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IJCP Group of Publications Volume 28, Number 5, October 2017

Dr Sanjiv Chopra Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor

Dr KK Aggarwal Padma Shri Awardee Group Editor-in-Chief

FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF

405 An MBBS/MD Degree Must to Sign Lab Reports

AMERICAN FAMILY PHYSICIAN

407 Diagnosis and Management of Endometrial Cancer

Dr Veena Aggarwal Group Executive Editor

IJCP Editorial Board Obstetrics and Gynaecology Dr Alka Kriplani, Dr Thankam Verma, Dr Kamala Selvaraj Cardiology Dr Praveen Chandra, Dr SK Parashar Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses, Dr Sidhartha Das, Dr A Ramachandran, Dr Samith A Shetty, Dr Vijay Viswanathan, Dr V Mohan, Dr V Seshiah, Dr Vijayakumar ENT Dr Jasveer Singh, Dr Chanchal Pal Dentistry Dr KMK Masthan, Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar, Dr Rajiv Khosla, Dr JS Rajkumar Dermatology Dr Hasmukh J Shroff, Dr Pasricha, Dr Koushik Lahiri, Dr Jayakar Thomas Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan, Dr Vineet Suri, Dr AV Srinivasan Oncology Dr V Shanta Orthopedics Dr J Maheshwari

Anand Gopal Bhatnagar Editorial Anchor Advisory Bodies Heart Care Foundation of India

Michael M. Braun, Erika A. Overbeek-Wager, Robert J. Grumbo

413 Practice Guidelines 415 Photo Quiz CARDIOLOGY

418 Emerging Role of Cardiac MRI in Ischemic and Nonischemic Cardiomyopathy

Mona Bhatia

COMMUNITY MEDICINE

426 Status of Biomedical Waste Generation and Its Disposal in Delhi

Rashmi Chowdhri, Laxmi Rawat, JK Sharma, Vishal Kamra

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432 Pediatric Oropharyngeal Trauma: A Retrospective Study with Brief Review of Literature

Neeru Chugh, Neelima Gupta, Lakshmi Vaid

437 Angina Bullosa Hemorrhagica as a Presenting Feature of Malignant Hypertension: A Case Report

Vikasdeep Gupta, Vandana Sharma, Kuldeep Thakur, Vidhu Sharma

INTERNAL MEDICINE

440 An Interesting Cause of Hyperhidrosis and Hyperphagia – Acromegaly

Mohamed Iliyas, Sundaramurthy

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Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

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NEUROLOGY

455 Functional Neuroimaging in Psychiatry

Krishan Kumar, Rajnish Kumar

OBSTETRICS AND GYNECOLOGY Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Ltd. and Published at E - 219, Greater Kailash Part - 1 New Delhi - 110 048 E-mail: editorial@ijcp.com

469 Sheehan’s Syndrome: A Case Report

Shikha Singh, Rekha Rani, Dibya Singh

472 An Unusual Case of Uterine Anomaly, Surgically Corrected with a Fruitful Pregnancy At Last

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474 Consent for Diagnostic Procedure cannot be Extended to Therapeutic Procedure

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Editorial Policies

483 53rd Annual Meeting of the European Association for the Study of Diabetes (EASD 2017)

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AROUND THE GLOBE

487 News and Views LIGHTER READING

495 Lighter Side of Medicine

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FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF

Dr KK Aggarwal

Padma Shri Awardee Group Editor-in-Chief

An MBBS/MD Degree Must to Sign Lab Reports

I

n a judgement in Association of Clinical Biochemists and Microbiologists ACBM (Regd) & Anr Vs Union of India & Ors delivered September 15, 2017, the Delhi High Court agreed with a Medical Council of India (MCI) notification that “all lab reports to be signed/ countersigned by persons registered with MCI/State Medical Council.”

The MCI had issued a notification to this regard vide a letter No. MCI - 211(2))(Gen.)/2014-Ethics/118642 dated 14.06.2017, which had been contested by the Association of Clinical Biochemists and Microbiologists, who petitioned that “the said letter was without jurisdiction and deprived members of their association of their valuable right to conduct their trade and profession.”

The Association of Clinical Biochemists and Microbiologists stated before the Court that “the members of the petitioner association are highly qualified persons and are engaged in the activity of laboratory testing.

Since members of the petitioner association do not hold degree of MBBS and/or MD Degrees, they are not entered in the register maintained by the MCI or State Medical Councils.

The petitioners state that the work of conducting laboratory test and submitting reports thereof is essentially a skilled task for which the members of the petitioner association are amply qualified and it is not necessary that the test report submitted by them be countersigned by a medical practitioner whose name is entered in the medical register. It is further stated that respondent No. 3 (National Accreditation Board for Testing and Calibrating Laboratories) is competent to provide accreditation to pathology laboratories and no accreditation from MCI is required.”

Referring to the Clinical Establishments (Registration and Regulation) Act, 2010, the Counsel appearing for MCI had submitted that “the said Act provides a comprehensive legal framework for registration of a clinical establishments.

Section 3 of the said Act provides for establishment of a National Council which consists of representatives of various bodies including the Secretary General of Quality Council of India. The said National Council is inter alia charged with the function of prescribing the minimum standards of facilities and services; and (ii) minimum requirement of personnel, in a clinical establishment.” He also stated that the IMC Act did not provide for any framework for prescribing the standards for technicians engaged in a pathology laboratory.

As per Clause (c) of Section 15(2) IMC Act, “No person other than a medical practitioner enrolled on a State Medical Register shall be entitled to sign or authenticate a medical or fitness certificate or any other certificate required by any law to be signed or authenticated by a duly qualified medical practitioner.” Citing this, the MCI Counsel had further submitted, “the members of the petitioner association were not entitled to sign any medical fitness certificate and a pathology report would fall within the scope of a medical certificate, if there is any expression of opinion and/or indicative diagnosis… it is in this context that MCI had issued the impugned communication insisting that a pathology report be countersigned by a medical practitioner.”

Section 15(3) IMC Act has defined punishment for violation of the above as follows: “Any person who acts in contravention of any provision of sub-section (2) shall be punished with imprisonment for a term which may extend to one year or with fine which may extend to one thousand rupees, or with both.”

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FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF COURT OBSERVATIONS “It is apparent from the above that no person other than a duly qualified medical practitioner is entitled to sign any medical report. Thus, members of petitioner association cannot sign a medical report or a medical certificate. However, the same does not preclude the members of the petitioner association to give a technical report as to the tests conducted by them.

Plainly, such report can only be for consumption of medical practitioners and pathologists. The said report cannot be treated as diagnosis of any medical condition. Thus, there can be no objection if the technical report submitted by the qualified technicians indicates the result of their tests or the technical analysis of the samples, as long as the members of the petitioner association refrain from expressing any medical opinion or holding out the technical result of the medical tests conducted by them as a diagnosis of any medical condition.”

“This Court is also of the view that although members of the petitioner association are not precluded from acting as a laboratory technicians and submitting the result of tests conducted by them, adequate safeguard must be maintained to ensure that the reports submitted by them are not mistaken as medical certificates or diagnostic reports as that would, concededly, violate Section 15(2)(d) of the IMC Act, 1956. Thus, it would be apposite that all test reports must necessarily bear a disclaimer to the effect that the reports are strictly for the use of medical practitioners and pathologists and the reports are not medical diagnostic results. Any pathological report which purports to record any opinion or to indicate any diagnosis must necessarily be co-signed by a qualified medical practitioner.”

After examining three questions (as below), the Ethics Committee had decided that “All lab reports to be signed/countersigned by persons registered with MCI/ State Medical Council.”

1. “Whether the M.Sc with PhD candidates who as a matter of fact are not registered with MCI are eligible to sign medical laboratory reports?

2. Can persons holding MBBS degree registered with MCI/ State Medical Council sign the medical test reports?

3. Can PhD (Medical Microbiology, Medical Biochemistry, Life Sciences, Applied Biology, Cytogenetics, Biotechnology) in relevant discipline be allowed to sign medical test reports? If not, Can the same be allowed if they are co-authorised with a person registered with MCI/State Medical Council?”

Taking note of this decision of the MCI Executive Committee, the Court said, “You are therefore requested to kindly abide the above said decision of the Council and widely publicise the above decision to all the concerned.”

“The said decision of the Executive answers question nos.

2 and 3 in the affirmative and there can be no dispute that MCI's decision in this regard is in conformity with the provisions of Section 15(2)(d) of the IMC Act and cannot be faulted.”

“Insofar as the first question is concerned - that is, whether MSc/PhD candidates, who are not registered with MCI, are eligible to sign medical laboratory reports - the same must be answered in the negative as has been done by MCI. However, MCI decision in this regard must be read in the context.

The expression "medical laboratory reports" as used in the first question cannot be misunderstood to mean test reports which merely indicate the result of tests and/or the manner in which, the tests are conducted.”

“The expression "medical laboratory reports" must in the context of the impugned communication, be understood to mean reports that contain medical diagnostic results and/or an opinion with regard to the tests results. A technical report stating test results and indicating the analysis of samples without recording any opinion thereon, would not fall within the scope of medical laboratory reports as contemplated under the impugned communication.”

The Court disposed of the petition stating that “The impugned communication, thus, cannot be understood in a wider sense as urged by the petitioner and must be read in the restrictive manner as indicated above. The petitioners can have no grievance if the impugned communication is read in the manner as indicated above and, therefore, no further orders are required to be passed in this petition.”

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AMERICAN FAMILY PHYSICIAN

Diagnosis and Management of Endometrial Cancer MICHAEL M. BRAUN, ERIKA A. OVERBEEK-WAGER, ROBERT J. GRUMBO

ABSTRACT Endometrial cancer is the most common gynecologic malignancy. It is the fourth most common cancer in women in the United States after breast, lung, and colorectal cancers. Risk factors are related to excessive unopposed exposure of the endometrium to estrogen, including unopposed estrogen therapy, early menarche, late menopause, tamoxifen therapy, nulliparity, infertility or failure to ovulate, and polycystic ovary syndrome. Additional risk factors are increasing age, obesity, hypertension, diabetes mellitus, and hereditary nonpolyposis colorectal cancer. The most common presentation for endometrial cancer is postmenopausal bleeding. The American Cancer Society recommends that all women older than 65 years be informed of the risks and symptoms of endometrial cancer and advised to seek evaluation if symptoms occur. There is no evidence to support endometrial cancer screening in asymptomatic women. Evaluation of a patient with suspected disease should include a pregnancy test in women of childbearing age, complete blood count, and prothrombin time and partial thromboplastin time if bleeding is heavy. Most guidelines recommend either transvaginal ultrasonography or endometrial biopsy as the initial study.

The mainstay of treatment for endometrial cancer is total hysterectomy with bilateral salpingo-oophorectomy. Radiation and chemotherapy can also play a role in treatment. Low- to medium-risk endometrial hyperplasia can be treated with nonsurgical options. Survival is generally defined by the stage of the disease and histology, with most patients at stage I and II having a favorable prognosis. Controlling risk factors such as obesity, diabetes, and hypertension could play a role in the prevention of endometrial cancer.

