consecutively in our pathology laboratory and 30 consecutive participants with normal gastric tissue, as a control group, were included in our study between 2011 and 2013. The samples were obtained from 255

doi: 10.5455/medscience.2019.08.9012

paraffin blocks with 5-micron thickness slices. Total miRNAs were obtained by using genomic miRNA extraction kit (QIAGEN Sample & Assay Technologies, Hilden, Germany) after the samples had been deparaffinized. miR-21, miR107, miR141, miR150, miR192, miR202, miR218, miR331 gene expressions were evaluated by using real time-PCR (RT-PCR) from the whole miRNA. Patient distribution: Of the 64 patients, 25 were female and 39 were male. Mean age of the patients were 65.15± 1 years (range 31 to 88), mean age of the female patients were 62.6 ± 1 years (range 33 to 88), and the mean age of the male patients were 66.6 ± 1 years (range 31 to 88). Forming of the groups: Gastric cancer and control groups were compared according to the fold change values obtained by using 2 Average delta CT values (Table 1). Gastric cancer group were divided into subgroups according to gender, tumor stage, localization, and histopathology for further analysis. Female and male patients were compared with control group separately (Table 2). Ages were divided into ≤45 and >45 (Table 3). Patients were staged according to the TNM system (Table 4) (12-13). Tumor localizations were: 1- antrum, 2- corpus-fundus, and 3- cardia (Table 5). Histopathological types of the tumor were: 1- signet ring cell carcinoma (n=11) and 2- adenocarcinoma (N=53) (Table 6). All of these groups were compared separately with the control group. SPSS 15.0 software was used for the analyzes of the data. The results were demonstrated as mean ± standard deviation. Variance analysis was used to evaluate whether there were differences

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between the groups. Analyzes were performed at the page of Qiagen’s data analysis expression with using the values of 2 Average delta CT. P values < 0.05 were accepted as statistical significance. Results miRNA expressions, miR-21, miR-141, miR-150, miR-202, were upregulated and miR-107 was downregulated in the gastric tumor tissue. However, these differences were not statistically significant (P > 0.05) (Table 1). miR-21 was significantly upregulated in the females comparing to the males. (P < 0.05). miR-107 was downregulated in the females. miR-331 was normal in both genders (Table 2). All miRNA types except miR-107 and miR-331 were upregulated without a statistical significance in the patients that were ≤ 45 years old (p > 0.05). miR-21, miR-141, miR-150, and miR-202 were upregulated without a statistical significance in the patients > 45 years old, whereas miR-107 was downregulated (p > 0.05) (Table 3). miR-331 was downregulated in the stage 2 patients and the rest of the miRNAs were significantly upregulated (p < 0.001). All miRNAs were significantly upregulated in the stage 3a patients (p < 0.001). In stage 3b, miR-21 was downregulated (p < 0.05), and miR-107, miR-141, miR-150, and miR-202 were upregulated (p < 0.001). In stage 4 patients, miR-107 was downregulated (p > 0.05) and miR-141, miR-150, miR-192, and miR-202 were upregulated (P > 0.05) (Table 4).

Table 1. miRNA expressions in gastric cancer group and control group Control Group 2^(Avg. (Delta(Ct))

2^(Avg. (Delta(Ct))

Gastric Cancer Group Fold Change

p value

0.163 1.673 0.363 4.163 0.933 0.127 0.118 0.249

0.124 4.084 1.637 7.989 3.980 0.052 1.447 0.243

0.760 2.440˄ 4.502˄ 1.918 4.264˄ 0.414˅ 12.227˄ 0.974

0.337 0.460 0.435 0.446 0.403 0.398 0.434 0.345

miR218 miR21 miR202 miR192 miR150 miR107 miR141 miR331 ˄, up-regulation ˅, down-regulation

Table 2. Comparison of miRNAs in gastric cancer and control groups according to gender Male

Control Group 2^(-Avg. (Delta (Ct))

2^(-Avg. (Delta(Ct))

miR218

0.163

0.201

miR21

1.673

miR202

Female Fold Change

Male Fold Change

p value

2^(-Avg. (Delta(Ct))

1.235

0.232

0.090

0.557

p value 0.219

4.863

2.905˄

0.037*

3.652

2.182˄

0.344

0.363

2.498

6.869˄

0.250

1.248

3.43˄

0.319

miR192

4.163

15.858

3.808˄

0.240

5.148

1.236

0.331

miR150

0.933

8.328

8.922˄

0.091

2.480

2.657˄

0.285

miR107

0.127

0.028

0.222˅

0.241

0.078

0.616

0.279

miR141

0.118

2.040

17.235˄

0.233

1.161

9.812˄

0.318

miR331

0.249

0.471

1.887

0.215

0.159

0.638

0.226

˄, up-regulation ˅, down-regulation *, significant p value

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Table 3. Comparison of miRNAs in gastric cancer and control groups according to the age differences. Age

Control Group 2^(-Avg. (Delta (Ct))

< 45

>45

2^(-Avg. (Delta(Ct))

Fold Change

p value

2^(-Avg. (Delta(Ct))

Fold Change

p value

miR218

0.163

0.356

2.181˄

0.054

0.104

0.640

0.435

miR21

1.673

10.386

6.205˄

0.053

3.505

2.094˄

0.439

miR202

0.363

7.697

21.168˄

0.054

1.270

3.494˄

0.438

miR192

4.163

12.846

3.085˄

0.054

7.392

1.775

0.440

miR150

0.933

7.293

7.814˄

0.054

3.605

3.862˄

0.439

miR107

0.127

0.169

1.333

0.054

0.043

0.342˅

0.437

miR141

0.118

4.221

35.660˄

0.054

1.214

10.263˄

0.434

miR331

0.249

0.206

0.827

0.054

0.2501

1.001

0.428

˄, up-regulation ˅, down-regulation Table 4. Comparison of miRNAs in gastric cancer and control groups according to the stages of tumors Tumor Stage

Control Group

Stage II

2^(Avg. (Delta (Ct))

Fold Change

miR218

0,163

0.239

Stage IIIa p value

2^(Avg. (Delta(Ct))

Fold Change

1.467

0.008*

3.415

Stage IIIb p Value

2^(Avg. (Delta(Ct))

Fold Change

20.924

0.008*

0.102

Stage IV p value

2^(Avg. (Delta(Ct))

Fold Change

0.626

0.488

0.160

0.985

0.213

p value

miR21

1.673

5.897

3.523˄

0.008*

269.100

160.782

0.008*

0.062

0.037

0.047*

2.652

1.585

0.213

miR202

0.363

19.400

53.349˄

0.008*

87.790

241.418

0.008*

1.426

3.922

0.053

3.374

9.280

0.212

miR192

4.163

14.340

3.444˄

0.008*

288.0149

69.172

0.008*

3.182

0.764

0.004*

8.754

2.102

0.213

miR150

0.933

2.179

2.332˄

0.008*

122.445

131.179

0.008*

2.236

2.396

0.023*

2.818

3.019

0.213

miR107

0.127

0.797

6.274˄

0.008*

2.496

19.636

0.008*

0.375

2.957

0.048*

0.015

0.121

0.213

miR141

0.118

2.751

23.239˄

0.008*

46.205

390.312

0.008*

1.271

10.738

0.082

1.179

9.959

0.213

miR331

0.249

0.171

0.686

0.008*

4.9519

19.816

0.008*

0.261

1.044

0.792

0.156

0.626

0.213

˄, up-regulation ˅, down-regulation *, significant p value

In the antrum localized tumors, miR-107, miR-150, miR-202, miR-218, and miR-331 were significantly upregulated, whereas miR-21, -192 were statistically downregulated (p < 0.05). In the corpus localized tumors, miR-21 was downregulated and miR-

107, miR-141, miR-150, miR-202, miR-218, and miR-331 were upregulated (p> 0.05). In the cardia localized tumors, miR-21 (p > 0.05) was downregulated and miR-107, miR-150, miR-202, miR218, and miR-331 were upregulated (p < 0.05) (Table 5).

Table 5. Comparison of miRNAs in gastric cancer and control groups according to the tumor localization Tumor Localization

Control Group

Stage II

Stage IIIa

2^(Avg. (Delta (Ct))

Fold Change

p value

2^(Avg. (Delta(Ct))

Fold Change

miR218

0,163

3,723

22,815˄

<0,001*

3,711

miR21

1,673

0,466

0,278˅

0,007*

miR202

0,363

33,423

91,912˄

0,002*

miR192

4,163

8,307

1,995

0,010*

miR150

0,933

25,428

27,242˄

<0,001*

miR107

0,127

13,328

104,826˄

0,006*

23,293

miR141

0,118

0,061

0,516

0,567

miR331

0,249

4,924

19,706˄

<0,001*

Stage IIIb p Value

2^(Avg. (Delta(Ct))

Fold Change

22,737˄

0,272

1,431

0,661

0,395˅

0,272

28,166

77,456˄

0,272

8,124

1,951

0,272

2,823

42,660

45,702˄

0,272

30,874

183,203˄

0,272

12,958

0,850

7,184˄

0,272

10,149

40,615˄

0,272

Stage IV p value

2^(Avg. (Delta(Ct))

Fold Change

8,770˄

<0,001*

0.160

0.985

0.213

0,341

0,203˅

0,075

2.652

1.585

0.213

1,241

3,413˄

<0,001*

3.374

9.280

0.212

0,678

0,667

8.754

2.102

0.213

33,076˄

<0,001*

2.818

3.019

0.213

101,919˄

<0,001*

0.015

0.121

0.213

0,138

1,168

0,758

1.179

9.959

0.213

2,637

10,554˄

0,085

0.156

0.626

0.213

p value

˄, up-regulation ˅, down-regulation *, significant p value

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According to histopathological type of the tumor, although miRNAs other than miR-21 and miR-107 were upregulated without statistical significance (p > 0.05) in the signet ring cell

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group. In the adenocarcinoma group, miR-107 was downregulated and miR-21, miR-141, miR-150, and miR-202 were upregulated (p > 0.05) (Table 6).

Table 6. Comparison of miRNAs in gastric cancer and control groups according to the histopathologic type of tumors Histopathologic Type

Control Group

Signet Ring Cell

Adenocarcinoma

2^(-Avg. (Delta (Ct))

2^(-Avg. (Delta(Ct))

Fold Change

p value

2^(-Avg. (Delta(Ct))

Fold Change

p value

miR218

0,163

0,654

4,011˄

0,068

miR21

1,673

2,318

1,385

0,060

0,091

0,559

0,430

4,536

2,710˄

0,435

miR202

0,363

15,358

42,235˄

miR192

4,163

24,134

5,796˄

0,068

1,081

2,974˄

0,434

0,068

6,510

1,563

miR150

0,933

13,104

0,436

14,039˄

0,068

3,192

3,420˄

miR107

0,127

0,435

0,101

0,798

0,068

0,046

0,366˅

miR141

0,433

0,118

7,808

65,958˄

0,068

1,059

8,949˄

0,429

miR331

0,249

0,503

2,013˄

0,068

0,212

0,852

0,424

˄, up-regulation ˅, down-regulation

Discussion miRNAs have been shown to act as an oncogenic or a tumor suppressor during cancer progress, metastasis, or invasion phases (14). After noticing the role of miRNAs, alterations of its expressions in variable cancer types have been investigated and differences in pathological tissues have been demonstrated (15). Several studies investigated the relationship between gastric cancer and miRNA mediated gene regulation. Genes encoding miRNAs act as a proto-oncogene (miR-516a-3p, miR-192, miR-199a, and miR-107) or tumor suppressor (such as miR-43c and miR-126) in the malign cells of the stomach. Several studies showed that modification of miRNA expressions enhance cell proliferation, apoptosis resistance, and ability of invasion and metastasis (1618). High levels of MiR-21 expression has been shown in acute or chronic myeloid leukemia, glioblastoma, and solid organ malignancies like pancreas, prostate, gastric, colon, lung, breast and liver cancers with its oncogenic potential. MiR-21 also has a role in invasion and metastasis process with altering mRNA of a tumor suppressor protein, called PTEN. Studies that showed miR21 upregulation in gastric cancer tissues and cell cultures suggest that it enhances proliferation and invasion of gastric cancer cells. When miR-21expression was blocked by inhibitors, proliferation process was significantly decreased, apoptosis was increased, and gastric cancer cell invasion or migration was markedly declined (19-21). Since upregulation of miR-21 has been demonstrated in various cancers, it is called oncomir (22). In our study, miR-21 was also upregulated in tumor tissues. According to the stages of the tumors, miR-21 was upregulated in the stage 2 and stage 3a (P < 0.05), downregulated in the stage 3b (P < 0.05), and nonregulated in the stage 4 patients. In addition, miR-21 was significantly upregulated in the women with gastric cancer (P < 0.05). According to the histopathological type of tumor, miR-21 was upregulated in adenocarcinoma (P < 0.05). When it was evaluated according to the localization of the tumor, it was surprisingly downregulated (Table 5). These results suggested

that miR-21 can be a good candidate to be a bio-marker during the assessment of gastric cancer. Many studies carried on miR-107 showed different results. Li et al (23) reported that miR-107 expression was increased in gastric cancer tissues, which was correlated with tumor metastasis and poor prognosis. However, another study reported that expression of miR-107 was decreased (24). The discrepancy between these studies may be due to the ethnic differences and the different number of subjects studied. Hence, further studies are needed to determine in vivo and in vitro biologic effects of miR-107 expression in gastric cancer cells. In our study, we found mir-107 expression downregulated in the gastric cancer tissues. According to the stages, miR-107 was upregulated in stage 2, 3a, and 3b, on the other hand downregulated in stage 4 (Table 2). Moreover, we observed that miR-107 was downregulated with advancing age. (Table 3). Expressions of miR-192 and miR-215 decreased in colorectal cancer, thus, it was suggested to be a tumor suppressor marker (25). Xu et al. stated that increase in miR-192 and miR-215 expressions is associated with lymph node metastasis in gastric cancer (26). In our study, expression was normal but was upregulated in the tumor tissues without statistical significance (p > 0.05). According to the stages miR-192 expressions was significantly upregulated (P < 0.05). In this study, miRNA 141, 150, 192, and 202 were upregulated in all stages, however, there was no statistically significant difference except the patients in stage 2 and 3a. When the gene expressions were evaluated according to the tumor stages, it is noticed that upregulation was significant in the early stages. Regarding gene expression in the tumor localizations, only antrum located tumors had significant downregulation. Furthermore, miR-192 was downregulated and miR-331 was upregulated in the antrum and miR-107, miR-50, miR-202, and miR-218 were upregulated significantly in the cardia and antrum localizations. These results suggest that miRNA expressions changes in different localizations of the tumor in addition to different histopathologic types of the tumor. 258

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In the recent years, with the advances in molecular biology, the role of the miRNAs in cancer development is better understood. Hence, may give rise to promising studies in targeted treatments in gastric cancer.

10. Nana-Sinkam SP, Croce CM. MicroRNAs as therapeutic targets in cancer. Transl Res. 2011;157:216-25.

Conclusion

12. Sobin LH, Fleming ID. TNM classification of malignant tumors. Cancer: Interdisciplinary. Intern J Am Cancer Society 1997;80:1803-4.

In conclusion, different gene expressions of miRNAs according to the different localizations of gastric cancer and different stages suggest that it can be tumor marker to predict the stage and localization of gastric cancer. Competing interests The author confirms that this article content has no conflict of interest. Financial Disclosure All authors declare no financial support. Ethical approval Mugla Sitki Kocman University Medical School after obtaining an approval from the clinical research ethics committee (05 August 2013, 13/109) Onder Ozcan ORCID: 0000-0001-8252-3339 Ahmet Korkut Belli ORCID: 0000-0003-1552-5697 Selami Ilgaz Kayilioglu ORCID: 0000-0002-2933-8983 Ozgur Ilhan Celik ORCID: 0000-0002-3549-822X Mehmet Kaplan ORCID: 0000-0002-8758-543X Murat Kara ORCID: 0000-0002-0230-4214 Murat Polat ORCID: 0000-0002-8492-6411

References 1.

Peter Boyle, Bernard Levin, editors. World cancer report. International Agency for Research on Cancer. Lyon: 2008.

Toyoda T, Tsukamoto T, Yamamoto M, et al. Gene expression analysis of a Helicobacter pylori-infected and high-salt diet-treated mouse gastric tumor model: identification of CD177 as a novel prognostic factor in patients with gastric cancer. BMC Gastroenterol. 2013;13:122.

11. Du L, Pertsemlidis A. microRNAs and lung cancer: tumors and 22-mers. Cancer Metastasis Rev. 2010;29:109-22.

13. Gobbi PG, Villano L, Pozzoli D, et al. Improving the AJCC/TNM classification for use in early gastric cancer. Journal of Gastrointestinal Surgery. 2011;15:935-41. 14. Tsukamoto Y, Nakada C, Noguchi T, et al. MicroRNA-375 Is Downregulated in Gastric Carcinomas and Regulates Cell Survival by Targeting PDK1 and 14-3-3ζ. Cancer Res. 2010;70:2339-49. 15. Leichter AL, Sullivan MJ, Eccles MR, et al. MicroRNA expression patterns and signalling pathways in the development and progression of childhood solid tumours. Molecular cancer. 2017;16:15. 16. Feng R, Chen X, Yu Y, et al. miR-126 functions as a tumour suppressor in human gastric cancer. Cancer Lett. 2010;298:50-63. 17. Li X, Zhang Y, Shi Y, et al. MicroRNA-192 and -215 are upregulated in human gastric cancer in vivo and suppress ALCAM expression in vitro. Oncogene. 2010;30:1577. 18. Dong G, Liang J, Han Y, et al. MicroRNA-107, an oncogene microRNA that regulates tumor Invasion and metastasis by targeting DICER1 in gastric cancer: MiR-107 promotes gastric cancer invasion and metastasis. J Cell Mol Med. 2011;15:1887-95. 19. Garzon R, Volinia S, Liu CG, et al. MicroRNA signatures associated with cytogenetics and prognosis in acute my¬eloid leukemia. Blood. 2008;111:3183-9 20. Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 2006;103:2257-61.

Silvera SAN, Mayne ST, Gammon MD, et al. Diet and lifestyle factors and risk of subtypes of esophageal and gastric cancers: classification tree analysis. Ann Epidemiol. 2014;24:50-57.

21. Meng F, Henson RH, Wehbe-Janek H, et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterol. 2007;133:647–58.

Jin Z, Jiang W, Wang L. Biomarkers for gastric cancer: Progression in early diagnosis and prognosis. Oncol Lett. 2015 9:1502-08.

Nobili S, Brun L, Landini I, et al. Genomic and genetic alterations influence the progression of gastric cancer. World J Gastroenterol. 2011;17:290.

22. Akagi I, Miyashita M, Ishibashi O, et al. Relationship between altered expression levels of MIR21, MIR143, MIR145, and MIR205 and clinicopathologic features of esophageal squamous cell carcinoma. Dis Esophagus. 2011;24:523-30.

Salloum FN, Yin C, Kukreja RC. Role of microRNAs in cardiac preconditioning. J Cardiovasc Pharmacol. 2010;56:581-88.

Lee DY, Deng Z, Wang CH, et al. MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression. Proc Natl Acad Sci U S A. 2007;104:20350-5.

8. 9.

Li LJ, Gao LB, Lv ML, et al. Association betweenSNPs in pre-miRNA and risk of chronic obstructive pulmonary disease. Clin Biochem. 2011;44:813-16. Jiang C, Chen X, Alattar M, et al. MicroRNAs in tumorigenesis, metastasis, diagnosis and prognosis of gastric cancer. Cancer Gene Ther. 2015;22:291-301.

23. Li X, Zhang Y, Shi Y, et al. MicroRNA-107, an oncogene MicroRNA that regulates tumor invasion and metastasis by targeting DICER1 in gastric cancer: MiR-107 promotes gastric cancer invasion and metastasis. J Cell Mol Med. 2011;15:1887-95. 24. Feng L, Xie Y, Zhang H, et al. miR-107 targets cyclin-dependent kinase 6 expression, induces cell cycle G1 arrest and inhibits invasion in gastric cancer cells. Med Oncol. 2012;29:856-63. 25. Chiang Y, Song Y, Wang Z, et al. microRNA-192, -194 and -215 are frequently downregulated in colorectal cancer. Exp Ther Med. 2012;3:560-6. 26. Xu YJ, Fan Y. MiR-215/192 participates in gastric cancer progression. Clin Transl Oncol. 2015;17:34-40.

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SHORT COMMUNICATION

Medicine Science International Medical Journal

Medicine Science 2019;8(1):229-30

Can bevacizumab administered together with beta radiation in treatment of pterygium play a role in additive effect and/or treatment of the side effects? Yasemin Benderli Cihan1, Fatma Bagci2 Kayseri Education and Research Hospital, Department of Radiation Oncology, Kayseri, Turkey 2 Kayseri Education and Research Hospital, Department of Ophthalmology, Kayseri, Turkey

Received 13 April 2018; Accepted 29 July2018 Available online 16.12.2018 with doi:10.5455/medscience.2018.07.8939 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Pterygium is one of corneal-conjunctival pathologies that are frequently encountered by ophthalmologists. Its etiology, pathogenesis and treatment have been caused controversy for many years and remain as a problem, which is yet to be fully enlightened. The main treatment of pterygium is surgery. The most crucial postoperative problem is recurrence of the disease. Surgical methods have been sought for years to minimize recurrence with complementary treatment have been added to these methods including conjunctival autografting, bevacizumab and β-irradiation. No study was found to investigate additive use of bevacizumab and beta-radiation in postop or recurrent pterygium. Further phase 1 and phase 2 trials are needed to investigate the effectiveness of additive use of bevacizumab and beta-radiation in treatment of pterygium. Keywords: Bevacizumab, beta radiation, pterygium

Introduction Pterygium is one of corneal-conjunctival pathologies that are frequently encountered by ophthalmologists. It is hyaline degenerative disease of the conjunctiva in which fibrovascular connective tissue advancing from the bulbar conjunctiva toward the cornea. Pterygium shows expansion over the cornea, causing both cosmetic and visual problems. The incidence differs between 2.8% and 30.8% worldwide with an increase observed with advancing age. Its etiology, pathogenesis and treatment have been caused controversy for many years and remain as a problem, which is yet to be fully enlightened [1,2]. The main treatment of pterygium is surgery. The most crucial postoperative problem is recurrence of the disease. Relapse has been reported between 30% and 89% following classical surgery in this lesion which behavior can’t be predicted. Surgical methods have been sought for years to minimize recurrence with complementary treatment have been added to these methods including conjunctival autografting, antimitotic drugs and β-irradiation [1-3]. *Coresponding Author: Yasemin Benderli Cihan, Kayseri Education and Research Hospital, Department of Radiation Oncology, Kayseri, Turkey E-mail:cihany@erciyes.edu.tr

Beta-radiation is among the additive medical treatment methods. Strontium-90 is preferred in the treatment of pterygium. These radioactive agents quickly and permanently block fibroblastic and arteriolar proliferation, thus reducing recurrence. After pterygium is excised, radioactive plaque is inserted on the sclera and kept until reaching the desired dose. [2]. There are numerous treatment protocols and dosage scheme for this method. In general, single dose (25 Gy) or divided doses (20 Gy/10, 27-30 Gray/3, 35 Gy/7 fractions) within 10-70 Gy range are administered [2-4]. The fraction dose and total dose applied in pterygium causes changes in the lens fibers and posterior subcapsular area. Accordingly several complications such as iris atrophy, corneal ulceration and edema, scleral ulceration, scleromalacia, restrictive diplopia, ptosis and infections are observed [2]. Vani et al. reported that no significant difference was found between high-dose fractionation vs. low-dose fractionation; cosmetic results were better and side effects were less with low-dose fractionation in patients who received postoperative adjuvant treatment using β-radiotherapy [4]. Vastardis et al. reported remarkable aesthetic and rehabilitative results with β-radiation compared to conventional treatments in relapsed pterygium lesions [3]. In their review, Ali et al. examined more than 6,000 lesions treated with surgical excision plus postoperative β-radiation using Strontium-90. The radiation was applied at doses differing between 10 and 60 Gy/1-6 fractions/1-6 229

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weeks and initiated within 3 days after the surgery. The incidence of local recurrence was lower than 15% with rarely observed major complications such as ulceration, scleral thinning, radiation related cataract and infections. The authors concluded that, postoperative β-radiation at 30 Gy/3 fractions/2-3 weeks initiating within the first 24h of the surgery is an effective and safe treatment modality and that local control rates were comparable to conjunctival autografting and chemotherapeutic agents and superior over simple surgical excision alone [2]. Studies have shown that angiogenic growth factors such as VEGF, bFGF, TGF β and PDGF are correlated with the formation and recurrence of pterygium. Recently, anti-VEGF/antiangiogenic treatment has been focused in order to treat pterygium, regress pterygium vessels, stop progression of pterygium and prevent postoperative recurrence [2]. Bevacizumab is a humanized monoclonal VEGF antibody, which binds to all VEGF isoforms and distrupt the interaction VEGF and its receptors, showing neutralizing effect [5]. Bevacizumab is widely used and reported to be effective in treatment of retinal and choroid diseases progressing with neovascularization, age related exudative macular degeneration, and macular edema diseases due to central retinal vein occlusion. Furthermore, bevacizumab is known to decrease side effects such as macular edema, maculopathy and optic neuropathy that reveal because of radiation [1,5]. Searching the literature, local control rates are reported as 90% to 94% and recurrence rates as 0% to 15% in patients receiving postoperative β-radiation [2]. Today, main target of beta-radiation therapy in pterygium is to reduce recurrence to 15%. In addition, new agents are being investigated in order to reduce, delay or prevent adverse effects developing in the eye due to radiation. Bevacizumab seems to be a preferred agent both in postoperation and recurrence of pterygium. Searching the literature, no study

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was found to investigate additive use of bevacizumab and betaradiation in postop or recurrent pterygium. Conclusion In conclusion; the lesion being in an early or advanced stage and a well-performed clinical evaluation plays a role in approach to pterygium. In addition, clinical classification should be taken into account in evaluation of treatment results. Further phase 1 and phase 2 trials are needed to investigate the effectiveness of additive use of bevacizumab and beta-radiation in treatment of pterygium. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Yasemin Benderli Cihan, ORCID: 0000-0001-9295-4917 Fatma Bagci ORCID: 0000-0002-8507-1478

References 1.

Hacıoğlu D, Erdöl H. Developments and current approaches in the treatment of pterygium. Int Ophthalmol. 2016 Sep 23 [Epub ahead of print]

Ali AM, Thariat J, Bensadoun RJ, et al. The role of radiotherapy in the treatment of pterygium: A review of the literature including more than 6000 treated lesions. Cancer Radiother. 2011;15:140-7.

Vastardis I, Pajic B, Greiner RH, et al. Prospective study of exclusive strontium-/yttrium-90 beta-irradiation of primary and recurrent pterygia with no prior surgical excision. Clinical outcome of long-term follow-up. Strahlenther Onkol. 2009 Dec;185:808-14.

Viani GA, De Fendi LI, Fonseca EC, et al. Low or high fractionation dose β-radiotherapy for pterygium? A randomized clinical trial. Int J Radiat Oncol Biol Phys. 2012;82:e181-5.

Mak RK, Chan TC, Marcet MM, et al. Use of anti-vascular endothelial growth factor in the management of pterygium. Acta Ophthalmol. 2016 Jul 30. [Epub ahead of print] Review.