Keywords: Endometrial cancer, transvaginal ultrasonography, endometrial biopsy, total hysterectomy with bilateral salpingo-oophorectomy, radiation, chemotherapy

E

ndometrial cancer is the most common gynecologic malignancy. It is the fourth most common cancer in women after breast, lung, and colorectal cancers. Projections from the American Cancer Society (ACS) for 2015 estimated 54,870 new cases of endometrial cancer and 10,170 deaths from the disease.1

The death rate for endometrial cancer has increased more than 100% during the past 20 years, rising by 8% since 2008. The mean age of patients at the time of diagnosis is 63 years, with 90% of cases occurring in women older than 50 years. Only 20% of patients with endometrial cancer receive a diagnosis before menopause.2

MICHAEL M. BRAUN, DO, FAAFP, is associate residency director of the Family Medicine Residency at Madigan Army Medical Center, Tacoma, Wash., and clinical faculty of family medicine at the University of Washington, Seattle.

ERIKA A. OVERBEEK-WAGER, DO, is a staff family physician at Evans Army Community Hospital, Fort Carson, Colo.

ROBERT J. GRUMBO, MD, FAAFP, is adjunct faculty in the Family Medicine Residency at Madigan Army Medical Center.

Source: Adapted from Am Fam Physician. 2016;93(6):468-474.

HISTOPATHOLOGY Endometrial cancer is generally classified into two types.2 Type I is the most common form, representing more than 70% of cases. Type I tumors are associated with unopposed estrogen stimulation and are known as endometrioid adenocarcinoma.3 These tumors are generally low grade. Type II tumors are more likely to be high grade and of papillary serous or clear cell histologic type. They carry a poor prognosis and have a high risk of relapse and metastasis. Type II accounts for only 10% of endometrial cancers, but it is associated with 40% of related deaths.2,3 Familial tumors are commonly found in association with Lynch syndrome (hereditary nonpolyposis colorectal cancer). Genetic disease represents 10% of cases of endometrial cancer.3 Endometrial hyperplasia represents a precursor lesion to endometrial cancer. Hyperplasia carries a 1% to 3% risk of progression to cancer. Atypical hyperplasia is associated with greater cancer risk than simple or complex hyperplasia; 30% to 40% of patients with atypical hyperplasia have concomitant adenocarcinoma.2

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AMERICAN FAMILY PHYSICIAN RISK FACTORS Risk factors for type I endometrial cancer are related to unopposed exposure of the endometrium to estrogen, including unopposed estrogen therapy, early menarche, late menopause, tamoxifen therapy, nulliparity, infertility or failure to ovulate, and polycystic ovary syndrome. Other risk factors not involving unopposed estrogen include family history of endometrial cancer, age older than 50 years, hypertension, diabetes mellitus, obesity, thyroid disease, and Lynch syndrome.2-6 Although they are less common overall, type II tumors are found predominantly in black women older than 50 years.2 Nearly 70% of patients with early stage endometrial cancer are obese.7,8 The relative risk of death increases with rising body mass index.8 Patients undergoing treatment with tamoxifen are at increased risk of endometrial cancer.9-11 Protective factors include prior use of combined oral contraceptives for one or more years and grand multiparity.2,3 SCREENING AND PREVENTION The ACS recommends that all women older than 65 years be informed of the risks and symptoms of endometrial cancer and advised to seek evaluation if symptoms occur. There is no evidence to support the screening of asymptomatic women, with the exception of those who have or are at increased risk of Lynch syndrome.4 Although the recommendation is controversial, these patients should be screened annually with an endometrial biopsy starting at age 35 because of a 22% to 50% lifetime risk of endometrial cancer.4,12 Patients with Lynch syndrome should be advised to keep a menstrual calendar and report abnormal bleeding. Women older than 40 years who have the mutation and do not wish to become pregnant in the future can consider a prophylactic hysterectomy.13,14 There are no recommendations on screening for endometrial cancer in patients who are taking tamoxifen; however, those who present with abnormal uterine bleeding should be considered for diagnostic workup.

Use of the levonorgestrel-releasing intrauterine system has not been proven to protect against endometrial hyperplasia or cancer in patients who take tamoxifen.15 Management of risk factors such as obesity, diabetes, and hypertension could play a role in the prevention

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of endometrial cancer. For women on hormone therapy, the addition of progesterone has been shown to decrease the risk of endometrial cancer.16 HISTORY Vaginal bleeding is the most common clinical presentation of endometrial cancer in postmenopausal women.2,17,18 Approximately 75% of postmenopausal women who are diagnosed with endometrial cancer are diagnosed at an early stage, which improves the chances of successful treatment.2 However, only 10% to 20% of postmenopausal women who are evaluated for uterine bleeding are diagnosed with endometrial cancer because the most common cause of postmenopausal bleeding is endometrial atrophy.17,18 All postmenopausal bleeding should be investigated, especially if risk factors for endometrial hyperplasia or cancer are present. Abnormal uterine bleeding can also be a sign of endometrial cancer in premenopausal women, who comprise 20% of cases of endometrial cancer.17 The American College of Obstetricians and Gynecologists (ACOG) recommends that women with abnormal uterine bleeding be evaluated for endometrial cancer if they are older than 45 years, or if they are younger than 45 years and have a history of unopposed estrogen exposure.2,3,19 Evaluation can be done with endometrial tissue sampling or ultrasonography.19 PHYSICAL EXAMINATION There are few physical examination findings in women with endometrial cancer. A pelvic examination should be performed to evaluate for other sources of abnormal bleeding, such as the vagina or cervix. The uterus and adnexa should be palpated for unusual masses.

Abnormal physical examination findings may be suggestive of more advanced disease.

LABORATORY EVALUATION There are no specific laboratory tests for the evaluation of endometrial cancer. Laboratory tests should include a pregnancy test in patients of childbearing age.

A complete blood count and prothrombin time and partial thromboplastin time may also be considered for patients with heavy bleeding. Papanicolaou smears are not a required part of the evaluation, but occasionally a Pap smear result can suggest endometrial cancer (i.e., atypical glandular cells).

AMERICAN FAMILY PHYSICIAN DIAGNOSTIC STUDIES Most guidelines recommend either transvaginal ultrasonography or endometrial biopsy as the initial study for the evaluation of endometrial cancer.6,17-19 The American College of Radiology Appropriateness Criteria include tables outlining the preferred imaging studies for the evaluation of abnormal vaginal bleeding, including postmenopausal bleeding, and the pretreatment evaluation and follow-up of endometrial cancer (https://acsearch.acr.org/list). The type of initial study depends on the availability of options and their level of invasiveness, and patient and physician preference.

Transvaginal Ultrasonography Transvaginal ultrasonography is often the initial diagnostic study of choice when evaluating for endometrial cancer because of its availability, costeffectiveness, and high sensitivity.17 Transvaginal ultrasonography can be used to measure endometrial thickness. There is some uncertainty regarding the optimal cutoff for endometrial thickness. Several metaanalyses that have used a cutoff measurement of 5 mm or less had a 96% sensitivity and a posttest probability of 2.5% for endometrial cancer in postmenopausal women.20,21 A recent ACOG committee opinion notes that the cutoff value for a normal transvaginal ultrasonography result should be 4 mm or less.18 Postmenopausal patients with endometrial thickness greater than 5 mm should be evaluated with a tissue sample, especially if bleeding is present. The American College of Radiology uses a cutoff of 5 mm or less.17 The optimal cutoff for evaluating premenopausal women has not been defined, but recommendations include a cutoff of 16 mm or less.

In all patients, if bleeding persists despite a normal transvaginal ultrasonography result, a tissue biopsy is warranted.2

Endometrial Sampling The definitive diagnosis of endometrial cancer requires an endometrial tissue sample.6 Curettage has been considered the preferred method for obtaining a tissue sample, but the newer Pipelle method offers an alternative.2,22 When an adequate sample is obtained, the Pipelle method has high diagnostic accuracy, with a positive predictive value of 81.7% and a negative predictive value of 99.1%.6 However, adequate samples can be difficult to obtain using the Pipelle method. One study showed that

only 34% of patients had an adequate sample.22 This percentage rose to 60% when evaluating women with an endometrial thickness of at least 5 mm. If an adequate sample cannot be obtained, a referral for dilation and curettage should be considered. Additional evaluation is needed if symptoms persist despite a benign biopsy result.6

Saline Infusion Sonohysterography Saline infusion sonohysterography can also be used to evaluate the endometrial cavity. This study technique uses saline infused into the endometrial cavity, followed by ultrasonography to allow better visualization of structural changes, particularly when patients have focal irregularities such as polyps, submucosal fibroids, or endometrial hyperplasia.17 Saline infusion sonohysterography is rarely used, but it can be considered when endometrial biopsy or transvaginal ultrasonography is inadequate.17

Hysteroscopy Hysteroscopy is commonly used to evaluate abnormal uterine bleeding and offers direct visualization of the endometrial cavity.2 Hysteroscopy can be performed in conjunction with a focal biopsy or curettage. A systematic review found that hysteroscopy had a sensitivity of 99.2% and specificity of 86.4% in the diagnosis of endometrial cancer.23

Additional Diagnostic Imaging Magnetic resonance imaging may be able to provide additional information on endometrial thickening or structural abnormalities such as fibroids or adenomyosis when transvaginal ultrasonography is not adequate and saline infusion sonohysterography is not tolerated.17 Computed tomography and positron emission tomography are generally not useful in the initial evaluation.17 TREATMENT The International Federation of Gynecology and Obstetrics tumor-node-metastasis staging system of endometrial cancer was updated in 2009 and appears better able to predict prognosis compared with the previously published 1988 system.24,25 Major changes to the new system included combining former stages IA and IB, elimination of stage IIA, and stratification of stage IIIC into pelvic nodes only or para-aortic nodal involvement26 (Table 15,24-26).

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AMERICAN FAMILY PHYSICIAN Endometrial Hyperplasia Management of endometrial cancer is broken down into surgical and nonsurgical therapies. All patients with endometrial hyperplasia should have testing to rule out concurrent adenocarcinoma.

The definitive treatment for complex atypical endometrial hyperplasia is hysterectomy. Surgical options include abdominal and minimally invasive procedures such as laparoscopy. Hysterectomy can be performed with or without bilateral salpingo-oophorectomy.27 ACOG does not recommend supracervical procedures as treatment because these procedures can leave behind residual disease.28 Abdominal surgery is associated with more pain, longer recovery, and longer hospital stay compared with laparoscopy.29 Additional procedures may be warranted if carcinoma is identified. Lymphadenectomy at the time of surgery is not recommended, as long as there are no intra-abdominal findings suggestive of invasive processes. Most patients with endometrial hyperplasia will not have carcinoma.27 Patients with low-risk endometrial hyperplasia (without atypia) or multiple comorbidities precluding surgery, and those who desire continued fertility, can be treated with nonsurgical options. The most common treatment option is progesterone therapy to stabilize the disease and prevent progression to endometrial cancer.