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Medicine Science 2019;8(1):231-2

Role of metformin in radiotherapy and chemotherapy Yasemin Benderli Cihan Kayseri Education and Research Hospital, Department of Radiation Oncology 38010 Kayseri, Turkey Received 5 June 2018; Accepted 01 September2018 Available online 08.11.2018 with doi:10.5455/medscience.2018.07.8923 Copyright ÂŠ 2018 by authors and Medicine Science Publishing Inc. Abstract There are several published reports showing antidiabetic agent metformin prevents the development of cancer and has an important role in the treatment of cancer. According to the recent studies, metformin is reported to enhance the effect of chemotherapy and radiotherapy, especially in cancer related to diabetes. But it is difficult to analyze the initiation of treatment as it has been recently started to be investigated. There is a need for prospective studies to investigate the efficacy and / or safety of metformin in combination with radiotherapy and chemotherapy in cancer treatment and in cancer patients. Keywords: Metformin, radiotherapy, chemotherapy

Introduction Diabetes mellitus (DM) and cancer are prevalent diseases with growing incidence. High morbidity and high mortality rates lead to high treatment costs and cumulative loss of manpower that are a heavy burden for society. In the recent years, despite significant advances in molecular genetics, the etiology and the pathophysiology of both DM and cancer are no fully understood. Diabetes Mellitus and cancer share similar risk factors that cannot be modified like ethnicity and some risk factor that can be modified by changes in lifestyle such as obesity, diet, alcohol, physical activity and smoking [1-3]. For over fifty years, the association between diabetes mellitus and cancer are known. Data from the meta-analyzes point at patients with DM that they are at risk for some types of cancer and also some types of cancer have been found to occur less often [1]. Although the mechanisms behind this are unknown, higher insulin sensitivity and increased insulin receptor expression in a cell was shown to contribute to the increased risk of malignant transformation by 2-6 fold [3-6]. In epidemiological studies, endometrium, liver and pancreatic cancers were found 2 times more; colon, breast, rectum and bladder cancers were found 1.2-1.5 times more than the

*Coresponding Author: Yasemin Benderli Cihan, Kayseri Education and Research Hospital, Department of Radiation Oncology 38010 Kayseri, Turkey E-mail: cihany@erciyes.edu.tr

normal population. Diagnosis of Diabetes Mellitus in pancreatic cancer patients at least 5 year before the initial disease suggest a positive relationship between DM and pancreas cancer. The reason behind lower incidence of prostate cancer in patients with DM is supposed to be a result of low testosterone levels and metabolic disorders related to diabetes [1]. There are still many questions that maintain complexity on whether presence of common risk factors for both DM and cancer or drugs used for DM treatment or pathophysiological mechanisms involved in the development of diabetes affect cancer development. In the latest studies, increased relation between cancer and diabetes associated metabolic abnormalities and clarification of role of adenosine monophosphate protein kinase activation (AMPK) in cancer metabolism raised deep interest in metformin that acts by AMPK activation [4, 6.7]. There are several published reports showing antidiabetic agent metformin prevents the development of cancer and has an important role in the treatment of cancer [2]. Metformin shows its anticancer effect by reducing insulin-like growth factor (IGF) and insulin production, inhibiting HER2mediated signaling, mammalian target of rapamycin (mTOR) signaling, angiogenesis. Indirectly, metformin causes cell cycle death and induces apoptosis [2,3,4,7]. Jung et al reported that Metformin which is used for type 2 diabetes treatment reduced tumor size and number significantly in breast, liver and pancreas cancer patients [4]. In Jiralerspong et al.â&#x20AC;&#x2122;s study, 2592 neoadjuvant chemotherapy patients were enrolled. While they found that 231

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patients taking Metformin for DM (157 patients) showed % 24 pathological complete response to chemotherapy, it was found 8% in patients not taking Metformin. At last, they reported that metformin increases the rate of response to chemotherapy [3]. Metformin has been reported to inhibit growth of various cancer types both in vitro and in vivo [5-7]. In another work, Shell et al. combined HER-2-targeted agents and metformin. Besides synergistic effects, they were found to reduce cardiotoxic side effects by inhibiting AMPK activation in cardiac cells and lower morbidity and mortality rates were observed as a result [8]. Metformin may also prevent resistance in HER-2-based therapy and prolong life. Mammalian target of rapamycin (mTOR) signaling increases mostly in human cancer and mTOR-dependent protein activation is responsible for malignancy progression. It is also associated with poor prognosis and development of resistance [2,4,5]. According to the recent experimental and retrospective studies, DM patients using metformin responded to the radiation therapy better. It was indicated that use of Metformin in non-DM patients can increase the effect of radiation therapy (RT) [2.7]. Sanli et al. implanted Metformin to the treatment plan of lung, prostate, and breast cancer patients while undergoing RT. They indicated that Metformin has radio sensitizer property [6]. According to the recent experimental and retrospective studies, DM patients using metformin responded to the radiation therapy better. It was indicated that use of Metformin in non-DM patients can increase the effect of RT [2.7]. Sanli et al. implanted Metformin to the treatment plan of lung, prostate, and breast cancer patients while undergoing RT. They indicated that Metformin has radio sensitizer property [6]. Metformin is a direct radio sensitizer and reduces tumor stem cell fraction, proliferation, and tumor hypoxia indirectly. Also in certain genetic backgrounds such as loss of tumor suppressors genes like p53 and LKB1 [2,6]. Conclusion In conclusion, limited pre-clinical and clinical studies support the use of metformin as an anti-cancer drug and radio sensitizer. In

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addition, it is known that metformin is reported to enhance the effect of chemotherapy and radiation, especially in cancer related to diabetes. But it is difficult to analyze the initiation of treatment as it has been recently started to be investigated. There are need for prospective studies investigating in which type of cancer Metformin will be used and in those cancers what will be the effectivity/reliability of Metformin. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves. Yasemin Benderli Cihan, ORCID: 0000-0001-9295-4917

References 1.

Ki YJ, Kim HJ, Kim MS, et al. Association between Metformin Use and Survival in Nonmetastatic Rectal Cancer Treated with a Curative Resection: A Nationwide Population Study. Cancer Res Treat. 2016 Jul 4 [Epub ahead of print]

Koritzinsky M. Metformin: A Novel Biological Modifier of Tumor Response to Radiation Therapy. Int J Radiat Oncol Biol Phys. 2015;93:454-64.

Jiralerspong S, Palla SL, Giordano SH, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009;27:3297–302.

Ji-Won Jung, Sang-Bum Park, Soo-Jin Lee, et al. Trosko, Kyung-Sun Kang. Metformin Represses Self-Renewal of the Human Breast Carcinoma Stem Cells via Inhibition of Estrogen Receptor-Mediated OCT4 Expression. PLoS ONE, 2011;6:e28068

Alimova IN, Liu B, Fan Z, et al. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell cycle. 2009;8:909–15.

Sanli T, Rashid A, Liu C, Harding S, et al. Ionizing radiation activates AMPactivated kinase (AMPK): a target for radiosensitization of human cancer cells. Int J Radiat Oncol Biol Phys. 2010;78:221-9.

Wang J, Xia S, Zhu Z. Synergistic effect of phenformin in non-small cell lung cancer (NSCLC) ionizing radiation treatment. Cell Biochem Biophys. 201571:513-8.

Shell SA, Lyass L, Trusk PB, et al. Activation of AMPK is necessary for killing cancer cells and sparing cardiac cells. Cell Cycle. 2008;7:1769–75.

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CASE REPORT

Medicine Science International Medical Journal

Medicine Science 2019;8(1):233-6

Amiodarone induced thyrotoxicosis may not respond to therapeutic plasma exchange like patients with graves’ disease: A report of two cases and literature review Ismail Yildiz, Gulsah Elbuken, Tugay Atasever, Sibel Ozkan Gurdal, Sayid Zuhur Namik Kemal University, Faculty of Medicine, Department of Endocrinology and Metabolism, Tekirdag, Turkey Received 08 August2018; Accepted 26 November 2018 Available online 11.01.2019 with doi:10.5455/medscience.2018.07.8954 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract The achievement of euthyroid state has been suggested in patients with thyrotoxicosis undergoing surgery to reduce the risk of thyroid storm. However, euthyroid state could not always be achieved by antithyroid drugs. Therefore, therapeutic plasma exchange (TPE) is an option in this condition. A 58-year-old male patient with a history of type-2 diabetes using 200 mg amiodarone per day, admitted for diabetic ketoacidosis (DKA), induced by thyrotoxicosis. with palpitation, sweating, polyuria, and polydipsia. Euthyroid state could not be achieved, despite all apropriate treatments for thyrotoxicosis. Therefore, preparation with TPE followed by total thyroidectomy was planned. A 35% decrease in fT3 (free T3) and fT4 (free T4) levels were achieved, after two sessions of TPE. A 74-year-old male patient, admitted for acute anterior myocardial infarction (AMI) induced by thyrotoxicosis due to Graves’ disease. Multiple vessel disease was detected on primer percutanous coronary angiography, and an emergency coronary artery bypass grafting (CABG) was planned. Therefore, preperation with TPE was planned before surgery. A substential decrease in fT4 and fT3 levels (45% and 72%, respectively) levels were achieved, after one session of TPE. Most of the studies evaluating the efficacy of TPE in patients with thyrotoxicosis are including patients with Graves’ disease and toxic multinodular goiter, and TPE was indicated as an effective option for preparation of these patients for surgery. However, as presented in case 1, TPE may not be effective in amiodarone induced thyrotoxicosis (AIT) as in cases with thyrotoxicosis due to Graves’ disease. Keywords: Thyrotoxicosis, amiodarone induced thyrotoxicosis, therapeutic plasma exchange

Introduction The term thyrotoxicosis refers to the hypermetabolic clinical condition resulting from the elevation of the serum thyroid hormone levels [1]. The most common etiologies are Graves’ disease, toxic multinodular goiter and toxic adenoma. Antithyroid drugs, radioactive iodine and thyroidectomy are three conventional treatment options generally selected according to the specific cause of hyperthyroidism [2].

Amiodarone has some side effects on thyroid gland, which are due to amiodarone’s high iodine content or its direct toxic effect on thyrocytes. The type-1 AIT is resulting from excess thyroid hormone synthesis and release, whereas the type-2 AIT is resulting from the destructive thyroiditis that leads to the release of preformed thyroid hormones [5].

Amiodarone is an antiarrhythmic agent used to maintain sinus rhythm after cardioversion of severe ventricular arrhythmias [3]. Each tablet contains 75 mg iodine and 10% of the iodine content is released as free iodine every day [4].

In a patient with severe thyrotoxicosis, or who is going to be operated for different causes, including thyroidectomy, the treatment options to achieve euthyroid state or to decrease fT4 and fT3 levels are lugol solution, glucocorticoids, lithium carbonate, beta blockers, cholestyramine, radiocontrast agents, and finally TPE [6].

*Coresponding Author: Sayid Zuhur, Namik Kemal University, Faculty of Medicine, Department of Endocrinology and Metabolism, Tekirdag, Turkey E-mail: zuhur744@gmail.com

TPE is a blood purification technique that patient’s blood can be separated into its components, with selective removal of the full plasma [7].

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A huge body of evidence supports the use of TPE as a possible treatment option for patients with thyrotoxicosis undergoing surgery for any reason, who are resistant to antithyroid drugs, or those requiring urgent treatment for thyrotoxicosis. However, the effect of TPE on different causes of thyrotoxicosis is not well known so far. Therefore, herein, we present two cases of severe thyrotoxicosis due to AIT and Graves’ disease who responded to TPE, differently. Case presentation Case 1 A 58-year-old male patient with a history of type-2 diabetes, using 200 mg amiodarone per day due to ventricular arrhythmia for several years, admitted to emergency room with palpitation, sweating, polyuria, and polydipsia. The physical examination was unremarkable except for a sinus tachycardia with a heart rate of 130 beats/min. Laboratuary analysis indicated the presence of DKA and thyrotoxicosis. His plasma glucose was 613 mg/dL, arterial pH was 7.19 log [H+], serum TSH was <0.005 mIU/mL (0.4-4), fT3 was 5.47 pg/ml (1.57-5.3), fT4 was 5.3 ng/dl (0.8-1.9) and TSH receptor antibody (TRAb) level was 5.3 IU/L (0-14). Neither nodule nor excess blood flow were present on grayscale and color Doppler ultrasonography of the thyroid gland. After appropriate physical examination and laboratory analysis, the underlying cause of DKA was shown to be associated with AIT. After appropriate treatment for DKA, propronolol 80 mg/ day, methimazole 40 mg/day, and methylprednisolone 60 mg/day were started for thyrotoxicosis. Despite all above treatments, the patient’s general condition deteriorated and his fT4 levels increased to >7.7 ng/dL, 3 weeks after admission (Figure 1). Therefore, total thyroidectomy and preparation with TPE before surgery was planned. TPE was performed with plasma exchange method by Spectra Optia Apheresis System and %5 albumin and isotonic saline were used for replacement of plasma. The exchange volume was 2 L for each session and every session was lasted for two and half hours. After two sessions, fT4 and fT3 levels decreased only modestly to 5.15 ng/dL and 2.22 pg/mL, respectively, which was consistent with a 35% decrease in thyroid hormone levels (Figure 1 and Figure 2). The patient underwent total thyroidectomy under medical treatment. No compliacation developed during or after surgery.

Figure 1. The fT4 levels of case 1 before and after TPE

Figure 2. The fT3 levels of case 1 before and after TPE

Case 2 A 74-year-old male patient admitted to emergency department with chest pain, palpitation, and sweating. On biochemical analysis his serum TSH was <0.005 mlU/mL, fT3 was 10.6 pg/ mL, fT4 was 4.5 ng/dL, and TRAb level was 24 IU/L (0-14). A diagnosis of AMI induced by thyrotoxicosis due to Graves’ disease was made according to ECG and biochemical analysis. Treatment with propranolol 80 mg/day, methimazole 40 mg/day, and 10 drops/ 3 times/ day of lugol solution was started. Multiple vessel disease was detected on primer percutanous coronary angiography and an emergency CABG was planned by cardiology department. Therefore a TPE was performed, after one session, fT4 and fT3 decreased to 2.48 ng/dL, and 2.96 pg/mL (Figure 3 and Figure 4), respectively, which were consistent with 45% and 72% decrease in fT4 and fT3 levels. The patient underwent CABG surgery without any complication. The patient became euthyroid after one month of treatment with antithyroid drugs. Both patients’ fT3 and fT4 levels, before and after TPE, was presented in Figures 1, 2, 3, and 4. Informed consents were obtained from both patients.

Figure 3. The fT4 levels of case 2 before and after TPE

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We used albumin for the replacement of plasma for both patients, because we thought that albumin would increase the binding of free thyroid hormones. However, in most case reports, fresh frozen plasma has been used for this purpose, due to its ability to increase the concentration of thyroglobulin to bind free thyroid hormones [11]. Whether the use of albumin or fresh frozen plasma is more effective in reducing thyroid hormone levels after TPE is not well understood and should be evaluated further.

Figure 4. The fT3 levels of case 2 before and after TPE

Discussion Antithyroid drugs, total thyroidectomy and radioactive iodine ablation are three conventional treatment modalities for the treatment of thyrotoxicosis [2]. In a patient with thyrotoxicosis,an euthyroid state should be achieved or the thyroid hormon levels should be decreased maximally, to minimize the risk of thyroid storm during surgery [8]. If the euthyroid state is not achieved, mortality associated with surgery can be up to 46%. Thyroid surgery should be considered for cases of thyrotoxicosis resistant to antithyroid drugs, and/or complicated with end organ failure that has not responded to the antithyroid drugs and appropriate treatments [9]. Lugol solution, glucocorticoids, lithium carbonate, beta blockers and radio contrast agents are therapeutic options for perioperative preperation of thyrotoxic patients. Sometimes all of these options can fail to achieve euthyroid state, immediately before surgery. TPE may be considered as a rescue treatment option before surgery in this condition, however, its effect is transient and it can not be used as definitive therapy. Our two patients were considered eligible for TPE because other treatment options failed to achieve an euthyroid state and there was no evident contraindication for TPE, such as hemodynamic instability, active infection, bleeding tendency or allergic reaction to albumin [10]. When using TPE as a rescue therapy before thyroidectomy in thyrotoxic patients, the timing for plasma exchange, the type of replacement fluid used, and the number of sessions needed before surgery have to be considered [11]. The number of sessions and the result of every session differ from patient to patient. AIT is an uncommon cause of serious thyrotoxicosis. Little is known about the role of TPE in the treatment of severe AIT, because of the rare occurrence of this condition. Ling Zhu et al. have described a case of type-2 AIT who achieved normal fT3 levels after 2 sessions of TPE [11]. However, in the present case, only 34 and 36% decrease were achieved after two sessions of TPE, in fT4 and fT3 levels.

Recently, in a study including 46 patients (87% with Graves’ disease and %13 with AIT and toxic nodular goiter), Simsir et al. found a significant decrease in fT4 levels after TPE. While 40 patients with Graves’ disease were treated with TPE for an average of 4 sessions, 6 patients with thyrotoxicosis other than Graves’ disease were treated with TPE for an average of 3 sessions. In their study, no significant difference was found between the two groups in terms of the number of TPE sessions [12]. However, the number of patients with AIT in their study was too low to make a comment on this issue. The disease group in which TPE is most effective is autoimmune diseases. Therefore, as an autoimmune disease, Graves’ disease is expected to benefit significantly from TPE. The results of case 2 in this paper supports this argument as a 45 and 72% decrease were achieved in fT4 and fT3 levels, respectively. Nevertheless, some cases of Graves’ disease unresponsive to TPE have been reported. Guillermo E. et al. described a patient with Graves’ disease who did not achieve a decrease in fT3 and fT4 levels after 2 sessions of TPE [13]. It is still unclear why some patients achieve the maximum benefit from TPE, regardless of the etiology, while some others did not respond. Up to date, it is not clear which factors are responsible for determining the patient’s response to TPE. Now, it is believed that the levels of fT4, fT3 and anti thyroid antibodies is a good initial way to approach the problem. If no change is noted in the levels of fT4 and fT3 six hours after the first session of TPE, there is no justification for an additional TPE session [13]. TPE is indicated as a bridge therapy before surgery for patients unresponsive to medical therapy for thyrotoxicosis, and is an option for the prevention of thyroid storm. In our first case thyrotoxicosis was due to AIT and TPE achieved only 35% decrease in plasma thyroid hormone levels, but it was still a good result before surgery. If euthyroid state is not possible to achieve, decreasing plasma thyroid hormone levels, as low as possible, may prevent the development of thyroid storm during surgery. Conclusion Plasmapheresis is a therapeutic procedure that is successfully used in the treatment of thyrotoxicosis in selected patients who need more rapid hormonal control, and who develop complications associated with anti-thyroid drugs. Although the first case with AIT achieved a temporary decrease in thyroid hormon levels, it did not provide a significant decrease in thyroid hormone levels before surgery. But in the second case with Graves’ disease, euthyroid state was achieved almost after one session of TPE. Most of the studies evaluating the efficacy of TPE in patients with thyrotoxicosis are including patients with Graves’ disease and toxic 235

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multinodular goiter, and TPE was indicated as an effective option for preparation of these patients for surgery. However, as presented in case 1, TPE may not be effective in patients with AIT as much as in patients with Graves’ disease. Further studies shoulde be carried out to adress the effect of TPE in patients with AIT.

Kennedy RL, Griffiths H, Gray TA. Amiodarone and the thyroid. Clin Chem. 1989;35:1882-7.

Newman CM, Price A, Davies DW, et al. Amiodarone and the thyroid: A practical guide to the management of thyroid dysfunction induced by amiodarone therapy. Heart. 1998;79:121-7.

Competing interests The authors declare that they have no competing interest

Fischli S, Lucchini B, Müller W, et al. Rapid preoperative blockage of thyroid hormone production / secretion in patients with Graves’ disease. Swiss Med Wkly. 2016;14;146:14243.

Restrepo CA, Márquez E, Sanz MF. Plasmaféresis terapéutica, tipos, técnica e indicaciones en medicina interna. Acta Med Colomb. 2009;34:23-32.

Baeza A, Aguayo J, Barria M, Pineda G. Rapid preoperative preparation in hyperthyroidism. Clin Endocrinol. 1991;35:439-42.

Scholz GH, Hagemann E, Arkenau C, et al. Is there a place for thyroidectomy in older patients with thyrotoxic storm and cardiorespiratory failure? Thyroid. 2003;13:933-40.

Financial Disclosure The financial support for this study was provided by the investigators themselves. Ismail Yildiz ORCID: 0000-0002-4990-0216 Gulsah Elbuken ORCID: 0000-0002-0920-6895 Tugay Atasever ORCID: 0000-0002-3174-1050 Sibel Ozkan Gurdal ORCID: 0000-0001-5649-6699 Sayid Zuhur ORCID: 0000-0001-8084-848X

References 1.

Braverman L, Utiger R. Introduction to thyrotoxicosis. In: Braverman L, Utiger R eds. The Thyroid. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2005;453-5.

Bahn Chair RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis. Management guidelines of the American thyroid association and American association of clinical endocrinologists. Thyroid. 2011;21:593-646.

Goldschlager N, Epstein AE, Naccarelli G, et al. Practical guidelines for clinicians who treat patients with amiodarone. Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology. Arch Intern Med. 2000;26;160:1741-8.

10. Mokrzycki MH, Kaplan AA. Therapeutic plasma exchange complica¬tions and management. Am J Kidney Dis. 1994;23:817-27. 11. Zhu L, Zainudin SB, Kaushik M, et al. Plasma exchange in the treatment of thyroid storm secondary to type II amiodarone-induced thyrotoxicosis. Endocrinol Diabetes Metab Case Rep. 2016;160039. 12. Simsir IY, Ozdemir M, Duman S, et al. Therapeutic plasmapheresis in thyrotoxic patients. Endocrine. 2018;62:144-8. 13. Guzmán GE, Bautista DF, Arango LG, et al. Therapeutic plasmapheresis in patients with thyrotoxicosis. Report of Two Cases. Rheumatology. 2015;5:162.

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Terra firma-forme dermatosis: Two cases Dursun Turkmen Malatya Training and Research Hospital, Clinic of Dermatology, Malatya, Turkey Received 23 May2018; Accepted 20 June 2018 Available online 28.09.2018 with doi: 10.5455/medscience.2018.07.8890 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Terra firma-forme dermatosis is a dermatosis with unknown etiology which causes dirt-like colour changes on the skin. It is frequently seen in children and adolescents. Its clinical emergence is in the form of gray-brown, mildly papillomatous, pigmented plaques especially on the face, neck, trunk and ankles. Lesions can’t be cleaned by water and soap; they can only be cleaned by rubbing with isopropyl alcohol or ethyl alcohol. In this study, two cases with terra firma-forme dermatosis were defined and the subject was reviewed in the light of literature. Keywords: Dermatosis, terra firma-forme, Duncan’s dirty dermatosis, isopropyl alcohol

Introduction Terra firma-forme dermatosis (TFFD) is a dermatosis with unknown aetiology, which causes dirt-like color changes on the skin [1]. While it is frequently seen in children and adolescents, there are cases of all ages in literature [2,3]. Its clinical emergence is in the form of gray-brown, mildly papillomatous, pigmented plaques especially on the face, neck, trunk and ankles and with less frequency on hairy skin, lips, belly button and extremities [1,4]. Lesions can’t be cleaned by water and soap; they can only be cleaned by rubbing with isopropyl alcohol or ethyl alcohol [1,3].

could not clean them. Her dermatological examination showed gray-brown hyperpigmented plaque lesions with a diameter of 4-5 cm on the medial side of left forearm, which were not clearly demarcated. A similar lesion was found on medial sides of bilateral ankle (Figure 1). The lesions were found to disappear when cleaned by rubbing lightly with a sponge wet with 70% alcohol.

This study presents two cases diagnosed with TFFD, which is rare but quite easy to treat once it is known. Case Report Case 1 A five-year-old girl referred to our outpatient clinic with her mother with complaints of non-healing spots on the arm and ankles. The mother said that the spot on the arm had been there for two years, while she had realized the ones on the legs recently. She stated that she tried lots of things to wash away dirt-like spots, but she

*Coresponding Author: Dursun Turkmen, Malatya Training and Research Hospital, Clinic of Dermatology, Malatya, Turkey E-mail: drturkmen44mlt@gmail.com

Figure 1. Gray-brown hyperpigmented plaque lesions on the medial sides of ankles

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Case 2 A seventeen-year-old female patient referred with intense brown spots on the face, neck and arm. The spots, which started on the face, a year ago had spread to other parts. The patient who did not have a complaint of itching stated that when she tried to make the spots which looked like dirt disappear by scrubbing, her skin was peeled but the spots never disappeared, instead they increased gradually. Her dermatological examination showed intense gray-brown hyperpigmented macular and plaque lesions on the forehead, cheeks, neck and medial side of left forearm which were not clearly demarcated (Figure 2) Cheek lesions reminded of melasma at first, however, the fact that the areas which did not receive the sun also had lesions brought TFFD to our mind. The lesions disappeared when cleaned by rubbing lightly with a sponge wet with 70% alcohol (Figure 3) and thus the diagnosis was made definitive.

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While a great number of factors have been put forward etiologically such as familial transmission, genetic predisposition, exposure to sun and delayed or missing keratinisation disorder [2,6,7]. It has also been put forward to occur with the accumulation of sebum, sweat and microorganisms in addition to melanin retention due to deterioration in the keratinocyte aging of varicose plaques [8]. The fact that lesions were more intense on the areas of the face which received sun in our second case brings to mind that exposure to sun can be a factor which increases lesions. When it is not thought of, unnecessary biopsies are made for diagnosis. Focal compact orthokeratosis was found with histopathologically lamellar hyperkeratosis, while increasing of melanin was found on basal layer and compact hyperkeratotic areas with Fontana-Masson staining [1]. In our cases, since TFFD diagnosis was brought to mind during first admission, diagnosis and treatment were made together. Dermatitis neglecta is considered the most in definitive diagnosis. Unlike TFFD, cases with Dermatitis neglecta have hygiene disorder. The lesions can be cleaned with both water and soap and alcohol. In TFFD, they continue by becoming more obvious when not treated [5]. Before referring to invasive methods to make a diagnosis and to move away from diseases considered in definitive diagnosis, it is enough for the diagnosis to clean the lesion area with 70% isopropyl alcohol. In both of our cases, we confirmed out diagnosis by cleaning the area with sponge wet by 70% isopropyl alcohol. Conclusion

Figure 2. Intense gray-brown hyperpigmented macular and plaque lesions on the forehead, cheeks, neck

As a conclusion, TFFD is rare; however, its treatment is quite easy when it comes to mind. In patients who refer with hyperpigmentation, TFFD should also be considered in definitive diagnosis. When met with a suspicious lesion, the lesion should be cleaned with 70% isopropyl alcohol to find out whether it is TFFD and unnecessary diagnostic methods and treatments should be avoided. Financial Disclosure The financial support for this study was provided by the investigators themselves. Dursun Turkmen ORCID:0000-0001-9076-4669

References

Figure 3. The lesions disappeared when cleaned by rubbing lightly with a sponge

Duncan WC, Tschen JA, Knox JM. Terra firma-forme dermatosis. Arch Dermatol. 1987;123:567-9.

Berk DR, Bruckner AL. Terra firma-forme dermatosis in a 4-month-old girl. Pediatr Dermatol. 2011;28:79–81.

Berk DR. Terra firma-forme dermatosis: a retrospective review of 31 patients. Pediatr Dermatol. 2012;29:297-300

Guarneri C, Guarneri F, Canavo S. Terra firma-forme dermatosis. Int J Dermatol. 2008; 47:482–4.

Browning J, Rosen T. Terra firma-forme dermatosis revisited. Dermatol Online J. 2005;11:15.

Pavlovic MD, Dragos V, Potocnik M, Adamic M. Terra firma-forme dermatosis in a child. Acta Dermatovenerol Alp Panonica Adriat. 2008;17:41-2.

Sezgin AÖ, Gerçeker Türk B, Yaman B, Dereli T. Terra firma-forme dermatozu. TÜRKDERM. 2013;47:187-9.

Ashique KT, Kaliyadan F, Goyal T. Terra firma-forme dermatosis: report of a series of 11 cases and a brief review of the literature. Int J Dermatol. 2016;55:769-74.

wet with 70% alcohol

Discussion Terra firma-forme dermatosis was first defined by Duncan [1] in 1987 as “Duncan’s dirty dermatosis”. It is known that the disease, the etiology of which is not completely clear, is not associated with insufficient hygiene. Very few cases have been reported in literature [3,5]. Its frequency is thought to be more than its actual frequency since its clinical appearance can be mistaken for a great number of dermatological diseases which course with pigmentation increase such as acanthosis nigricans, confluent and reticulated papillomatosis, dermatitis neglecta, neurodermatitis and tinea versicolor and it can be misdiagnosed [1, 3-5].