Use of the levonorgestrel-releasing intrauterine system and oral progesterone (e.g., medroxyprogesterone, 10 mg daily for 10 to 14 days per month) for the treatment of low- to medium-risk endometrial hyperplasia showed a reduction in hyperplasia six months after treatment.27,30 The optimal route, dose, and duration of therapy have not been well defined.

General consensus is to treat patients for six months, with tissue samples obtained every three months to evaluate for disease regression. Multiple endometrial samplings in the posttreatment surveillance period have also been recommended.27

Endometrial Cancer Surgical Approaches The mainstay of treatment is total hysterectomy with bilateral salpingo-oophorectomy, para-aortic and pelvic lymphadenectomy, and pelvic washing to stage the disease. Laparoscopy has been associated with fewer postoperative complications than laparotomy. Vaginal hysterectomy is generally not recommended because it precludes abdominal survey and lymphadenectomy.3 Most patients who have endometrial cancer will have stage I carcinoma. Need for further treatment is based

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on intraoperative and histologic findings.2 Pelvic and para-aortic lymphadenectomy remain controversial.

Several studies have noted an associated improvement in survival, whereas others have not.31 There is no consensus about which patients will require lymph node staging.2 Adjuvant Radiotherapy Radiation therapy does not affect overall survival in patients with low-grade carcinoma. It is associated with a reduction in quality of life and increased morbidity when used in patients with low-risk endometrial cancer.3,32 Radiation therapy is an option for patients who are medically inoperable.33 Chemotherapy and Hormone Therapy Cytoreduction therapy (debulking with surgery and chemotherapy or radiation) appears to improve survival time in patients with intra-abdominal disease by increasing survival and decreasing recurrence.34 Evidence to support the use of adjuvant progesterone therapy to prevent endometrial cancer recurrence is lacking.35 Progesterone is a treatment option for patients with stage I endometrial cancer who wish to preserve fertility.36 There is a 30% chance that the patient whose biopsy noted a grade I carcinoma may have a grade II or III carcinoma instead.37 Patients should be counseled on immediate hysterectomy once childbearing is completed.

PROGNOSIS Survival is based on the stage and histology of the diagnosis. Most patients with stage I and II endometrial cancer will have a favorable prognosis, whereas patients with stage III or IV endometrial cancer will have a worse likelihood of survival24 (Table 15,24-26). Posttreatment surveillance is recommended for detection of recurrent disease. The Society of Gynecologic Oncology recommends follow-up symptom surveillance and pelvic examinations every three to six months for two years posttreatment, then every six months for three years, and annually thereafter.3 Note: For complete article visit: www.aafp.org/afp.

REFERENCES 1. American Cancer Society. Cancer Facts and Figures 2014. http://www.cancer.org/acs/groups/content/@research/ documents/webcontent/acspc-042151.pdf.

Accessed October 27, 2014.

2. Sorosky JI. Endometrial cancer. Obstet Gynecol. 2012;120 (2 pt 1):383-397.

AMERICAN FAMILY PHYSICIAN 3. Practice Bulletin No. 149: Endometrial cancer. Obstet Gynecol. 2015;125(4):1006-1026.

4. Smith RA, et al.; ACS Prostate Cancer Advisory Committee, ACS Colorectal Cancer Advisory Committee, ACS Endometrial Cancer Advisory Committee. American Cancer Society guidelines for the early detection of cancer: update of early detection guidelines for prostate, colorectal, and endometrial cancers [published correction appears in CA Cancer J Clin. 2001;51(3):150]. CA Cancer J Clin. 2001;51(1):38-75.

5. Buchanan EM, et al. Endometrial cancer. Am Fam Physician. 2009;80(10):1075-1080.

6. Saso S, et al. Endometrial cancer. BMJ. 2011;343:d3954.

7. Courneya KS, et al. Associations among exercise, body weight, and quality of life in a population-based sample of endometrial cancer survivors. Gynecol Oncol. 2005;97(2): 422-430.

8. Calle EE, et. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.

N Engl J Med. 2003;348(17):1625-1638.

9. Fisher B, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90(18): 1371-1388.

10. Davies C, et al.; Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial [published correction appears in Lancet. 2013;381(9869):804]. Lancet.

2013;381(9869):805-816.

11. Nelson HD, et al. Systematic review: comparative effectiveness of medications to reduce risk for primary breast cancer. Ann Intern Med. 2009;151(10):703-715,W-2 26-W-235.

12. Lindor NM, et al. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA. 2006;296(12): 1507-1517.

13. Vasen HF, et al.; Mallorca group. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut. 2013;62(6):812-823.

16. Grady D, et al. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol.

1995;85(2):304-313.

17. Khati NJ, et al.; Expert Panel on Women’s Imaging. ACR Appropriateness Criteria: abnormal vaginal bleeding.

Reston, Va.: American College of Radiology; 2014:1-13. http://www.guideline.gov/content.aspx?id=48294.

Accessed February 27, 2015.

18. American College of Obstetricians and Gynecologists. The role of transvaginal ultrasonography in the evaluation of postmenopausal bleeding. ACOG Committee Opinion No. 440, August 2009. Obstet Gynecol. 2009;114:409-411.

19. American College of Obstetricians and Gynecologists.

Management of acute abnormal uterine bleeding in nonpregnant reproductive-aged women. ACOG Committee Opinion No. 557, April 2013. Obstet Gynecol.

2013;121(4):891-896.

20. Smith-Bindman R, et al. Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA. 1998;280(17):1510-1517.

21. Gupta JK, et al. Ultrasonographic endometrial thickness for diagnosing endometrial pathology in women with postmenopausal bleeding: a meta-analysis. Acta Obstet Gynecol Scand. 2002;81(9):799-816.

22. Elsandabesee D, et al. The performance of Pipelle endometrial sampling in a dedicated postmenopausal bleeding clinic. J Obstet Gynaecol. 2005;25(1):32-34.

23. Clark TJ, et al. Accuracy of hysteroscopy in the diagnosis of endometrial cancer and hyperplasia: a systematic quantitative review. JAMA. 2002;288(13):1610-1621.

24. Lewin SN, et al. Comparative performance of the 2009 International Federation of Gynecology and Obstetrics’ staging system for uterine corpus cancer. Obstet Gynecol.

2010;116(5):1141-1149.

25. Edge SB; American Joint Committee on Cancer. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.

26. Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium [published correction appears in Int J Gynaecol Obstet. 2010;108(2):176]. Int J Gynaecol Obstet. 2009;105(2):103-104.

27. Trimble CL, et al.; Society of Gynecologic Oncology Clinical Practice Committee. Management of endometrial precancers. Obstet Gynecol. 2012;120(5):1160-1175.

14. Schmeler KM, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med. 2006;354(3):261-269.

28. American College of Obstetricians and Gynecologists.

Supracervical hysterectomy. ACOG Committee Opinion No. 388, November 2007. Obstet Gynecol. 2007;110(5): 1215-1217.

15. Chin J, et al. Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen. Cochrane Database Syst Rev. 2009;(4):CD007245.

29. Ghezzi F, et al. Postoperative pain after laparoscopic and vaginal hysterectomy for benign gynecologic disease: a randomized trial. Am J Obstet Gynecol. 2010;203(2):118. e1-8.

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AMERICAN FAMILY PHYSICIAN 30. Orbo A, et al. Levonorgestrel-impregnated intrauterine device as treatment for endometrial hyperplasia: a national multicentre randomised trial. BJOG. 2014;121(4): 477-486.

31. Aalders JG, et al. Endometrial cancer—revisiting the importance of pelvic and para aortic lymph nodes.

Gynecol Oncol. 2007;104(1):222-231.

32. Kong A, et al. Adjuvant radiotherapy for stage I endometrial cancer. Cochrane Database Syst Rev. 2012;(3): CD003916.

34. Barlin JN, et al. Cytoreductive surgery for advanced or recurrent endometrial cancer: a meta-analysis. Gynecol Oncol. 2010;118(1):14-18.

35. Martin-Hirsch PP, et al. Adjuvant progestagens for endometrial cancer. Cochrane Database Syst Rev. 2011;(6):CD001040.

36. Gunderson CC, et al. Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review. Gynecol Oncol. 2012;125(2):477-482.

37.

33. Podzielinski I, et al. Primary radiation therapy for medically inoperable patients with clinical stage I and II endometrial carcinoma. Gynecol Oncol. 2012;124(1): 36-41.

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Eltabbakh GH, et al. Surgical stage, final grade, and survival of women with endometrial carcinoma whose preoperative endometrial biopsy shows welldifferentiated tumors. Gynecol Oncol. 2005;99(2):309-312.

AMERICAN FAMILY PHYSICIAN

Practice Guidelines AAFP RELEASES POSITION PAPER ON PRECONCEPTION CARE Preconception care is defined as personalized care for men and women that is focused on reducing maternal and fetal morbidity and mortality, increasing chances of conception, and preventing unintended pregnancies.

Family physicians have the opportunity to discuss risk factors that negatively impact maternal and infant health such as being overweight, smoking, hypertension, and diabetes mellitus.

There are multiple barriers to providing comprehensive preconception care. Usually, preconception is focused on patients planning a pregnancy. Because one-half of U.S. pregnancies are reported as unintended, the timing of addressing preconception is a challenge. Most women recognize the need for counseling before conception to achieve optimal health outcomes, but the majority reported that they did not receive any counseling, and most physicians did not provide or recommend counseling to their patients of reproductive age. The American Academy of Family Physicians (AAFP) has released a position paper providing evidence-based recommendations that address reproductive health care.

Preconception Interventions for Women A woman’s reproductive plan should be discussed at each visit because her plans may change depending on life circumstances. These discussions should include risks due to age, maternal or paternal conditions, and obstetric and family history. Women who wish to prevent pregnancy should be offered contraceptive methods approved by the U.S. Food and Drug Administration, an assessment to identify safe methods, counseling to help choose a contraceptive method, and prompt delivery of the contraceptive method selected. Shared decision making and tailored information should focus on patient preferences. Routine counseling about emergency contraception should also be available when needed.

Source: Adapted from Am Fam Physician. 2016;94(6):508-510.

Overall health and management of chronic conditions are essential for proper preconception care. Women of reproductive age should take a daily supplement of 400 to 800 mcg of folic acid, starting before conception and continuing through 12 weeks of pregnancy, and consume a balanced diet of folate-rich foods to reduce the risk of neural tube defects.

Obesity, chronic hypertension, diabetes, and lifestyle risks (e.g., use of alcohol, tobacco, illicit substances) can lead to pregnancy complications and should be addressed, as well as counseling on medication use.