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CASE REPORT

Medicine Science International Medical Journal

Medicine Science 2019;8(1):239-41

Fascia iliaca block for postoperative analgesia in a hip fracture patient Onur Baran1, Ayhan Sahin2, Bunyamin Kir1, Irem Ates1 2

1 Palandoken State Hospital, Department of Anesthesiology and Reanimation, Erzurum, Turkey Namik Kemal University, Medicine Faculty, Department of Anesthesiology and Reanimation, Tekirdag, Turkey

Received 13 May 2018; Accepted 25 June 2018 Available online 01.10.2018 with doi: 10.5455/medscience.2018.07.8889 Copyright ÂŠ 2019 by authors and Medicine Science Publishing Inc. Abstract The incidents of hip fractures rise as the population gets older. Weakness of bones cause fractures easily due to falling, which can occur by balance deficiency, side effects of medications and maneuvering difficulties through environmental hazards. Patients with hip fractures are cared by clinicians in different specialties who should be familiar with the management of these injuries. The fascia iliaca compartment block, an easy to perform and low-cost procedure, provides efficient perioperative analgesia for patients who suffer from hip or femur fractures. Increased success rates are due to the facilitation of the block via ultrasound which is easily accessible in many operation theaters and emergency services. Anterior thigh and knee surgery as well as analgesia following hip and knee procedures are the basic indications for this block. In this case, we performed an ultrasound guided fascia iliaca compartment block for postoperative analgesia after a hip fracture surgery. Keywords: Fascia iliaca compartment block, ultrasound guidance, hip fracture

Introduction The incidents of hip fractures rise as the population gets older. Weakness of bones cause fractures easily due to falling, which can occur by balance deficiency, side effects of medications and maneuvering difficulties through environmental hazards. Patients with hip fractures are cared by clinicians in different specialties who should be familiar with the management of these injuries [1]. The fascia iliaca compartment block (FICB) was initially described by Dalens et al. on children using a landmark technique. It is an easy to perform and a low-cost procedure which provides efficient perioperative analgesia for patients who suffer from hip or femur fractures. Increased success rates are due to the facilitation of the block via ultrasound which is easily accessible in many operation theaters and emergency services. Anterior thigh and knee surgery as well as analgesia following hip and knee procedures are the basic indications for this block [2].

*Coresponding Author: Onur Baran, Palandoken State Hospital, Department of Anesthesiology and Reanimation, Erzurum, Turkey E-mail: dronurbaran@hotmail.com

The fascia iliaca block (also called the fascia iliaca compartment block) is considered an alternative to a femoral nerve or a lumbar plexus block [3]. Case Report A 65-year-old male who had hip fracture after ground-level falling was scheduled for operation by the Orthopedics and Traumatology Department. The patient was evaluated bedside preoperatively. He was 75 kg and had no systemic disease, no surgery history but 40 packets/year smoking history. The patient was consulted to the Department of Chest Diseases. Chronic obstructive pulmonary disease was diagnosed and general anesthesia was found to be too risky for him. As blood count and coagulation marks were in normal ranges, he was planned for regional anesthesia. After getting patientâ&#x20AC;&#x2122;s written consent, elective surgery was planned. Routine monitorization including standard heart rate, electrocardiography, non-invasive arterial pressure and peripheral oxygen saturation was made after getting the patient to the operation theatre. 2 mg midazolam was admitted iv for sedation. The patient was positioned lateral decubitus to upside the fractured extremity. Spinal anesthesia was admitted in sterile conditions and 2 ml of 0.5% bupivacaine was preferred for a hypobaric solution. Surgery was allowed after ensuring adequate anesthesia. After 3 hours of surgery with no intraoperative complications, fascia iliaca 239

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block was agreed for postoperative analgesia.

Discussion

The patient was positioned supine, inguinal crease was cleared with povidone-iodine and covered up sterilely. Sonosite M-Turbo ultrasound machine (FujiFilm SonoSite®, WA, USA) with 6–13 mHz linear probe covered by sterile cover and 100 mm 21G ultrasound needle (PAJUNK® GmbH Medizintechnologie, Germany) was used.

Hip fracture patients are in severe pain and pain treatment is traditionally based on systemic opioids, which have a large potential for side effects in these frail and elderly patients [47]. Postoperative analgesia has many benefits such as decreased morbidity, facilitation of postoperative rehabilitation and reducing postoperative hospital discharge time [8, 9].

Firstly, pulsating femoral artery was found in the infrainguinal region with the transversely located ultrasound probe. While moving the probe laterally, sartorius muscle, iliacus muscle and iliac fascia were identified. As the analgesia of spinal anesthesia continues, no local anesthesia was made and the needle was inserted in an in-plane technique. Under the ultrasound image, the needle was clearly visible and skin, subcutaneous adipose tissue, fascia lata, sartorius muscle and the posterior fascia of sartorius muscle was passed (Figure 1). While passing through the fascia lata and the posterior fascia of sartorius muscle, “pop” was felt twice. 30 ml of 0.5% bupivacaine was injected with care with episodic aspirations. The distribution of local anesthetic between the sartorius and iliacus muscles was observed (Figure 2).

In this case, we preferred ultrasound guided fascia iliaca block to facilitate the management of postoperative pain after hip surgery, which is very painful. As we could have made spinal anesthesia in lateral decubitus position easily, we made the blockade under spinal anesthesia just after the surgery.

After the procedure, the patient was transferred to the orthopedics and traumatology service and the 2nd, 6th, 12th VAS scores were recorded as 0 – 1 and 3. The patient was comfortable and had no severe pain after the operation. As no postoperative complication was seen, the patient was discharged from hospital by Orthopedics and Traumatology Department after 3 days.

Domaç et al. aimed to search the effect of preoperative fascia iliaca compartment block on postoperative analgesic use in patients with femoral fracture. 40 patients were enrolled in the study, where 20 patients were in the block group and 20 patients were in the control group. In the block group, they made fascia iliaca block preoperatively and performed spinal anesthesia 30 minutes after the block. Postoperative VAS scores were as follows: 0.8 ± 1.1, 2.8 ± 0.8, 2.9 ± 0.7, and 2.4 ± 0.5, which was significantly less than the control group and they found it easier to position the patient for spinal anesthesia in the block group [10]. Among hip fractures and thrombectomy operations, fascia iliaca block is used for reduction of hip dislocations in the emergency rooms. A 22-year-old man with no previous history of hip pain or injury was brought to the emergency service after a motor vehicle accident. After the evaluation, an anterior dislocation of the hip was diagnosed. The physicians elected to perform a fascia iliaca block with light sedation to reduce the dislocation. Under ultrasound guidance 40 ml of 0.2% ropivacaine was injected and the hip was reduced after adequate block was supplied [11]. Kaldirim et al. also performed a fascia iliaca block for dislocated hip reduction in emergency service. After being struck by a motor vehicle, a 26-year-old male was brought to the emergency service. A total of 30 ml injection was used for this patient, which contained of 10 ml normal saline, 10 ml 0.5% bupivacaine and 10 ml 1% lidocaine and the reduction of the dislocated femur was made successfully [12].

Figure 1. The advancing needle through the sartorious muscle

Conclusion Ultrasound guided fascia iliaca compartment block can be used for reducing hip dislocations, positioning patients for spinal anesthesia in hip fractures, postoperative analgesia and even for thrombectomy. It’s easy and safe to perform, long lasting and efficient for postoperative analgesia. Competing interests The authors declare that they have no competing interest. Financial Disclosure The financial support for this study was provided by the investigators themselves.

Figure 2. The spread of local anesthetic in the compartment of iliac fascia

Onur Baran ORCID:0000-0003-0007-6315 Ayhan Sahin ORCID:0000-0002-3539-2353 Bunyamin Kir ORCID:0000-0001-6158-4351 Irem Ates ORCID:0000-0001-9867-5011

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References

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Foss NB, Kristensen BB, Bundgaard M, et al. Fascia iliaca compartment blockade for acute pain control in hip fracture patients: a randomized, placebo-controlled trial. Anesthesiology. 2007;106:773-8.

Capdevila X, Barthelet Y, Biboulet P, et al. Effects of perioperative analgesic technique on the surgical outcome and duration of rehabilitation after major knee surgery. Anesthesiology. 1999;91:8-15. Kehlet H, Holte K. Effect of postoperative analgesia on surgical outcome. Br J Anaesth. 2001;87:62-72.

Katherine Walker Foster M. Hip fractures in adults 2014. Available from: https://www.uptodate.com/contents/hip-fractures-in-adults - H31.

Range C, Egeler C. Fascia Iliaca Compartment Block. Anaesthesia Tutorial of The Week. 2010;193.

Hadzic A. Hadzic’s Textbook of Regional Anesthesia and Acute Pain Management, Secon Edition: McGraw-Hill; 2017.

Roberts HC, Eastwood H. Pain and its control in patients with fractures of the femoral neck while awaiting surgery. Injury. 1994;25:237-9.

Herr K, Titler MG, Schilling ML, et al. Evidence-based assessment of acute pain in older adults: current nursing practices and perceived barriers. Clin J Pain. 2004;20:331-40.

10. Aladdin Domaç, Ebru Kelsaka, Sarıhasan B. The effect of preoperative fascia iliaca compartment block on postoperative analgesic use in patients with femoral fracture. J Anaesth. 2015;23:144-51.

Foss NB, Kristensen MT, Kristensen BB, et al. Effect of postoperative epidural analgesia on rehabilitation and pain after hip fracture surgery: a randomized, double-blind, placebo-controlled trial. Anesthesiology. 2005;102:1197-204.

11. West C, Ranganath Y, Willey M. Fascia Iliaca Block for Reduction of Anterior Native Hip Dislocation: a Case Report. Iowa Orthop J. 2017;37:1921. 12. Kaldirim U, Dural F, Tuncer SK, et al. Fascia iliaca compartment block in dislocated hip reduction. Afr J Emerg Med. 2015;5:e11-e3.

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CASE REPORT

Medicine Science International Medical Journal

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Common Demodex spp. identified on the arm and abdominal region of patient monitored for widespread pruritus Yasemin Kaya1, Sevda Onder2, Ulku Karaman3, Gamze Kacmaz4 Ordu University Medicine Faculty Department of Internal Medicine, Ordu, Turkey 2 Ordu University Medicine Faculty Department of Dermatology, Ordu, Turkey 3 Ordu University Medicine Faculty Department of Medical Parasitology, Ordu, Turkey 4 Giresun University Science Literature Faculty Department of Medical Microbiology Giresun, Turkey 1

Received 11 April 2018; Accepted 16 July2018 Available online 01.10. 2018 with doi: 10.5455/medscience.2018.07.8888 Copyright ÂŠ 2019 by authors and Medicine Science Publishing Inc. Abstract Demodex mite is a compulsory human ecto-parasite situated in or near pilo-sebase units. Demodex folliculorum and Demodex brevis are two species found in humans. In this case; there were long-term complaints of severe pruritus (six months), and common erythematous papules on the body. Other physical examination findings, complete blood count, biochemistry, sedimentation and C-reactive protein levels were normal. However, Demodex spp. was detected in standard superficial skin biopsy taken from the patientâ&#x20AC;&#x2122;s skin. Demodex should be considered prediagnosis for unexplained and continued pruritus complaints and maculopapular lesions. Keywords: Demodex, house dust mite, pruritus

Introduction Demodex mites are compulsory human ecto-parasites that have to exist within or near pilosebaceous units [1].The demodex species of Demodex folliculorum and Demodex brevis are commonly encountered in humans. It has been reported that they feed with epithelial cells and cause skin diseases in humans [2-4]. All skin diseases caused by demodex mites are called demodicosis. In the literatures it has been reported that some species of demodex play a role in the pathogenesis of rosacea, acne vulgaris, perioral dermatitis, seborrheic dermatitis, pustular folliculitis and blepharitis. It also spreads from human to human close contact [4,5-10]. Demodex infestations in humans are usually asymptomatic. Increased pathogenicity in mites may occur due to skin care is not taken care of, intensive use of cosmetic products and not direct washing of these products, increase in sebum production with sweating as in summer, the immune system is congenital *Coresponding Author: Yasemin Kaya, Ordu University Medicine Faculty Department of Internal Medicine, Ordu, Turkey E-mail: ysmnkcmz@gmail.com

inadequate or afterwards immune deficiency development (use of steroids ect.) [4,11]. It has been reported that under normal conditions there are mechanisms to control the increase in the mite population in follicles, but some local and systemic factors can increase the proliferation of parasites [4,9,11]. This case report presents a patient applying with pruritus complaint for more than 6 months and and Demodex spp.caused by pruritus. This case was presented in order to draw attention to the fact that Demodex species may cause these complaints even though physical findings and blood tests are normal in common pruritus cases. Case Report sA seventy-year old male patient had applied to several clinics with complaints of severe pruritus continuing for 6 months on the abdomen, groin, hips, shoulder and chest regions. He received a variety of diagnoses and used a variety of medications but the complaints had not resolved. The patient had previously used Tavegyl (clemastine), fexofen (fexofenadine), lordes (desloratadine), fucidin cream (fusidic acid), excipial lotion (urea (carbamide)), terminus (Terbinafine), clovate (Clobetasol Propionate), hipokort 242

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(hydrocortisone acetate), and for scabies diagnosis Kwellada lotion (5% permethrin) medications. The anamnesis of the patient was taken and physical examination performed. The patient had hypertension, and benign prostate hyperplasia and Dermatologic examination observed widespread erythematous, occasionally excoriated macules and papules on the body but it was not found clear pathology in the other physical examination (Figure 1). Whole blood count, biochemical parameters, sedimentation, and C-reactive protein levels were normal. Ig E levels were measured as 293.5 IU/ml (normal range; 1-100 IU/ml). The patient was sent to Ordu University parasitology laboratory for stool examination and to take samples for house dust mites. The patient provided a stool sample and had skin sample taken using standard surficial skin biopsy methods. The stool sample and skin sample were examined with a light microscope. Considering a parasite living on the skin may cause pruritus, samples from the calf and abdomen were examined and Demodex spp. were identified (Figure 2). As mites were found in dust from the patientâ&#x20AC;&#x2122;s house, treatment was begun and he was called for check-up one month later. The patientâ&#x20AC;&#x2122;s complaints had resolved, lesions were regressing and there was a reduction in the number of mites. At check-up two months after treatment, lesions had healed (Figure 3). There was a clear reduction in the density of Demodex spp.

Figure 1. Erythematous, occasional excoriated macules and papules

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Figure 3. Two months after starting treatment

Discussion The most common demodex species found on humans of D. folliculorum and D. brevis spend all stages of their lives in hair follicles and sebaceous glands [1]. Demodicosis is a parasitic skin disease caused by follicular parasites including D. folliculorum and D. brevis. These parasites may be localized on the face, hairy skin, hair follicles, oil-secreting glands of the skin, eyelashes, forehead, nose, ear and genital areas. Demodex species feed on oil and protein-rich fluid found in inflamed follicles. Though the pathologic mechanism is still not fully known, the medical significance of this parasite that may spread through close contact is still debated. They may be found in a variety of areas of the body. They may be seen on healthy skin, hair follicles and oil glands without any pathologic situation. When the immune system is suppressed the incidence of the parasites increases and an abnormal immune reaction and skin lesions may be provoked. In the literature it is reported that demodex parasites are more commonly observed in patients with suppressed immune system and those who use immunsuppressive medications [12]. Our patient did not have any immunsuppressive disease identified in anamnesis. Additionally there was no history of using immunsuppressive medications. A study of Demodex spp. identified in this case has been completed in our city. A total of 799 individuals, 438 males and 361 females aged above 18 years, had samples taken with standard surficial skin biopsy methods from the facial region and parasites were encountered in 669 (83.7%) samples [4]. Our patient had dense amounts of Demodex spp. identified in the abdominal, groin, hip, shoulder and chest regions.

Figure 2. Two mature Demodex spp. in a sample taken from the arm

Electron microscope studies have shown that Demodex spp. has a piercing oral structure and the mouth destroys adipose tissue and carries a variety of bacteria into the skin. Within the skin epithelium cells and sebum are used as sources of nutrition. Though the correlation of demodex with a variety of skin diseases has been shown in publications, the pathologic effects in the occurrence of skin diseases is still a topic of debate[1]. Recent studies have reported Demodex spp. may be a factor in diseases like rosacea, acne vulgaris, blepharitis, perioral dermatitis, pustular folliculitis, papulopustular lesions of hairy skin, pityriasis 243

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folliculorum, pustular lesions in basal cell carcinoma and acquired immunodeficiency syndrome along with blepharitis, keratoconjunctivits and recurring salivary [13,14]. In our case, erythematous excoriated macules and papules had developed on the body due to widespread pruritus.

Ulku Karaman ORCID:0000-0017-0271-613 Gamze Kacmaz ORCID: 0000-0002-3125-9379

Akcınar UG, Unal E, Akpınar M. Tedaviye direçli şalazyon ve folikülit ile ilişkili Demodexspp. enfestasyonu. Turkiye Parazitol Derg 2016;40:208-10.

Pruritus is defined as an unwanted situation of itchy skin resulting in irritation. Pruritus may be classified as acute or chronic. According to the guidelines of the International Forum for the Study of pruritus, pruritus may be classified as lasting 6 weeks or more [15]. Our patient’s pruritus had continued for nearly 6 months and possible diseases were assessed as a cause of chronic pruritus.

Aycan ÖM, Otlu GH, Karaman Ü, ve ark. Çeşitli hasta ve yaş gruplarında Demodex sp. görülme sıklığı. Türkiye Parazitoloji Dergisi. 2007;31:115-8.

Karaman U, Şener S, Çelik T, ve ark. Derinin enfeksiyoz ve benign durumlarında histopatolojik yöntemle Demodex spp. araştırılması. İnönü Üniversitesi Tıp Fakültesi Dergisi. 2008;15:5-7.

RatherPA, Human IH. Demodex mite: the versatile mite of dermatological importance. Indian J Dermatol. 2014;59:60–6.

Pelletier JS, Capriotti K, Stewart KS, et al. Demode Blepharitis Treated with a Novel Dilute Povidone-Iodineand DMSO System: A Case Report. Ophthalmol Ther. 2017;6:361-6.

Moran EM, Foley R, Powell FC. Demodexand rosacea revisited. Clin Dermatol. 2017;35:195-200.

Zhao YE, Hu L, Wu LP, et al. A meta-analysis of association between acne vulgaris and Demodex infestation. J Zhejiang UnivSci B. 2012;13:192-202.

Tehrani S, Tizmaghz A, Shabestanipour G. The Demodex mites and their relation with seborrheic and atopic Dermatitis. Asian Pac J Trop Med. 2014;7:82-4.

Rufli T, Mumcuoglu Y, Cajacob A, et al. Demodexfolliculorum: aetiopathogenesis and therapy of rosacea and perioral dermatitis (author’stransl). Dermatologica. 198;162:12-26.

The cause of pruritus is not known in 8-15% of patients. The International Forum for the Study of pruritus divided the causes of pruritus into 5 groups according to etiology; skin diseases, systemic diseases, neurologic diseases, psychological problems, mixed diseases and other undefined causes. Skin diseases causing pruritus include psoriasis, atopic dermatitis, contact dermatitis, dry skin, invisible dermatoses, inflammatory dermatoses like medication reactions, infectious dermatoses, autoimmune dermatoses, genodermatoses, pregnancy dermatoses and neoplasms. Common causes include mycotic, bacterial, and viral skin infections, folliculitis, scabies, pediculosis, arthropod reactions and insect bites [15]. Demodex spp. infestation is a significant public health problem. As a result it is necessary for clinicians to be aware of this topic. Conclusion We present our case to draw attention to the fact that in addition to infesting the human body, Demodex spp. may cause widespread pruritus common in every region where follicles are found, contrary to the general literature. In conclusion, in patients applying with resistant pruritus of the face and body, identification of infestation by house dust mites and Demodex spp. may play a role in diagnosis. In this way it is recommended that in addition to diagnosis, broad series comprehensive controlled studies be completed. Competing interests The authors declare that they have no competing interest. Financial Disclosure The financial support for this study was provided by the investigators themselves. Yasemin Kaya ORCID: 0000-0001-7360-8090 Sevda Onder ORCID: 0000-0002-2213-6292

References

10. Yun CH, Yun JH, Baek JO, et al. Demodex mite density determinations by standardized skin surface biopsy and direct microscopic examination and their relations with clinical types and distribution patterns. Ann Dermatol. 2017;29:2. 11. Karaman Ü, Kolören Z, Enginyurt Ö, et al. Prevalence of demodexectoparasites among humans in orduprovincein Turkey. South east Asian J Trop Med Public Health. 2016:47;207-13. 12. Karaman U, Kolören Z, Enginyurt Ö, et al. The epidemiology of demodex mites at the college students living in dormitories in thecity of Ordu. Turkiye Parazitol Derg. 2014;38:166-71. 13. Dokuyucu R, Kaya OA, Yula E, et al. The Presence of Demodexfolliculorum in Various Obese Groups Accordingto BMI Levels. Arch Iran Med. 2016;19:210-4. 14. Yula E, Kaya OA, Atambay M, et al. Blefarit Etiyolojisinde Demodexfolliculorum ve D. brevis’ in Onemi Nedir? Turkiye Klinikleri J Med Sciences. 2013;33:420-4. 15. Ständer S, Weisshaar E, Mettang T, et al. Clinical classification ofitch: a position paper of the International Forum for the Study of Itch. Acta Derm Venereol. 2007;87:291-4.

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CASE REPORT

Medicine Science International Medical Journal

Medicine Science 2019;8(1):245-6

Acute aortic transection caused by traffic accident: As a forensic case Ahsen Kaya, Ali Varlihan, Ekin Ozgur Aktas Ege University, Faculty of Medicine, Department of Forensic Medicine, İzmir, Turkey Received 06 August 2018; Accepted 28 August 2018 Available online 26.09.2018 with doi: 10.5455/medscience.2018.07.8886 Copyright © 2019 by authors and Medicine Science Publishing Inc. Abstract Traffic accidents are one of the most common causes of blunt traumatic injuries and also significant causes of mortality and morbidity. To know injury patterns of traffic accidents will ensure early medical intervention and will reduce mortality and morbidity and also will facilitate the assessment of prevailing findings in criminal and compensation cases. In this case report, it was aimed to draw attention to the forensic subjects and the features of forensic cases via a 46-year-old male patient who had acute aortic transection due to traffic accidents. Keywords: Traffic accident, injury patterns, aortic transection, mortality, morbidity

Introduction Traffic accidents are one of the most common causes of blunt traumatic injuries and forensic incidents. Behind this, they are significant causes of mortality and morbidity. Blunt traumatic aortic injuries which most commonly occur in traffic accidents are life-threatening lesions [1,2]. It is reported that approximately 80% of patients with aortic injuries died at the scene and half of the remaining patients died within 24 hours if not intervened emergently [3]. So, to know injury patterns of traffic accidents will ensure early medical intervention and will reduce mortality and morbidity. In this case report, it was aimed to draw attention to the forensic subjects and the features of forensic cases via a 46-yearold male patient who had acute aortic transection due to traffic accidents. Case Report A 46-year-old male injured in traffic accident when his car collided on another one. On the same day he was brought to university hospital by an ambulance. On arrival, chest pain was the only complaint he stated. He was examined in Emergency Medicine Department, none of the findings noted was suggesting any pathology apart from mild hypotension. His complaints-oriented, contrast-enhanced thoraco-abdominal computed tomography

*Coresponding Author: Ahsen Kaya, Ege University, Faculty of Medicine, Department of Forensic Medicine, İzmir, Turkey E-mail: pekcanahsen@yahoo.com

angiography (CTA) was performed. CT images revealed traumatic full layer transection of descending aorta and periaortic hematoma on same level as transection. Left atrium was partially pressed by hematoma. Additionally, displaced fracture of left sixth rib, non-displaced fracture of left seventh rib and atrophy of right kidney were noted. Therefore, emergency endovascular treatment was planned. All of the patient’s laboratory findings were within reference values of university hospital. When questioned for his medical history before operation, his history of 35 years of smoking and diagnosis of benign prostate hyperplasia were noted. There were no predisposing diseases suggesting aortic dissection such as hypertension, connective tissue diseases, underlying aortic malformations and so on. He was operated aiming repair of Type 3 aortic dissection the day after the accident. No endoleak was seen during postoperative angiography. Then he was taken to Intensive Care Unit, two units of erythrocyte suspension were replaced to him and after a night long stay there, he was transferred to Cardio-vascular Surgery Department. On the first postoperative day, he came up with intense bronchial secretion complaint and had fever at the same time; his medical treatment was regulated by Infectious Diseases Department. He was discharged on the eighth postoperative day, no complications were found on following examinations. When questioned for the details of accident, the patient stated that he was driving the car when another car hit his one head on head. He was conscious, his seatbelt was fastened and airbags on his chest level were activated just after the crush. His length was measured 171 centimeters, and his weight was 84 kilograms. 245

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Discussion Blunt aortic injuries are most commonly the result of traffic accidents [4]. Descending thoracic aorta as in this case, is the most frequent anatomic region of injury regardless of the mechanism, followed by multi-location injuries and aortic arch [2]. Aortic dissections caused by acute trauma have high risk of mortality [5]. 80% of aortic injuries die in the scene and half of the survivors die as well in following 24 hours if not treated urgently [2,3]. It is a critical issue to make a diagnosis of aortic dissection due to a traffic accident quickly and to make the treatment without losing time. Injury patterns and traffic accident’s characteristics affect mortality and morbidity of the cases [6]. To know traffic accident’s characteristics and injury patterns will ensure early medical intervention and will reduce its mortality and morbidity. There is usually no specific physical examination finding in these cases [5]. In the present case, no speciﬁc symptom was noted, too. Mild hypotension and chest pain were the only findings on physical examination. However, as a result of the radiological examinations, the diagnosis was made quickly and the treatment was passed without loss of time. Studies show that the sensitivity and specificity of Thoracic Computerized Tomography, including the arterial phase, is nearly 100% for diagnosis. Also, transthoracic echocardiography, transesophageal echocardiography, digital subtraction angiography were recommended for diagnosis [7]. Today, security precautions in vehicles have been increased. Although, the installation of a belt in the vehicle and the presence of airbag systems may reduce injury and mortality rates due to traffic accidents, injuries can still result as aortic injuries as in this case report. In presented case, he was reported that his seatbelt was fasten and airbags on his chest level were activated just after the crush. Conclusion The injuries and deaths due to traffic accidents have an important place in forensic medicine applications. In cases of nonpenetrating chest trauma, it should be kept in mind that vascular damages may have occurred even though signs and symptoms are not manifesting which makes questioning details and mechanism of trauma and meticulous physical examination vitally important. Also, the development of medical algorithms for these kinds of

Med Science 2019;8(1):246-7

forensic cases where the risk of mortality and morbidity is high is important for against to medical malpractice claims. Another important issue is that sometimes aortic rupture occurs spontaneously during the usage of the vehicle and then traffic accidents occur. Determining which one is the cause of another is crucial to criminal and compensation claims. For this reason, it is necessary for physicians to make an evaluation by taking this issue into consideration. Apart from these, considering to improve designs of airbags and make them more ergonomic, to define safe intervals of chest-toburst distances for various body types may be helpful to decrease thoracic aorta injuries caused by such accidents, however further studies are required to confirm these hypothesis. Competing interests The authors declare that they have no competing interest. Financial Disclosure The financial support for this study was provided by the investigators themselves. Ethics committee approval While this study is a case report, there isn’t any ethics committee approval. There is the case’s informed consent form. Ahsen Kaya ORCID: 0000-0002-6969-1562 Ali Varlihan ORCID: 0000-0003-1662-5710 Ekin Ozgur Aktas ORCID: 0000-0003-0934-3731

References 1.

Neschis DG, Scalea TM, Flinn WR, et al. Blunt aortic injury. N Engl J Med. 2008;359:1708-16.