Many commonly prescribed medications are considered unsafe in pregnancy and it may be necessary to switch to safer medications before conception. A mental health assessment should be included in preconception care because mood and anxiety disorders are highly prevalent in women of reproductive age, with a high prevalence of relapse of a previously diagnosed mental health disorder or a new-onset disorder in pregnancy.

Treatment for these disorders during pregnancy should be individualized. Immunization status should be evaluated annually in all women of reproductive age.

Table 1 shows general recommendations preconception interventions for women.

for

Preconception Interventions for Men The Centers for Disease Control and Prevention and the U.S. Department of Health and Human Services have recognized the need for improvements in meeting men’s reproductive health needs. The objective of preconception interventions for men is to ensure positive outcomes of their reproductive and sexual behaviors, while minimizing negative consequences of unhealthy lifestyle choices. Men should be counseled on contraception, overcoming fertility issues, ensuring a healthy pregnancy for his partner, and ensuring optimal postpartum outcomes for his partner and child (Table 2).

Fertility and Conception Studies have identified several factors that affect sperm quality, quantity, concentration, and motility.

Health concerns such as diabetes, erectile dysfunction, and testicular conditions may affect fertility.

Certain medications can alter the hypothalamicpituitarygonadal axis, contribute to reduced male

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AMERICAN FAMILY PHYSICIAN libido and erectile dysfunction, and have toxic effects on sperm. Tobacco, alcohol, and drug use can affect spermatogenesis. Other factors that can affect sperm quality and production are stress, obesity, genetic disorders, and exposure to certain hazardous materials.

Effects on Maternal and Fetal Outcomes A man’s lifestyle factors can directly impact his partner’s pregnancy (e.g., tobacco smoking, sexually transmitted infections). Secondhand smoke can lead to low birth weight, intrauterine growth restriction, and preterm birth, as well as increase the risk of sudden infant death

syndrome. Paternal involvement during pregnancy can have a positive effect on health outcomes for himself, his partner, and child. During wellness visits, physicians have the opportunity to discuss issues such as intimate partner violence and coercive relationships, and to promote consensual sexual relationships.

A link between paternal genetics and age and conditions such as autism and schizophrenia has been found.

Screening for genetic conditions should be discussed and offered if needed.

Note: For complete article visit: www.aafp.org/afp.

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AMERICAN FAMILY PHYSICIAN

Photo Quiz PERSISTENT LOWER-LIMB ULCERS IN A PATIENT WITH DIABETES A 60-year-old woman presented with enlarging ulcers on her ankle and foot. Despite treatment, the ulcers worsened and became more painful, and she noted a new ulcer on her left shin. The problem started as a small ulcerated lesion on the lateral dorsal area of her foot that had developed two years earlier after she bumped into a dresser.

She had a history of diabetes mellitus, hypertension, hyperlipidemia, and myeloproliferative disease.

At the time of presentation, her medications included enalapril, metoprolol, furosemide, fenofibrate, insulin aspart, insulin detemir, metformin, prednisone, dapsone, topical silver sulfadiazine and clobetasol cream. She was previously taking hydroxyurea and anagrelide for her myeloproliferative disease. She was a nonsmoker.

Figure 1.

On examination, she was afebrile and had ulcers of varying size on her left lower leg over the lateral malleolus and foot (Figures 1 and 2). There were larger ulcerations exposing muscles and tendons, with sharp margins, an undermined and violaceous border, and granulation tissue over the ulcer beds. A smaller area of ulceration was noted in the left midpretibial area.

A complete blood count revealed a white blood cell count of 17,200 per mm3 (17.2 Ă— 109 per L). Her blood glucose level was 126 mg per dL (7.0 mmol per L).

Findings from Doppler ultrasonography and wound cultures were unremarkable.

Question Based on the patient’s history and physical examination findings, which one of the following is the most likely diagnosis?

A. Cutaneous malignancy.

B. Factitial ulcers.

Figure 2.

C. Infectious ulcers.

D. Pyoderma gangrenosum.

E. Venous stasis ulcers.

SEE THE FOLLOWING PAGE FOR DISCUSSION.

Source: Adapted from Am Fam Physician. 2016;93(9):783-784.

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AMERICAN FAMILY PHYSICIAN Discussion

Summary Table

The answer is D: pyoderma gangrenosum. Pyoderma gangrenosum is an inflammatory, noninfectious, ulcerative skin disorder characterized by rapidly enlarging, painful lesions. Although the most common sites of involvement are the lower legs, buttocks, and abdomen, it may occur anywhere, including on mucosal surfaces.1,2 Multiple lesions are usually present.1 It is most common in adults 40 to 60 years of age.3 It is rare in children, but head and anogenital involvement is more common in children than in adults.1,2 There are four variants: ulcerative, pustular, bullous, and vegetative. These variants may occur simultaneously.1 Lesions begin as tender pustules or erythematous nodules that enlarge, undergo necrosis, and then ulcerate.2 A primary lesion is not always seen. Fully developed lesions are sharply marginated, undermined ulcers with violaceous borders.3 The condition may develop spontaneously or at the site of trauma. Postsurgical pyoderma gangrenosum may be misdiagnosed as wound dehiscence or infection.1 Because there are no diagnostic serologic or histologic features, pyoderma gangrenosum is diagnosed through exclusion.3 An underlying chronic disease is present in around 50% of patients.3 Inflammatory bowel disease is the most common association, but other conditions that have been reported include rheumatoid arthritis and myeloproliferative diseases.4 Cutaneous malignancies such as squamous cell carcinoma, basal cell carcinoma, and melanoma may develop in nonhealing ulcers, but there is often a history of a growth preceding the ulceration.4 Biopsy is required for definitive diagnosis.5 Factitial ulcers may be suspected in patients with a history of psychiatric disease. The patient may present with geometric, unusual shaped lesions.

These ulcers generally heal quickly if there is no repeated trauma.5 Bacterial, deep fungal, parasitic, and atypical mycobacterial infections can lead to ulcers.

A travel history is important in considering tropical and parasitic diseases such as amebiasis and leishmaniasis.

Tissue culture may be required for diagnosis.5 Venous stasis ulcers are nonhealing ulcers that are associated with chronic venous insufficiency. They are located on the medial aspects of the lower legs and

Condition

Location

Characteristics

Cutaneous malignancies

Anywhere on skin

May be a result of squamous cell carcinoma, basal cell carcinoma, or melanoma; nonhealing ulcers

Factitial ulcers

More common on the extremities

Geometric, unusual shaped lesions; associated with psychiatric disease

Infectious ulcers

Anywhere on skin

May be caused by bacterial, deep fungal, parasitic, or atypical mycobacterial infections; diagnosed with tissue culture

Pyoderma gangrenosum

Most common on the lower leg

Sharply marginated, undermined ulcers with violaceous borders; associated with several chronic diseases such as inflammatory bowel disease; may occur after minor trauma

Venous stasis ulcers

Typically on the medial aspects of the lower legs

Nonhealing ulcers; associated with chronic venous insufficiency; comprise up to 80% of leg ulcers

comprise up to 80% of leg ulcers.1,5 Stasis ulcers rarely occur below the level of the malleoli.4 REFERENCES 1. Pyoderma gangrenosum. In: Habif TP, et al., eds. Skin Disease: Diagnosis and Treatment. 3rd ed. Edinburgh, Scotland: Elsevier; 2011:624-627.

2. Pyoderma gangrenosum. In: Paller A, Mancini AJ, Hurwitz S. eds. Hurwitz Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescence. 3rd ed. Philadelphia, Pa.: Elsevier Saunders; 2006:665-666.

3. Pyoderma gangrenosum. In: James WD, Berger TG, Elston DM, Odom RB, eds. Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia, Pa.: Elsevier Saunders; 2006:147-148.

4. Ulcers. In: Marks JG, Miller JJ, Lookingbill DP, eds.

Lookingbill and Marks’ Principles of Dermatology. 4th ed.

Philadelphia, Pa.: Elsevier Saunders; 2006:255-259.

5. Hwang J, Wong E. Non-healing, non-tender ulcer on shin.

J Fam Pract. 2015;64(7):421-424.

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CARDIOLOGY

Emerging Role of Cardiac MRI in Ischemic and Nonischemic Cardiomyopathy MONA BHATIA

ABSTRACT Cardiac magnetic resonance imaging (MRI), on account of its high resolution and 3D imaging of cardiovascular structures, with capability of evaluation of blood flow, pressure gradients, ventricular volumetrics, ventricular contractile function even for the right ventricular (RV) and myocardial characterization with less operator dependence in comparison to echocardiography, is fast emerging as an extremely robust and comprehensive noninvasive, nonionizing imaging tool in assessment of cardiovascular diseases. Presently, cardiac MRI has entered an important phase in its evolution, and is likely to alter the way cardiology is practiced in the future. Contrast-enhanced MRI may be used to guide interventions. These include real-time monitoring of electromagnetic catheter-directed radiofrequency ablations (e.g., for treatment of atrial fibrillation) within the heart with the potential to provide more precise positioning of the site of radiofrequency ablation. However, there are certain disadvantages.

These include long scan times, making it unsuitable for unstable and uncooperative patients, higher cost, limited availability and incompatibility with pacemakers and cochlear implants. Also, gadolinium-based contrast agents have been linked to the development of nephrogenic systemic fibrosis or nephrogenic fibrosing dermopathy.

Keywords: Cardiac MRI, high resolution, 3D imaging, operator dependence, assessment, cardiovascular diseases

C

ardiac disease is a leading cause of death worldwide. Cardiovascular magnetic resonance (CMR) with its recent advances has overcome the obstacles of spatial and temporal resolution with resultant unparalleled resolution and excellent soft tissue contrast, thus enabling accurate and reliable assessment of cardiac morphology, function (Table. 1) and pathology including myocardial viability, cardiomyopathies, pericardial disease, cardiac masses, congenital and valvular heart diseases, aortic and pulmonary vessel evaluation.1,2

Emerging applications include assessment by CMR for electrophysiology and interventional procedures.1 CMR is hence fast emerging as an extremely robust and comprehensive noninvasive, nonionizing imaging tool in cardiovascular evaluation.