Teixeira PGR, Inaba K, Barmparas G, et al. Blunt thoracic aortic injuries: An autopsy study. J Trauma. 2011;70:197-202.

Alsalehi S, Şaşmazel A, Tuncer A, et al. Traumatic aortic rupture and surgical repair: A Case Report. Turk Gogus Kalp Dama. 2012;20:918-20.

Prijon T, Ermenc B. Classification of blunt aortic injuries a new systematic overview of aortic trauma. Forensic Sci Int. 2010;195:6-9.

Karbek Akarca F, Korkmaz T, Çınar C, Çakal ED, Ersel M. Evaluation of patients diagnosed with acute blunt aortic injury and their bedside plain chest radiography in the emergency department: a retrospective study. Ulus Travma Acil Cerrahi Derg. 2016;22:449-56.

Meral O, Aktas EO, Ersel M. Examination of morbidity and mortality of cases according to intra-vehicle position and accident mechanism. Ulus Travma Acil Cerrahi Derg 2018; 24:216-23.

Canyiğit M, Küçüker A, Hıdıroğlu M, et al. Endovascular aortic repair with periscope graft technique in traumatic aortic transection. Turk Gogus Kalp Dama. 2015;23:129-33.

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CASE REPORT

Medicine Science International Medical Journal

Medicine Science 2019;8(1):247-9

Coexistence of PFAPA syndrome with separation anxiety Yunus Emre Donmez1, Ozlem Ozcan2, Yilmaz Tabel3 1

Malatya Training and Research Hospital, Department of Child and Adolescent Psychiatry, Malatya, Turkey 2 Inonu University, Faculty of Medicine, Department of Child and Adolescent Psychiatry, Malatya, Turkey 3 Inonu University, Faculty of Medicine, Department of Pediatric Nephrology, Malatya, Turkey Received 06 July 2018; Accepted 28 August 2018 Available online 26.09.2018 with doi: 10.5455/medscience.2018.07.8887 Copyright ÂŠ 2019 by authors and Medicine Science Publishing Inc.

Abstract PFAPA syndrome is an auto inflammatory disease. Researchers have stated that auto inflammatory mechanisms can play a role in etiology of several psychiatric diseases and for this reason auto inflammatory diseases are frequently associated with psychiatric disorders. The purpose of this paper, it is aimed to report two cases diagnosed with PFAPA syndrome and having psychiatric symptoms and to discuss them accompanied by literature data. As authors, in the light of cases we report and literature knowledge, we think that children with PFAPA syndrome could be under risk in terms of psychiatric problems due to common inflammatory etiology. Keywords: Auto inflammation, PFAPA syndrome, separation anxiety

Introduction Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA syndrome) is an autoinflammatory disease characterized by existence of fever attacks with at least one of the three major symptoms as aphthous stomatitis, pharyngitis, and cervical adenitis [1,2]. Researchers have stated that autoinflammatory mechanisms can play a role in etiology of several psychiatric diseases and for this reason autoinflammatory diseases are frequently associated with psychiatric disorders [3]. The purpose of this paper is to report two cases diagnosed with PFAPA syndrome and having separation anxiety disorder. Case Report Case 1 A student in the 1st class of primary school, 6-year-old male, was admitted to child psychiatric clinic with complaints of difficulty in leaving his mother and father, and all the time staying with his teacher at school. According to information received from parents, these were learned that he had difficulties in staying at school after he started to school, he left his parents after his parents waited at *Coresponding Author: Yunus Emre Donmez, Malatya Training and Research Hospital, Department of Child and Adolescent Psychiatry, Malatya, Turkey E-mail: dryemredonmez@gmail.com

school a few months, but at this time, he did not leave his teacher at school, and he did not leave the classroom without his teacher in the breaks. In addition, these were learned that the patient did not leave his parents after school, he wanted his parents even when he was playing with his peers, he experienced intense anxiety about it, he had fear of harm to his parents or himself, the difficulty of leaving from his parents remained since infancy. Family of the patient had no psychiatric disease history. In the psychiatric assessment by authors, these were observed that the patient dressed in consistent with his age and socio-economic status, verbal and non-verbal communication were normal, his mood was euthymic, his affection was anxious, he had not perceptual disorder, his cognitive functions were consistent with his age. At the result of administered psychiatric examination and psychometric assessments considering for DSM-5 diagnostic criteria, the patient was diagnosed with separation anxiety disorder. Cognitive behavioral therapy and psychopharmacological treatment were planned for the patient. As a psychopharmacologic treatment, 5 mg/day fluoxetine was administered to the patient. After four weeks, dose of fluoxetine was increased to 10 mg/ day. In three months, 12 cognitive behavioral therapy sessions implemented by authors. In the second month of psychiatric treatment, the patient referred to our pediatric rheumatology and otolaryngology clinic for recurrent 247

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and resistant fever attacks and cervical adenitis. Laboratory tests for infectious diseases, familial mediterranean fever, immunological and hematological diseases and pandas were negative. Pediatric rheumatology clinic was diagnosed with “Ppapa Syndrome” due to cervical adenitis and recurrent-resistant fever attacks. Patient who did not benefit enough from cognitive behavior therapy for three months continued to be followed only by psychopharmacologic treatment (Fluoxetine 10mg / day). At six months of psychopharmacologic treatment, the patient had no significant improvement in symptoms of separation anxiety. During the sixth month of psychiatric treatment, the patient underwent surgery for tonsillectomy because of PFAPA syndrome. Symptoms of separation anxiety of the patient who continued psychopharmacologic treatment after tonsillectomy operation decreased significantly within six months. The patient doesn’t have any problem in the school now, and he can join the activities of peers without family members and teachers. Case 2: A kindergarten student, four years old male, was admitted to our clinic in with complaints of difficulty in leaving his parents. According to information received from his family, these were learned that the patient did not want to leave his parents, he was reluctant to go to school, so that he cried often and he presented aggressive behavior, he did not allow his parents to leave the school, and he experienced intense anxiety when he went to school, but he was compatible when his parents were next to himself, he has fear of harm to his parents or himself. The complaints of the patient started seven months ago and family of the patient had no psychiatric disease history. Additionally, it was learned that the patient had recurrent attacks of fever refractory to medical treatment and cervical adenitis, therefore, he was evaluated by pediatric rheumatology clinic in our hospital and he was followed with the diagnosis of PFAPA syndrome. The patient’s laboratory tests for infectious diseases, familial mediterranean fever, immunological and hematological diseases and pandas were negative.

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criteria (existence of fever attacks with at least one of the three major symptoms as aphthous stomatitis, pharyngitis, and cervical adenitis) and exclusion of other reasons (infectious diseases, familial mediterranean fever, immunological, hematological diseases, etc.) that may cause recurrent fever [1,4]. Both of our cases were diagnosed by our pediatric rheumatology clinic within this scope and other causes that may result in recurrent fever were eliminated. In the first case, symptoms of separation anxiety occurred before the symptoms of PFAPA syndrome. In the second case, symptoms of separation anxiety occurred after the symptoms of PFAPA syndrome. Autoinflammatory mechanisms are studied by emphasizing a possible irregularity in natural immune system for etiology of PFAPA syndrome. Treatment is symptomatic and applied when fever attacks occur [5]. The fact that patients benefit from steroids and tonsillectomy used in symptomatic therapy is another finding which indicates that this disease might be resulted from autoinflammatory mechanisms. In immunological studies, CRP, TNF-alpha, IL-1, IL-6, IFN-gamma levels were determined to be higher in these patients [5]. Likewise, CRP, TNF-alpha, and IL-6 levels were shown to be higher in children with anxiety disorder [3,6]. However, it is not clear that whetherthese immunological factors elevated due to increasing stress observed in anxiety disorder or whether immunological mechanisms caused anxiety disorder. Some researchers speculate that inflammatory mechanisms may play role in etiology of psychiatric disorders and proinflammatory markers may have biomarker potential in terms of diagnosis and course of psychiatric diseases and therapeutic interventions. In addition, it was emphasized in some studies that antiinflammatory treatments such as aspirin, nonsteroidal antiinflammatory drugs, tumor necrosis factor (TNF)–a antagonists and omega-3 fatty acids could be potential psychiatric interventions [3].

In the psychiatric assessment by authors, these were observed that the patient dressed in consistent with his age and socio-economic status, verbal and non-verbal communication were normal, his mood was euthymic, his affection was anxious, he had not perceptual disorder, his cognitive functions were consistent with his age. At the result of administered psychiatric examination considering for DSM-5 diagnostic criteria, the patient was diagnosed with separation anxiety disorder. Cognitive behavioral therapy was planned for the treatment.

Conclusion

The patient, whose psychiatric symptoms partially regressed as a result of weekly intensive psychiatric interview and cognitive behavioral therapy lasting approximately two months, failed to complete the follow-up and treatment process because of the change of address. This case has not undergone tonsillectomy operation yet and has not received a regular treatment for PFAPA syndrome, and was undergoing symptomatic treatments for bringing the fever down when fever attacks occurred.

As authors, in the light of cases we report and literature data, we think that children with PFAPA syndrome could be under risk in terms of psychiatric problems due to common inflammatory etiology and further controlled studies are needed to guide to assess the risk of psychiatric disorders in PFAPA syndrome.

Discussion

Financial Disclosure The financial support for this study was provided by the investigators themselves.

PFAPA syndrome was first described by Marshall in 1987 [4]. The syndrome usually begins before the age of 5 years and ends in adolescence. The diagnosis is based on the basic clinical

The immunologic markers are not continuous high in the PFAPA syndrome. In some patients, periodic elevations can be seen, and in some cases immunologic markers can be always normal. Immunologic markers were normal in our both cases. However, the decline of PFAPA syndrome and separation anxiety symptoms after tonsillectomy in the first case suggests that autoinflammatory mechanisms may play a role in the etiology of both diseases.

Competing interests The authors declare that they have no competing interest.

Ethics committee approval While this study is a case report, there isn’t any ethics committee approval. There is the case’s informed consent form.

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References

Med Science 2019;8(1):247-9

Mitchell RH, Goldstein BI. Inflammation in children and adolescents with neuropsychiatric disorders: a systematic review. J Am Acad Child Adolesc Psychiatry. 2014;53:274-96.

Marshall GS, Edwards KM, Butler J, et al. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr. 1987;110:43-6.

Thomas KT, Feder HM, Lawton AR, et al. Periodic fever syndrome in children. J Pediatr. 1999;135:15-21.

Vigo G, Zulian F. Periodic fevers with aphthous stomatitis, pharyngitis, and adenitis (PFAPA). Autoimmun Rev. 2012;12:52-5.

Brown KL, Wekell P, Osla V, et al. Profile of blood cells and inflammatory mediators in periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. BMC Pediatr. 2010;10:65.

Henje BE, Lekander M, Ingvar M, et al. Proinflammatory cytokines are elevated in adolescent females with emotional disorders not treated with SSRIs. J Affect Disord. 2012;136:716-23.

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REVIEW ARTICLE

Medicine Science International Medical Journal

Medicine Science 2019;8(1):250-4

Parenteral systemic antifungal drugs and their clinical drug informations Irem Bozbey1, Zeynep Ulku Gun2, Arzu Karakurt1 Inonu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Malatya, Turkey 2 Inonu University Faculty of Pharmacy, Department of Clinical Pharmacy, Malatya, Turkey

Received 12 July 2018; Accepted 26 August 2018 Available online 08.11.2018 with doi:10.5455/medscience.2018.07.8915 Copyright © 2018 by authors and Medicine Science Publishing Inc. Abstract Invasive fungal infections are an important cause of morbidity and mortality, especially in with patients’ immune-compromised conditions such as AIDS, cancer, diabetes and burn patients, neonates, organ transplant patients. Therefore, treatment of fungal infections is still a major problem. The drugs used to treat these infections are very limited due to toxicity or inappropriate pharmacokinetic properties. Nowadays, there are three molecules class used in the clinical for these infections: polyenes, azoles and echinocandins. Amphotericin B and lipid formulations have been used for a long time in the treatment of these infections. The development of new triazole derivatives has provided different treatment options (fluconazole, voriconazole and posaconazole). In addition, three echinocandin derivatives (caspofungin, micafungin, and anidulafungin) have been approved for use in medication. The broad-spectrum triazoles and echinocandin derivative drugs have offer more effective and less toxic alternatives to antifungal therapy. This review provides a brief of the pharmacologic principles and clinical usage involved in treatment of systemic fungal infections. Keywords: Antifungal, fungus, parenteral, systemic

Introduction Funguses are eukaryotes that reproduce in single-celled colonies (yeast) or multicellular aggregates (molds). Pathogenic fungus such as Aspergillus, Candida and Cryptococcus cause infections in humans and it’s called as mycosis. Fungal infections can be classified as superficial, cutaneous, subcutaneous, and systemic mycoses [1-3]. Fungal infections are opportunistic infections and they cause systemic infections in patients with immune deficiency such as organ transplants, implants, after cancer treatment, AIDS and intensive care patients [4,5]. The drugs should be given intravenously or orally in systemic infections.

bones. Candida is part of the normal microbial flora on mucosal surfaces and can cause local infections such as thrush in the mouth cavity and vaginitis. However, Candida species fungus may also cause fulminant invasive candidiasis and their mortality rate is estimated to be 30-40% [7]. C. krusei, C. glabrata, C. tropcalis, C. parapsilosis and C. albicans which are thought to be responsible pathogens in 5070% of infections are the most isolated species from the invasive candidiasis [7]. However, in recent years, non-albicans Candida species have also been isolated at increasing rates.

Yeast and molds, which are systemic fungal infectious agents, cause primary or opportunistic infections. Pathogenic fungal spores are systemic infections resulting from inhalation and spreading through the internal organs. The most common fungal pathogens in systemic infections are Candida, Pneumocystis, Histoplasma, Aspergillus, Cryptococcus, Mucor, Rhizopus [6]. Invasive fungal infections involve various organs such as blood, heart, brain,

Invasive fungal infections due to Aspergillus species account for 4-5% of all invasive fungal infections. Candida species are the third most common cause of bloodstream infections in intensive care units in the United States and the fourth cause of bloodstream infections [8]. Neutropenia secondary intensive and long-standing cytotoxic chemotherapy, corticosteroid therapy, prolonged antibiotic therapy, organ transplantation, or AIDS are the risk factor for invasive fungal infections [1-3].