TECHNICAL ASPECTS OF CARDIAC MRI Pulse sequences in cardiac magnetic resonance imaging (MRI), are broadly divided into black blood or bright Table 1. Left Ventricle and Right Ventricle Functional Analysis Results

(not corrected, corrected)

Left ventricle End-diastolic volume (mL)

101.9

76.9

End-systolic volume (mL)

67.0

45.3

Ejection fraction (%)

34.3

41.0

Stroke volume (mL)

34.9

31.5

Stroke index (mL/beat/m²)

27.5

24.8

Cardiac output (L/min)

3.5

3.1

Cardiac index (L/min/m²)

2.7

2.5

End-diastolic volume (mL)

74.2

39.0

End-systolic volume (mL)

59.4

24.1

Ejection fraction (%)

20.0

38.2

Stroke volume (mL)

14.8

14.9

Stroke index (mL/beat/m²)

11.7

11.7

Cardiac output (L/min)

1.5

1.5

Cardiac index (L/min/m²)

1.2

1.2

Right ventricle

Head of Department Dept. of Radiodiagnosis and Imaging Fortis Escorts Heart Institute, New Delhi Address for correspondence Dr Mona Bhatia Head of Department Dept. of Radiodiagnosis and Imaging Fortis Escorts Heart Institute, Okhla Road, New Delhi - 110 025

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CARDIOLOGY blood techniques. The black blood sequences have higher resolution, and are used for anatomic evaluation of the heart and great vessels. Gradient echo sequences are used for functional analysis. The high accuracy and reproducibility of cardiac MRI in functional analysis has made it rise to the level of the “gold standard� in the calculation of the ventricular indices such as enddiastolic, end-systolic and stroke volumes, ejection fraction (Table 1), cardiac output and myocardial mass assessment.3,4 Steady-state free precession sequences permit evaluation of wall motion and volumetrics. MRI permits phase contrast imaging for quantifying flow and in calculation of pressure gradient across lesions based on blood velocities.3 Inversion recovery sequences are used to null signal from the normal myocardium to evaluate abnormal myocardium. Post-gadolinium contrast enhancement is used in the evaluation of myocardial perfusion, myocardial infarctions, infiltrative processes and in differentiating masses from thrombi.3

stunned myocardium from infarcted myocardium to determine viability.3 Delayed hyperenhancement, is a more reliable indicator of infarction (Fig. 2) as it is associated with myocyte necrosis. Enhancement patterns based on first-pass and delayed imaging correlation assess viability and predict functional recovery.4 The presence of a high-grade perfusion deficit or delayed enhancement in the earlyphase MRI study is highly predictive of scar formation.2 Both acute and chronic myocardial infarctions demonstrate regional wall motion abnormalities.

Acute infarctions; however, show increased signal on T2-weighted imaging due to myocardial edema.

IMAGE ACQUISITION Cardiac imaging has the challenges of image degradation due to respiratory and cardiac motion, hence breath holding and ECG gating are desirable to ensure image acquisition during a specific phase of the cardiac cycle.

Vector cardiogram gating is sometimes preferred to overcome the magnetohydrodynamic effect of blood ions in magnetic fields.3 CMR images are obtained in the axial, coronal and sagittal planes. However, cardiac imaging is also acquired in specific planes as the vertical long axis, horizontal long axis (four-chamber view), short axis and three-chamber view.

INDICATIONS AND APPLICATIONS

Figure 1. Mid-cavity anteroseptal perfusion defect.

Cardiac MRI has the following common clinical applications.

Ischemic Heart Disease In ischemic heart disease (IHD), MRI today is considered the gold standard for ventricular volumetric analysis and can evaluate both regional and global myocardial function. Cardiac MRI can most accurately, reliably and reproducibly quantify end-diastolic, end-systolic, stroke volume, ejection fraction and ventricular mass for the right and left heart. Myocardial wall motion abnormality, thickness and perfusion defect (Fig. 1) is assessed visually and quantitatively. Myocardial tagging further evaluates circumferential and torsional strain. CMR is extremely useful in differentiating acute and chronic infarcts, assessing salvageable myocardium, quantifying myocardial ischemia and distinguish hibernating and

Figure 2. Delayed post-contrast enhanced scar quantification.

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CARDIOLOGY In severe acute infarctions, a dark central area of a nonenhancement may be present, surrounded by an area of enhancement. This pattern represents microvascular obstruction (MO). The presence of MO on delayed enhanced images is indicative of a poor clinical prognosis.3 The extent and transmurality of delayed enhancement after acute myocardial infarction form the basis of prognostic implications (Fig. 3) being inversely proportional to the degree of functional recovery.2 Increasing transmural extent of infarction (e.g., hyperenhancement involving >50% of the wall thickness) predicts regions less likely to improve in function after revascularization or β-blocker therapy (Table 2).

Myocardial infarction eventually may progress to myocardial thinning (<6 mm) (Fig. 4) with hypertrophy of the noninfarcted myocardium, ventricular dilation and aneurysmal changes. Intraventricular thrombi adjacent to akinetic myocardium after infarction are also well depicted by MRI.3 The ultimate focus of MRI is in identifying acute infarction and for differentiating viable myocardium from nonviable myocardium. In the setting of ischemia, transient hypoperfusion can cause myocardial stunning.

Myocardial delayed enhancement in combination with cine MRI helps differentiate wall-motion abnormalities of myocardial stunning, which are reversible, from those

Figure 4. Mid-cavity anteroseptal wall thinning in ischemic heart disease.

of myocardial infarction, which are often irreversible.2 While both conditions cause wall-motion abnormality, delayed enhancement occurs only with infarcts. Lack of delayed enhancement indicates stunning.

Viability assessment also is possible by cine MRI without contrast during a low-dose infusion (5-10 Îźg/kg/min) of dobutamine or after administration of adenosine.1 Improved left ventricular (LV) wall thickening with stress in a segment that functions poorly at rest indicates viability.2 Dobutamine stress MRI can also be used to detect ischemic myocardium.2 Comparison with Other Imaging Modalities Comparison of perfusion MR at rest and after infusion of pharmacologic agents (adenosine and persantine) with standard methods (angiography or radionuclide scintigraphy) has demonstrated reasonable sensitivity (67-83%) and specificity (75-100%).1

Figure 3. Post-contrast spatial enhancement.

Table 2. Percentage of Left Ventricle Myocardium Scarred Enhanced volume

20,003 mm3

Myocardial volume

10,3574 mm3

Percentage enhanced volume

420

19%

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Delayed-enhancement myocardial MRI has the major advantage of superior spatial resolution, simultaneous anatomic and cine imaging with better depiction of wall motion, cardiac morphology and myocardial viability. In particular, MRI is superior in detecting subendocardial infarction.2 Results of myocardial delayed enhancement correlate well with dobutamine stress echocardiography.5 Excellent agreement has been found with positron-emission tomography (PET). A study demonstrated 96% sensitivity and 84% specificity for myocardial delayed enhancement, with 18F-fluorodeoxyglucose (18F-FDG) PET as the

CARDIOLOGY standard.6 Good agreement is also found with singlephoton emission computed tomography (SPECT).2 In a study, SPECT depicted all of the nearly transmural infarctions but missed 47% of subendocardial infarctions, which were easily seen at myocardial delayed-enhancement MRI.7 Differential Diagnosis Delayed hyperenhancement can also be seen in diseases other than acute and chronic infarcts as myocarditis, cardiomyopathy, sarcoidosis, amyloidosis and arrhythmogenic RV dysplasia.8 The pattern and distribution of enhancement in these disorders i.e., midwall, epicardial (Fig. 5) or global endocardial being different from the subendocardial or transmural hyperenhancement seen in infarcts.4

Nonischemic Cardiomyopathy and Myocarditis The tremendous advantage of cardiac MRI in accurately assessing ventricular morphology, function, myocardial wall enhancement pattern and wall motion abnormalities has established its role in the characterization on nonischemic cardiomyopathy and myocarditis.1 Cardiomyopathies may be classified as hypertrophic, dilated, restrictive and arrhythmogenic RV cardiomyopathy.

Hypertrophic Cardiomyopathy

of hypertrophy in HCM. Different forms of HCM include asymmetric, concentric or papillary muscle hypertrophy. Asymmetric hypertrophy involving the interventricular septum is the commonest and may involve the left ventricular outflow tract (LVOT) when it is referred to as hypertrophic obstructive cardiomyopathy (HOCM).3 Cardiac MRI is excellent at demonstrating apical HCM, LVOT obstruction and systolic anterior motion of the mitral valve,1 including asymmetric septal, symmetrical and apical HCM.9 Further, it can quantify turbulent flow and velocity in LVOT obstruction and evaluate mitral regurgitation. Delayed hyperenhancement on CMR evaluates scar tissue within the hypertrophied myocardium, which may act as a nidus for fatal arrhythmias and may have prognostic implications in the future. Cardiac MRI is also useful in the followup of patients after ventricular septal resection or percutaneous ablation.1,3

Dilated Cardiomyopathy In dilated cardiomyopathy, CMR can accurately analyze wall thickness, dilated chambers and delayed enhancement characteristics.1 Midwall and epicardial myocardial enhancement permits differentiation from subendocardial enhancement as seen in ischemic origin (Fig. 6). The degree of enhancement correlates with the severity of functional abnormality.2

Hypertrophic cardiomyopathy (HCM) manifests as hypertrophied myocardium with diastolic failure.

Cardiac MRI is excellent at demonstrating the extent

Restrictive Cardiomyopathy

Figure 5. Nonischemic epicardial scar/scar on the RV aspect of the septum.

Figure 6. Dilated cardiomyopathy with mid wall enhancement.

MRI is extremely useful in the evaluation of restrictive diseases where myocardial tissue characterization,

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CARDIOLOGY infiltration and fibrosis can be assessed, which leads to restrictive cardiomyopathy.1,3,9 The condition manifests as normal LV size and systolic function, severe diastolic dysfunction and biatrial enlargement. Frequently encountered conditions in this group include: ÂÂ

Sarcoidosis: Sarcoid lesions vary in signal characteristics in different stages of the disease from high intensity to central low intensity on T2weighted imaging surrounded by a high signal ring.1 Post-gadolinium contrast enhancement is more typically patchy with midwall and epicardial distribution. Advanced disease may demonstrate septal thinning, LV dysfunction and pericardial disease.2

ÂÂ

Hemochromatosis: Dysfunctional myocardium in conjunction with an abnormally “dark” liver confirms the diagnosis of iron deposition and systemic hemochromatosis1 with extensive signal loss in native T1- and T2-weighted images. Iron deposition is predominantly subepicardial.

ÂÂ

Amyloidosis: Amyloid may manifest as ventricular wall thickening with delayed hyperenhancement and thickening of the atrial septum. Thickness of the atrial septum or the right atrial posterior wall of 6 mm is fairly specific for amyloid infiltration.1,10

ÂÂ

Endomyocardial fibrosis: Endomyocardial fibrosis (also termed Loeffler’s endocarditis) is characterized by extensive subendocardial fibrosis, apical thrombus formation and progressive diastolic dysfunction.9 The morphologic and functional features can be well-quantified by MRI.

Arrhythmogenic RV Dysplasia In the diagnosis of arrhythmogenic right ventricular dysplasia (ARVD), MRI is the technique of choice. The revised Task Force Criteria sets new guidelines of the major and minor criteria for ARVD/arrhythmogenic right ventricular cardiomyopathy (ARVC) based on global or regional dysfunction and structural alterations, tissue characterization of wall, repolarization abnormalities, depolarization/conduction abnormalities, arrhythmias and family history. Major MRI criteria include regional RV akinesia or dyskinesia or dyssynchronous RV contraction and one of the following: Ratio of RV end-diastolic volume to body surface area (BSA) ≥110 mL/m2 (male) or ≥100 mL/m2 (female) or RV ejection fraction ≤40%. Hence RV dilatation, reduced ejection fraction and additionally fatty infiltration, wall thinning, regional wall motion abnormalities, dysplastic trabecular structures,9 localized early diastolic bulging and saccular aneurysmal outpouchings may be seen.1

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Delayed enhancement of the RV myocardium may have a diagnostic role.2,3

Myocarditis Myocarditis of viral or other origin, initiates as a focal myocardial T2-weighted increased signal intensity (Fig. 7) with post-contrast midwall/epicardial enhancement with wall motion abnormality and proceeds to a more diffuse and transmural biventricular enhancement and RV pseudoaneurysm formation.11 Early and delayed post-contrast hyperenhancement have a prognostic role in myocarditis. In hypereosinophilic syndrome myocardial involvement is seen together with ventricular thrombi.2 MRI also enables visualization of inflamed areas that would aid determining a biopsy site during endomyocardial biopsy.1

Pericardial Disease The first-line of evaluation for pericardial disease is echocardiography, effusion and tamponade being the most common indications. Echocardiography is however limited if no effusion exists or if the effusion is complex.4 Cardiac MRI based T1-weighted spin echo imaging demonstrates normal pericardium as a thin band (2 mm) of low signal, bordered by epicardial and pericardial fat. MRI reliably assesses pericardial thickening, unlike echocardiography. A pericardial thickness of 4 mm is considered abnormal and suggestive of inflammatory/fibrous pericarditis based on additional findings (Fig. 8).1 On spin echo imaging, simple effusions are seen as low signal intensity on T1-weighted imaging and high signal intensity on T2-weighted imaging. MRI, demonstrates effusions complicated with adhesions or loculations and aids differentiating transudative from exudative

Figure 7. Acute myocarditis on T2-weight imaging.

CARDIOLOGY CONCLUSIONS MRI is fast emerging as a dominant noninvasive imaging modality in the assessment of cardiovascular diseases. The disadvantages of cardiac MR; however, include long scan times, making it unsuitable for unstable and uncooperative patients, higher cost, limited availability and incompatibility with pacemakers and cochlear implants.1,3 Further, gadolinium-based contrast agents have been linked to the development of nephrogenic systemic fibrosis or nephrogenic fibrosing dermopathy.4

Figure 8. Constrictive pericarditis.

or hemorrhagic effusion based on signal characteristics and contrast enhancement.1 Cine MRI can demonstrate associated findings in the ventricles and cardiac valves1 such as small RV chamber, restriction of diastolic filling, biatrial dilation and ventricular or septal alterations and septal bounce.

Tagged images may demonstrate adhesions between the pericardium and epicardium.3 Diastolic collapse of the chambers indicates tamponade.

MRI has high sensitivity in differentiating constrictive pericarditis from restrictive cardiomyopathy. In constrictive pericarditis, diffuse/heterogeneous pericardial thickening of 4 mm or greater has an accuracy of 93%.4 The inability to image pericardial calcification is however a limitation of MRI in the diagnosis because the specificity of pericardial calcification is high.4 FUTURE DEVELOPMENTS In the future, contrast-enhanced MRI may be used to guide interventions. These include real-time monitoring of electromagnetic catheter-directed radiofrequency ablations (e.g., for treatment of atrial fibrillation) within the heart with the potential to provide more precise positioning of the site of radiofrequency ablation.12 New treatments for heart failure involve the transplantation of primitive cell types (e.g., stem cells or myoblasts) into the damaged tissue, where they can trans-differentiate into functional tissue.13 Stem cells have been labeled with iron-based contrast agents to determine myocardial localization after implantation14,15 and in vivo evaluation of stem cell retention, engraftment and migration. In an animal study, MRI was able to accurately localize the targeted catheter-based implantation of iron-loaded myogenic precursor cells into locally infarcted LV myocardium.16

However, on account of its high resolution and 3D imaging of cardiovascular structures, with capability of evaluation of blood flow, pressure gradients, ventricular volumetrics, ventricular contractile function even for the RV and myocardial characterization with less operator dependence in comparison to echocardiography and no interference form adjacent bone or air,3 cardiac MRI has hence entered an important phase in its evolution, and is likely to alter the way cardiology is practiced in the future.

REFERENCES 1. Lima JA, Desai MY. Cardiovascular magnetic resonance imaging: current and emerging applications. J Am Coll Cardiol. 2004;44(6):1164-71.

2. Edelman RR. Contrast-enhanced MR imaging of the heart: overview of the literature. Radiology. 2004;232(3):653-68.

3. Norton PT, Nacey NC, Caovan DB, Gay SB, Kramer CM, Jeun BS, et al. Cardiac MRI: The Basics. Available at: http://www.med-ed.virginia.edu/courses/rad/cardiacmr/ index.html 4. Eugene C Lin. Cardiac MRI, Technical Aspects. Available at: http://emedicine.medscape.com/article/352250overview 5. Zamorano J, Delgado J, Almería C, Moreno R, Gómez Sánchez M, Rodrigo J, et al. Reason for discrepancies in identifying myocardial viability by thallium-201 redistribution, magnetic resonance imaging, and dobutamine echocardiography. Am J Cardiol.

2002;90(5):455-9.

6. Kühl HP, Beek AM, van der Weerdt AP, Hofman MB, Visser CA, Lammertsma AA, et al. Myocardial viability in chronic ischemic heart disease: comparison of contrastenhanced magnetic resonance imaging with (18) F-fluorodeoxyglucose positron emission tomography.

J Am Coll Cardiol. 2003;41(8):1341-8.

7. Wagner A, Mahrholdt H, Holly TA, Elliott MD, Regenfus M, Parker M, et al. Contrast-enhanced MRI and routine single photon emission computed tomography (SPECT) perfusion imaging for detection of

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CARDIOLOGY subendocardial myocardial infarcts: an imaging study.

Lancet. 2003;361(9355):374-9.

on three-dimensional magnetic resonance images in real time. Circulation. 2003;108(19):2407-13.

8. Weinsaft JW, Klem I, Judd RM. MRI for the assessment of myocardial viability. Cardiol Clin. 2007;25(1):35-56, v.

13. Orlic D, Hill JM, Arai AE. Stem cells for myocardial regeneration. Circ Res. 2002;91(12):1092-102.

9. Friedrich MG. Magnetic resonance imaging in cardiomyopathies. J Cardiovasc Magn Reson.

2000;2(1):67-82.

14. Hill JM, Dick AJ, Raman VK, Thompson RB, Yu ZX, Hinds KA, et al. Serial cardiac magnetic resonance imaging of injected mesenchymal stem cells. Circulation.

2003;108(8):1009-14.

10. Fattori R, Rocchi G, Celletti F, Bertaccini P, Rapezzi C, Gavelli G. Contribution of magnetic resonance imaging in the differential diagnosis of cardiac amyloidosis and symmetric hypertrophic cardiomyopathy. Am Heart J. 1998;136(5):824-30.

15. Kraitchman DL, Heldman AW, Atalar E, Amado LC, Martin BJ, Pittenger MF, et al. In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation. 2003;107(18):2290-3.

11. Inoue S, Murakami Y, Shimada T, Inoue A, Maruyama R. Right ventricular aneurysm caused by acute myocarditis. Can J Cardiol. 2000;16(8):1025-8.

16. Garot J, Unterseeh T, Teiger E, Champagne S, Chazaud B, Gherardi R, et al. Magnetic resonance imaging of targeted catheter-based implantation of myogenic precursor cells into infarcted left ventricular myocardium. J Am Coll 12. Dickfeld T, Calkins H, Zviman M, Kato R, Meininger G, Lickfett L, et al. Anatomic stereotactic catheter ablation Cardiol. 2003;41(10):1841-6.

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Prevalence, Predictors and Prognostic Implications of PR Interval Prolongation in Patients with Heart Failure The goal of a new article published in Clinical Research in Cardiology was to determine the prevalence, incidence, predictors and prognostic implications of PR interval prolongation in patients referred with suspected heart failure. This prospective study included consecutive patients referred with suspected heart failure. The results revealed that the prevalence of first-degree heart block was higher in patients with heart failure. While in patients with heart failure and reduced ejection fraction (HeFREF); heart failure and normal ejection fraction (HeFNEF); and in those with HeFREF treatment with amiodarone or digoxin, longer baseline PR interval (PRc) was associated with greater age, male sex and longer QRS duration. On the other hand, patients with heart failure in the longest PRc quartile had worse survival compared to those with shorter PRc quartiles. However, PRc was not independently associated with survival. Furthermore, for patients without heart failure, shorter baseline PRc was independently associated with worse survival. Hence, it was concluded that PRc prolongation is common in patients with HeFREF or HeFNEF and associated with worse survival, although not an independent predictor of outcome. It was stated that further investigation would be required to investigate the therapeutic potential of shortening the PR interval by pacing.

Coronary Calcium Score Influences Referral for Invasive Coronary Angiography After Normal Myocardial Perfusion SPECT A new article published in the Journal of Nuclear Cardiology assessed whether high coronary artery calcium (CAC) scores are associated with increased referral for invasive angiography following normal single-photon emission computed tomography (SPECT). This study assessed 2,286 consecutive patients with normal SPECT, of which 39% were males. The findings showed that a total of 100 patients (4.4%) underwent early angiography; the rate of which increased with their CAC scores. The incidence rate of an early angiography was found to be 1% in the group with a CAC score of 0; whereas the values were 2.6% for CAC score 1-100; 8.4% for CAC score 101-400 and 11.7% for CAC scores above 400. In addition, a CAC score above 400 was independently associated with referral to angiography. Likewise, CAC score above 400 was an independent predictor for MACE (late revascularization, myocardial infarction or death). Moreover, early angiography did not influence prognosis.

Thus, it was inferred that CAC scoring impacts clinical decision-making and increases referral rates for invasive angiography after normal SPECT.

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COMMUNITY MEDICINE

Status of Biomedical Waste Generation and Its Disposal in Delhi RASHMI CHOWDHRI*,†, LAXMI RAWAT*, JK SHARMA†, VISHAL KAMRA†

ABSTRACT Medical care is very essential and crucial for our life and health, but the waste generated from medical activities creates a real problem in our country. Improper management of waste generated in healthcare facilities causes a direct health impact on our nation. The main objective of this paper is to present a view of hospital waste management and environmental problems due to current practices and compliances. This paper summarizes the management and handling of medical wastes. The categories of biomedical wastes, storage containers, the effects of medical waste in Delhi on environment have been described.

Medical waste management in Delhi should be given utmost importance and attention as it plays a vital role for human and environmental health resulting in more effective and stringent regulations. The survey works carried out on medical waste have been discussed in the present paper.