*Coresponding Author: Zeynep Ulku Gun, Inonu University Faculty of Pharmacy, Department of Clinical Pharmacy, Malatya, Turkey E-mail: ulkuduzgun@gmail.com

Mechanisms of Action The antifungal drugs are divided into fungicidal and fungistatic according to their effects. While fungicidal compounds kill fungus, fungistatic compounds prevent fungus from multiplying. 250

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Antifungal chemotherapy is based on biochemical differences between fungus and mammalian cells. Bacterial cells are prokaryote, mammalian and fungal cells are eukaryote. For this reason, the biochemical differences between mammalian and fungus cells are very limited. The biggest difference at the cellular level is that the fungus cell has cell wall on the cell membrane. In mammalian cells, there are only cell membranes. Sterols play an important role on enzyme and ion transport proteins in cell membrane. Fungus cell membrane sterol is ergosterol [9-11]. Azoles inhibit the conversion step of lanosterol to C14-demethyl lanosterol, and thus ergosterol cannot be synthesized. Polyenes bind to the double-layered lipid layer of the membrane and forms complexes with ergosterol. Echinocandins inhibit the enzyme β-(1,3)-D-glucan synthase and this condition leads to fungal cell lysis (Figure 1). Classification of Parenteral Systemic Antifungal Drugs Parenteral systemic antifungals that currently using in the market in our country are classified below [12]. Besides, the properties of the antifungal agents are given in Table 1 [13,14]. 1. Polyenes antibiotics Amphotericin B conventional, Ampothericin B liposomal 2. Azole derivatives Fluconazole, Voriconazole, Posaconazole 3. Echinocandins Caspofungin, Anidulafungin, Micafungin

Figure 1. Antifungal agent targets

Amphotericin B Amphotericin B is an antifungal antibiotic originally produced by Streptomyces nodosus. Amphotericin B is prepared as a colloidal suspension of sodium deoxycholate in order to use as injectable form since it is not water soluble [9]. It targets ergosterol in fungal membranes and binds to the double-layered lipid layer of the membrane and forms complexes with ergosterol. This complex leads to form pores, leak out the cytoplasm, and the oxidative damage results death of the fungal cell [15]. Amphotericin B cannot not be absorbed orally, so intravenous administration is essential. The comparisons of amphotericin B formulations have shown Table 2 [13-18].

Table 1. Antifungal agents Generic name

Dosage forms

Dose

Elimination

Amphotericin B(conventional)

0.5-1 mg/kg q24h

Unknown

Amphotericin B (liposomal)

3-7 mg/kg q24h

Unknown

Caspofungin

70 mg once and then 50 mg q24h

Hepatic

Micafungin

100 mg q24h

Hepatic

Anidulafungin

200 mg once and then 100 mg q24h

Chemical degradation

Fluconazole

IV, po

100-800 mg q24h

Renal

Voriconazole

IV, po

200 mg po q12h; 6 mg/kg IV q12h 2 doses, then 4 mg/kg IV q12h

Hepatic

Posaconazole

IV, po

200 mg qid initially and then 400 mg bid

Hepatic

IV: intravenous, po: per oral, q12h: every 12 hours, q24h: every 24 hours, bid: two times a day, qid: four times a day Table 2. Comparison of Amphotericin B formulations Property

AmBd

L-AmB

Molecular Structure

Micelles

Liposome

Size (nm)

0.035

Cmax (µg/mL)

1.5-2.9

83±35.2

AUC (µg.h/mL)

17.1-36

555±311

Half-life (h)

8.6±3.1

Infusion-related toxicity

+++

Nephrotoxicity

+++

Hepatotoxicity

AmBd: Conventional amphotericin B, L-AmB: Liposomal amphotericin B, AUC area under the concentration–time curve, Cmax peak plasma concentration. ±indicates range of values, Plus signs indicate degree of toxicity: +, mild; ++, moderate; and +++, severe.

Amphotericin B (Conventional) Infusion-related side effects of amphotericin B are fever, chills, hypotension, pain, thrombophlebitis and anaphylaxis. To prevent these side effects, 1 mg of amphotericin B may be administered by intravenous infusion for 20-30 min. Nephrotoxicity is the major toxicity that limits the dose. Liposomal formulations has been developed to reduce toxicity and allow higher doses to be given. In addition to renal dysfunction, hypokalemia, hypocalcemia and hypomagnesaemia may occur, but these effects usually reverse when the drug is discontinued. It should be avoided concomitant drugs which have nephrotoxic side effects (13,17). Reducing the production of erythropoietin may cause normocytic and normochromic anemia. Elevation of ALT, AST, ALP and bilirubin levels may be occur (14). 251

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Amphotericin B can reconstituted only with dextrose solutions such as 5% dextrose, 10% dextrose. It is incompatible with 0.9% NaCl. After dilution in the form of 0.1 mg/ml dilution, it should administered as IV infusion for 2-6 hours (13).

to be use 50% of the appropriate dose. After dialysis on dialysis patients, the appropriate dose should be applied immediately, and on days without dialysis dose adjustment should be made according to creatinine clearance [13,18].

For systemic fungal infections, after administering 0.25-0.5 mg/kg loading dose, It is used at a dose of 0.25-1 mg for 24 hour interval. (13,18).

If fluconazole is used more than 400 mg/day in women with fertility potential, birth control should be applied and should be continued until 1 week after the last dose of the drug [14].

Amphotericin B (Liposomal) The infusion-related reactions and side effects, and those to protect against these side effects are the same as for conventional Amphotericin B (13,17).

The infusion rate should not exceed 200 mg/h and should be infused within 1-2 hours [13,18].

It is prepared by diluting not exceeding 1-2 mg/ml in adults and 0.2-0.5 mg/ml in pediatric patients. It is prepared solution by diluting 1-2 mg/ml and 0.2-0.5 mg/ml for adults and pediatric patients, respectively. The duration of the infusion should be at least 2 hours [13,18]. Azole Antifungals Azoles are the most common using antifungals in the clinic practice. Azol antifungals inhibit ergosterol synthesis and their target locus is cytochrome P450 lanosterol 14Îą-demethylase, encoded by the ERG11 gene which is part of the ergosterol biosynthetic pathway [19]. Sterol 14Îą-demethylase (14DM, CYP51) is an important microsomal cytochrome P450 for the biosynthesis of sterols required for membrane formation in eukaryotes and for the survival of numerous organisms [20]. They carry an imidazole or triazole ring as a pharmacophore azole group. These group compounds have broad spectrum of action, good oral bioavailability and low toxicity. Triazole derivatives have some advantages over imidazoles, such as their less effect on human sterol synthesis and their faster metabolization [21]. Drug interactions are important in the azole group of antifungal drugs. Since systemic azoles which inhibitors of various CYP450 isoforms, they interact with a large number of drugs, the result of which is the duration and toxicity of their own or other drugs [22,23]. For example; potential interactions between fluconazole and warfarin extend the duration of action of warfarin. The interaction of itraconazole and statins increases the potential toxicity of statins [10,11]. Fluconazole Fluconazole which is a synthetic triazole antifungal is a fungistatic agent. Itâ&#x20AC;&#x2122;s using for invasive Candida infections, but it is resistant to C. krusei, C. glabrata and C. lusimiatae [14]. Their gastrointestinal side effects are nausea, vomiting, abdominal pain and diarrhea as well as cholestasis, AST, ALT, GGTP elevation, hepatic necrosis and liver failure. Liver enzymes should be checked regularly during the treatment. Regular blood count should be done in order to check leukopenia, neutropenia, thrombocytopenia and anemia. The other rare, side effects are dizziness, headache, drowsiness, seizures, coma can also be seen [14]. Dose adjustment is necessary for patients with renal insufficiency. If creatinine clearance is 50 ml/min or less of patients are required

Voriconazole It has been approved for use in Aspergillus and invasive Candida infections, including fluconazole resistant isolates [25]. Side effects such as hepatitis, cholestasis, fulminant liver failure as well as visual disturbances and hallucinations can also be seen. Dermatological side effects such as pruritus, rash, anaphylactoid reactions, Stevens Johnson syndrome, and photosensitivity may occur [14]. The dose used in invasive aspergillosis and severe fungal infections is 6 mg/kg, which is to be used intravenously for the first 24 hours, 12 hours interval. After first dose, 4 mg/kg is used with a 12 hours interval. The dosage is 6 mg/kg intravenously administered in the first 24 hours, with 12 hour intervals and then 3-4 mg/kg for 12 hour interval for invasive Candida infections. The average duration of IV therapy for aspergillosis is 10 days (2-90 days) [13,18,24]. Dose adjustment is required for kidney and liver failure. Patients with creatinine clearance below 50 ml/min should be avoided IV route, oral forms should be preferred. In patients with Child Pugh score A or B, the maintenance dose should be reduced by 50% by keeping loading dose. There are no dose-adjusted study data in Score C patients and hepatitis B or C patients [13,18]. In drug administration, infusion rate should not exceed 3 mg/kg per hour; infusion time should be over 1-2 hours [13,24]. Posaconazole It has been approved for Aspergillus and invasive Candida infections. In vitro activity is shown in Zycomycetes and Aspergillus strains, which are highly resistant to other azoles and amphotericin B [25]. Gastrointestinal side effects such as nausea, vomiting, diarrhea and abdominal pain, as well as dermatological side effects such as pruritus and rash can be seen. Regular ECG follow-up should be done as it may cause prolonged QT interval and ventricular dysrhythmia. Other medications that prolong QT interval (levofloxacin, citalopram etc.) should be avoided. It may cause cholestasis or elevation of liver function tests. It can cause headache, dizziness, confusion [14,18]. Invasive Aspergillus and Candida infections are administered 300 mg intravenous infusion on the first day of 12 hours interval and 300 mg on the following days each 24 hours. The duration of treatment depends on the development of neutropenia or immunosuppression [13,18,26]. Patients with impaired renal function should be followed up regularly creatinine levels. Patients with GFR less than 50 ml/ 252

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min should avoid I.V. administration and should prefer oral administration [13,18]. It should be diluted with only 5% dextrose and 0.9% NaCl solution and stored in the refrigerator at 2-8 °C after preparation. Bolus injection should be avoided; duration of the infusion is 30 minutes for the peripheral venous and 90 minutes for the central venous [13,24]. There are no safety studies for tablets and oral suspensions under 13 years of age, and for IV form under 18 years [13]. Echinocandins There are many components in the fungus wall that are unique to the fungus cell that are not found in mammalian cells. β-[1,3]-Dglucan forms more than 50% of the cell wall and is responsible for the structural integrity of the cell wall. Echinocandins are large cyclic peptides linked by a long chain fatty acid. They inhibit the β-(1,3)-D-glucan synthase. Inhibition of β(1,3)-glucan synthase leads to fungal cell lysis with cell wall destabilization and leakage of intracellular components [6,9]. Caspofungin, micafungin and anidulafungin are compounds of the echinocandin group approved in 2001, 2005 and 2006, respectively. Echinocandins are effective against many funguses, including Candida and Aspergillus. Because of their high molecular weight, these drugs are poorly absorbed from the gastrointestinal tract and are therefore only using intravenously. The toxicity of these molecules is low, slowly degraded, a daily injection is sufficient, and unlike other antifungal drugs, the interaction of echinocandins with other drugs is rare [6, 27-32]. Anidulafungin It has been approved for use in invasive Candida infections [14]. There is no need for dose adjustment in kidney and liver failure [13,18]. It may cause hypersensitivity reactions such as itching, rash, and anaphylaxis. Depending on the rate of infusion, side effects such as fever, thrombophlebitis, nausea, vomiting, and myalgia may occur [14]. Administered at a dose of 50 mg for 24 hour interval after 100 mg IV administration on the first day for esophageal candidiasis is. 100 mg IV is administered as an infusion after a loading dose of 200 mg, with an interval of 24 hours sufficient for the other indications. The bolus should not be administered and the IV infusion rate should not exceed 1.1 mg/min [13,18]. Caspofungin It has been approved for use in resistant Aspergillus and invasive Candida infections [14]. The loading dose is 70 mg for patients with invasive candidiasis, aspergillosis and febrile neutropenia and subsequent dose was determined as 50 mg/day i.v. every day at the same time [13,18]. There is no need for dose adjustment in renal failure. However, dose adjustment is required for liver failure. While dose adjustment is not required at Child Pugh 5-6, for level 7-9 following a 70 mg loading dose, 35 mg daily dose should be administered intravenously in the same hour every day. If Child Pugh is above

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9, safety studies are not enough [13,18]. When caspofungin is prepared, it should not be mixed with solutions containing dextrose. The prepared infusion solution can be stored at room temperature for 24 hours and in the refrigerator for 48 hours. The duration of the infusion should be at least 1 hour [13,18,24]. Micafungin It has been approved for treatment of invasive Candida infections [14]. There is no need for dose adjustment in kidney and liver failure. It may cause ALT and AST elevation and hypersensitivity reactions such as itching, rash, and anaphylaxis [13,18]. It may cause increase of BUN and creatinine. Depending on the rate of infusion, it may cause side effects such as fever, thrombophlebitis, nausea, vomiting, and myalgia [14,18]. 150 mg is given as a 24-hour interval for the esophageal candidiasis, and 100 mg I.V. is infused as a 24-hour interval for other indications. The bolus should not be applied and the duration of the infusion should be at least 1 hour [13,18,24]. Conclusion For the treatment of systemic infections, clinicians can use a large number of antifungal agents. However, in the selection and application of antifungal therapy, the selection of antifungal drugs and the properties of the drug should be accurately assessed. Since the pharmacokinetic and pharmacodynamic properties of each drug are different, the concurrent disease, the drugs used for these diseases, the clinical condition of the patient and the laboratory results should be considered in the treatment regimen. For an effective and accurate treatment, it is necessary to evaluate all the parameters together to achieve the patient-specific treatment regimen. Competing interests The authors declare that they have no competing interest Financial Disclosure The financial support for this study was provided by the investigators themselves.

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