Keywords: Hospital waste, biomedical waste, expired medicines, waste in Delhi, management

B

iomedical waste (BMW) is the waste generated in the diagnosis, treatment or immunization of human beings or animals in research or in the production of testing of biological products. It is estimated that 0.33 million tons of hospital waste is generated in India, ratio of generation of which ranges from 0.5 to 2.0 kg/bed day.

The waste is increasing in its amount type due to advances in scientific knowledge and has impact on human lives.

Lack of awareness of all categories of health workers and improper management of BMW poses a risk for health and environment. Besides infection concern, it also causes chemical and radiological hazards. Aim of BMW is proper segregation, collection, transport, handling and disposal in such a way that it is safe for environment as well as community. There are number of legislations to enforce proper disposal of BMW in India e.g., BMW rules, Solid Waste Management (Management & Handling) Rules, Hazardous Waste (Management & Handling) Rules, 1989. These rules are applicable to each hospital, nursing home, veterinary institutions, animal house or slaughter house’s which generates BMW. In this regard healthcare workers have

an important responsibility to properly segregate and impart training to the staff for disposal.

Delhi is the capital of India and has a current population of 19.07 million which accounts for nearly 25.5% of India’s population (134 crores). Its population grew at a rate of 31.8% during last three decades to 1.68 crores.

Rapid increase in urbanization and industrial growth has led to change in lifestyle and social status of the population. This in turn has influenced the setting up of hospitals, dispensaries in Delhi generating hospital waste, which has tremendously increased over the years. Delhi is not only facing a challenge of increasing population, available services and shortage of resources, but also for better management of medical waste.

Waste management is one of the important public health measures. Proper management of medicinal waste in Delhi has an enormous gap to fill. Drug wastage is a direct measure of efficiency and success of overall healthcare system. It is a cause of concern for both, Delhi government and environment. This waste, if not managed properly, can have an adverse impact on the environment and human health arising from contamination of air, soil and water through spread of diseases in Delhi and its vicinity.

BIOMEDICAL WASTE: SOURCES AND CLASSIFICATION

*Shriram Institute for Industrial Research, Delhi †Amity School of Business, Amity University, Noida, Uttar Pradesh Address for correspondence Dr Laxmi Rawat Shriram Institute for Industrial Research, 19, University Road, Delhi - 110 007

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Waste is a substance or object which is intended to be disposed of, by the provisions of environmental laws and regulations. In our daily activities, a large variety

COMMUNITY MEDICINE of it is generated and depending upon their physical state, they are categorized into solid, liquid and gas.

The rising quality-of-life and high rates of resources consumption has resulted in enormous quantity of waste generation. Hospitals, clinics, diagnostic centers, nursing homes, research organizations and healthcare centers use a variety of drugs including antibiotics, corrosive chemicals and radioactive substances, which ultimately contribute to BMW. The disposal of BMW can be hazardous particularly when it gets mixed with municipal solid waste and dumped in uncontrolled landfills. This can lead to a higher degree of environmental pollution.

The priority is to segregate waste, preferable at the point of generation into reusable and nonreusable, hazardous and nonhazardous components. This involves four steps, namely segregation, transportation, treatment and final disposal.

Hospital waste are classified on the basis of their source of waste (Fig. 1). They are categorized into BMW, hazardous waste. Around 80% of the waste produced by healthcare facilities is nonrisk and noninfectious waste, which is comparable to domestic waste. However, the remaining 20% of healthcare waste is regarded as hazardous and infectious waste, which creates a variety of health risks. The main constituents of the hospital waste are as given in Table 1. The infectious waste includes materials such as cloth, plastic, paper, glassware, fluids, etc. as shown in Table 2.

Contaminated waste Noninfectious 20%

80%

Figure 1. Sources of hospital waste.

In the absence of proper management, the noninfectious waste also becomes infectious and poses environmental threat to the society.

MAJOR SOURCES OF BMW IN DELHI BMW is a major area of attention in Delhi. In Delhi as per National Green Tribunal (NGT) findings, several hospitals are violating the BMW disposal rules. The sources of BMW can be categorized into primary and secondary sources according to quantities produced (Table 3).

CLASSIFICATION AND TYPES (COMPOSITION OF BMW) The World Health Organization (WHO) has classified medical waste into 8 categories: general waste, pathological, radioactive, chemical, infectious to potentially infectious, sharps, pharmaceuticals and pressurized containers. However, MoEF in India has notified BMW into 10 different categories (Table 4), which are listed according to their type and their major constituents, respectively in a table.

HAZARDS FROM BMW Inadequate implementation of rules and regulation of BMW system in Delhi is the major drawback. Large amount of medical facility is available in Delhi which is the main sources of BMW such as bandages, cotton, soiled linen with blood or body fluids, body parts and Table 2. Typical Composition of Infectious Waste Category

Composition in percentage (%)

Cloth and paper

50-70

Plastics

20-60

Glasswareâ&#x20AC;&#x2122;s

10-20

Fluids

1-10

Table 3. Primary and Secondary Sources of BMW Primary source

Secondary source

Table 1. Composition of Hospital Waste (%)

Medical colleges

Clinics

Constituents

Hospitals

Slaughter houses

Contaminated waste

Approximate percentage (%) 20

Nursing Homes

Funeral services

Pathological waste

Dispensaries

Ambulance services

Infectious waste

Research Labs

Educational institutions

Blood Banks

Home treatment

Noninfectious Paper, plastic, metal, etc.

80

Animal Houses

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COMMUNITY MEDICINE Table 4. Categories of Biomedical Waste Category

Type of waste

Constituents of waste

No. 1

Anatomical waste

Human tissue, body parts, experimental animal carcasses

No. 2

Animal waste

Animal tissue, organs, body parts carcasses, blood and experimental animals

No. 3

Microbiology and biotechnology and other clinical laboratory waste

Laboratory cultures, stocks on specimens of microorganisms live or attenuated vaccines, human , cell culture, infectious agents, wastes from production of biological, toxins, dishes, devices used for cultures, etc.

No. 4

Waste sharps including metals

Needles, syringes, scalpels, blades, glass, etc.

No. 5

Expired/Discarded medicines

Outdated, contaminated and discarded medicines

No. 6

Soiled waste

Items contaminated with blood, body fluids including cotton, dressings, plaster casts, linens, beddings, other material contaminated with blood

No. 7

Disposal waste

Items such as tubing, catheters, intravenous sets, etc.

No. 8

Liquid waste

Waste generated during washing, cleaning and disinfectant activities

No. 9

Incineration Ash

Ash from incineration of biomedical waste

No. 10

Chemical waste

Chemical used in production of biological, used discarded disinfectants

tissues. Doctor, nurses, technicians, sweepers, hospital visitors, patients, rag pickers, etc. are generally exposed in routine to these BMW at are high risks due to indiscriminate management of BMW. Due to improper management, BMW mixes with solid waste and during rainy season the infectious substances may get added to the ground water or spread hazardous diseases.

The problem with BMW disposal is aggravated due to rapid and uncontrolled growth of medical care facilities, increase in waste generation rate owing to increase in disposal medical care materials, illegal and unsafe methods of waste recycling due to increased cost of disposal medical care materials.

The situation can cause a potential health hazard to public at large especially rag pickers, hospital waste and municipal corporation employee involved in waste recycling. Waste handlers and the community they lives in the proximity are at high risk due to improper handling of the waste. Skin contact, infection and inhalation are possible routes of exposure, which could cause chronic effects and acute problems.

PRESENT SCENARIO OF BMW MANAGEMENT IN DELHI Incineration of BMW is one of the most common treatment in Delhi as it is low cost but resulting in bad environmental effects. Other treatment are autoclaving, microwave treatment, pyrolysis-oxidation, direct heating, depolymerization, but all of them involve high costing, therefore, not in common use.

There are 109 hospitals (including Ayurvedic and Maternity homes) in government sector, 1050 registered

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nursing homes in private sector and large number of primary health centers run by the Govt. as well as nonGovt. organizations. No. of healthcare establishments in Delhi is 2,070 out of which 39 are Govt. dispensaries/ polyclinics are 266, Mohalla clinics are 66. Quantity of BMW generated in Delhi as per Delhi Pollution Control Committee (DPCC) estimates is 1364.22 kg/day. In order to facilitate the proper treatment of BMW generated from small nursing homes/clinics/blood banks, diagnostic centers, etc.; the government has taken initiative to establish centralized waste treatment facilities in Okhla and Nilothi in Delhi. The waste is segregated into non-infectious and infectious and hazardous waste (Fig. 2) in colored container according based on waste generation.

PRESENT BMW TREATMENT FACILITY IN DELHI Under Biomedical Waste (Management & Handling) Rules, 1998, all healthcare institutions are required to handle biomedical waste in a suitable manner.

Service providers in common BMW facility in collaboration with Government of India are given in Table 5.

Detail of BMW Handled by CBMWFs (Common BMW Treatment Facility) At present, Delhi generates yearly 4,979 tons of BMW, treated - 1,392 and common - 3,587. The disposal of waste in Delhi is not good as it requires considerate efforts. Improper disposal of waste deteriorates public health, causes environmental pollution, accelerates resources degradation, causes climate change and

COMMUNITY MEDICINE

Biomedical waste segregation and disposal

Noninfectious waste

General waste such as needle caps, wrappers, empty boxes, waste paper, packing materiel, etc.

Vials, empty bottles

Infectious and hazardous waste

Sharps such as needles, broken ampoules, broken glass, broken bottles, blades, etc.

Infected plastic items such as gloves, BT seats Ryle's tube, catheters, urobags, blood bags, dialyzer set, etc.

Swabs, cotton, dressing materials, etc.

Contaminated with blood and body fluids/ solid plaster casts/human tissues/organs parts.

Black container

Viral and bacterial infected waste, human tissue, blood bandage, soiled cotton dressings, etc.

Syringes after cutting in blue container

Deep in 1% bleach solution for 24 hours

Dried and shredded Yellow container

Blue container

Red container Send for treatment

Biohazard disposal

Figure 2. Noninfectious and infectious and hazardous waste.

Table 5. Service Providers for Common BMW Management in Delhi Service provider

Operational Address

Installed capacity

Districts allocated by DPCC

SMS water grace BMW Pvt. Ltd.

April 2011

Nilothi STP Complex of DJB, Nilothi, New Delhi - 110 041

19 tons per day

West, South West, Central East, Shahdara, North East District

Biotic Waste Solutions Pvt. Ltd.

Oct 2009

46, SSI, Industrial Area, Delhi - 110 033

13 tons per day

North, North West, New Delhi, South and South East Delhi

therefore, affects the quality-of-life. BMW generated at other places such as blood banks, research institutions, clinics, dispensaries and drug stockiest, etc. has not been taken into account.

The BMW generation rate ranges between 0.5 and 2.0 kg bed-1/day-1. The solid waste from hospitals consists of bandages, linen and other infectious waste (30-35%), plastics (7-10%), disposable syringes (0.3-0.5%), glass (3-5%) and other general waste including food (40-45%). Out of the total amount of municipal waste generated in Delhi, only 1-1.5% is hospital waste out of which 10-15% is considered infectious. It is estimated/that in Delhi, with about 45,266 hospital beds, is generated about 13.6 metric tons of BMW per day.

In Delhi, some of the private hospitals are reusing the disposable items like catheters, guidewires,

percutaneous transluminal coronary angioplasty (PTCA) kits, inflammation devices, etc. This practice could add to the risk of infection to the patients and is against BMW management.

FINDINGS The safe management of BMW has received much attention over recent years in India including Delhi.

Emphasis is given on proper handling, segregation and disposal of waste. However, waste minimization and recycling is still not well-promoted and understood by a common man. Main issues considered arise from poor handling of waste causing environmental pollution and health impacts. Management of the BMW is becoming a challenging issue in Delhi. Government and non-Government agencies have recognized BMW as a matter of concern. More and more studies must be

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COMMUNITY MEDICINE conducted qualitatively and quantitatively for BMW, so that the proper method of treatment can be developed for the safety of health and environment.

People managing BMW must understand the gravity of the issue and they must be able to differentiate between hospital waste and general waste. They must ensure proper identification, segregation at the source of generation, collection in prescribed containers, safe transportation, appropriate treatment and extremely sound disposal. They should be provided proper health education and training for the management and handling of BMW. More and more training camps must be organized with compulsory participation of the concerned staff. Effective implementation of rules by surprise visits and inspections by appropriate authorities and fixing the accountability of each and every person involved in the management of BMW is very essential.

Due to increase in medical facilities, more common BMW treatment facilities need to be established by government in Delhi. This is also a need for the strict implementation of BMW management rules in the private sector; illegal dumping of BMW need to be controlled with stringent rules regulations. Nonregistered BMW units should be closed if not operating as per regulations. There is a need for evolving policy and protocols by healthcare institutions from government to manage recyclables.

Different methods of treatment technologies need to be used with the help of government in economical and effective ways e.g., hydroclave treatment, microwave

treatment, mechanical/chemical disinfecting, etc.

Government should set up more treatment plants in Delhi NCR with more modern effective technologies.

SUGGESTED READING 1. Patil AD, Shekdar AV. Health-care waste management in India. J Environ Manage. 2001;63(2):211-20.

2. Rao SKM, Garg RK. A study of hospital waste disposal system in service hospital. J Acad Hosp Admin.

1994;6(2):27-31.

3. Hazardous Waste (Management & Handling) Rules, Ministry of Environment & Forests, Govt. of India, New Delhi (Internet). 1989. (cited 2013 Sep). Available at: http:envfor.nic.in/Legis/hrm/html.

4. Municipal Solid Waste (Management & Handling) Rules, MoEF, Govt. of India, New Delhi (Internet). 2000. (cited 2013 Sep 14). Available at: http;www.moef.nic.in, legis/ hrm/mswhr.html.

5. Delhi Population 2017. Available at: http:// worldpopulationreview.com/world-cities/delhipopulation/ 6. www.indionline Paper.com.> population 7. Bhatta B. Analysis of urban growth and sprawl from remote sensing data. 2010.

8. Shakil S. National Green Tribunal says nine Delhi hospitals flout biomedical waste disposal rules, New Delhi, July 25, 2013.

9. Ugendee Y (2000) biomedical waste definition 11. aale.livs (2013) World Health Organization, WHO Handbook on Health Care Waste Management.

10. B Nirmala MN. The Times of India-Medical Tourism. 28th March 2009.

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Global Task Force on Cholera Control Commits to Reduce Cholera Deaths by 90% by 2030 The Global Task Force on Cholera Control (GTFCC), a diverse network of more than 50 UN and international agencies, academic institutions and NGOs has devised a new strategy to reduce deaths from cholera by 90% by 2030. The GTFCC’s new plan, “Ending Cholera: A Global Roadmap to 2030” recognizes that cholera spreads in endemic “hotspots” where predictable outbreaks of the disease occur year after year. By implementing the Roadmap, up to 20 affected countries could eliminate cholera by 2030. The new plan focuses on ÂÂ

Early detection and quick response to contain outbreaks at an early stage

ÂÂ

A multisectoral approach to prevent cholera in hotspots in endemic countries (including improved water, sanitation and hygiene [WASH] and through use of oral cholera vaccines [OCV])

ÂÂ

An effective mechanism of coordination for technical support, resource mobilization and partnership at local and global level - with the GTFCC providing a strong framework to support countries in intensifying efforts to control cholera.

(WHO, October 3, 2017).

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ENT

Pediatric Oropharyngeal Trauma: A Retrospective Study with Brief Review of Literature NEERU CHUGH*, NEELIMA GUPTA†, LAKSHMI VAID‡

ABSTRACT Background: Children often present in emergency with history of trauma in the oral cavity. This review was done to evaluate our treatment protocol and compare it with the protocol followed in the developed world. Material and methods: Retrospective review of cases of trauma to the oral cavity and oropharynx from 2006 to 2010 in a tertiary care hospital. Results: Twentyfour patients were included in the study. The average age was 4.3 years and male to female ratio was 3:1. About 79% patients underwent surgical intervention. Four patients were admitted for antibiotics and observation only. Conclusion: The outcome in all patients was satisfactory. In our setting, where poor compliance is common and parents may not be vigilant enough to recognize complications, we suggest a protocol of admission and repair of the wound rather than a conservative approach advocated by western world. In our knowledge, no Indian studies are available with which we can compare our treatment protocol.

Keywords: Pediatric, oropharyngeal trauma, impalement injury palate

I

njuries of oral cavity and oropharynx are common in pediatric patients, the common site being the soft palate. Most of the injuries occur from a fall while carrying a pointed object in mouth. Various treatment protocols have been cited in studies, ranging from no treatment, observation and conservative management to hospitalization and surgical repair of the wound.

Carotid artery injury and subsequent neurological sequelae are rare but well-documented complications of penetrating injuries of lateral oropharynx in the medical literature.

We planned this study with the objective of studying the epidemiology and clinical presentation of children with oropharyngeal injuries and the subsequent management approach with outcome in these patients.

The evaluation was aimed at helping the caregiver in formulating a management protocol for patients presenting with such injuries.

*Ex-Resident †Associate Professor ‡Professor Dept. of ENT University College of Medical Sciences and GTB Hospital, Delhi Address for correspondence Dr Neelima Gupta A-304, Abhyant Apartments 2, Vasundhara Enclave, Delhi - 96 E-mail: write2drneelima@yahoo.com

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MATERIAL AND METHODS Data were collected retrospectively, of all pediatric patients admitted with impalement injuries of oral cavity and oropharynx, over a 5-year period from 2006 to 2010 at ENT Department of a tertiary care hospital.

Patients were evaluated for age, sex, mechanism of injury, object causing injury, site of injury, type of wound, time lag in presenting to hospital, presenting complaints, treatment received, hospital stay and postoperative course. The common presenting complaints were bleeding from the mouth after history of a fall or running against a wall with some object inside the mouth; pain in the throat, drooling and difficulty in swallowing food. The salient observations are presented in Table 1.

OBSERVATIONS AND RESULTS Case records of 24 patients with injuries to oral cavity and oropharynx were reviewed. The demographic characteristics are shown in Table 1. The most common mechanism of injury was falling down while playing with an object in mouth.

Majority of children were brought immediately to hospital due to bleeding from mouth. All the patients were admitted and were put on intravenous (IV) antibiotics and analgesics. The lacerations were located laterally or in midline, either at junction of hard and

ENT Table 1. Clinical Details and Management of Patients with Penetrating Injuries of Oral Cavity and Oropharynx Age

yy Range: 1-12 years yy Mean: 4.3 years

Sex

yy Male: 18 yy Female: 6

Site of injury yy Left: 10

yy Hard palate alone: 6

yy Right: 8

yy Soft palate alone: 11

yy Midline: 6

yy Hard and soft palate both: 6 yy Buccal mucosa: 1

Objects causing injury yy Wooden stick: 6 yy Metal rod: 3 yy Sugarcane: 3 yy Flute: 2

yy Plastic pen: 2 yy Nail head: 1 yy Toothbrush: 3 yy Miscellaneous: 4

Type of wound

yy Linear and superficial to deep: 18 yy Avulsion flap type: 6

Treatment

yy Conservative management: 4 yy Surgical repair under GA: 19 yy Absconded: 1

soft palate or involving only hard or soft palate. Only, 1 case in our study had injury which involved buccal mucosa between second and third molar.

Injuries were mostly linear and superficial (75%). Rest 25% injuries resulted in creation of a flap of the palate.

None of the injuries resulted in palatal perforation and none of them had any retained foreign bodies.

None of the patients presented with or developed any neurovascular complications.

Nineteen of the patients underwent surgical repair of wound under general anesthesia. Postoperative recovery was uneventful and we achieved our objective of good primary healing and restoration of function.

DISCUSSION Palatal and lateral oropharyngeal injuries are common in children. They commonly present with pain and transient oral bleeding. Usual occurrence is due to fall during playing while carrying an object in mouth, as also observed in our study. Other mechanisms involved in injury are, direct force applied to an object held in mouth and falling onto a stationary object with mouth open.1 The result can be either a penetrating or a nonpenetrating injury. The term â&#x20AC;&#x153;pencil injuryâ&#x20AC;? was coined by Bickerstaff for intraoral injuries caused by sharp objects in 1964.

The mean age of our patients was 4.3 years, comparable to that of 4 years in a study involving review of 131 patients with oropharyngeal impalement injuries.1 Male children are injured more commonly, reflecting more outdoor activity in males; M:F ratio (3:1, our study), (2:1)1 and (9:4).2 There was no significant site preponderance observed in our cases, as compared to higher incidence of left side (53%) involvement in a previous study.1 The common objects causing injury were wooden sticks, metal rods, sugarcane, flute and pens, etc. Wooden sticks, pens, toothbrushes, plastic toys, straws were the commonly implicated agents in other studies also.1,2 We admitted all patients and started IV antibiotics and analgesics. Surgical repair was done in 19 cases and 4 patients were managed conservatively. In a review of 131 cases, only 18% patients underwent surgical exploration and antibiotics were administered in 88% cases.1 In another review,2 bleeding was controlled by suturing in only 1 case. Surgical intervention was reserved for cases with large avulsion flap or in cases where wound exploration was required for a foreign body. Similar view is advocated in more recent reviews.3,4 Antibiotic administration is advocated if laceration is over 1-2 cm in length.

Commonly, these injuries heal uneventfully without complications. Complications reported include internal carotid artery thrombosis5,6 and rarely internal jugular vein thrombosis.7 It is proposed that the internal carotid artery gets compressed between the penetrating object and the second or third vertebra leading to disruption of intima and resultant thrombosis.6 A lucid period of 3-48 hours between injury and appearance of neurologic sequelae has been reported. Signs indicative of severe injury are dysphagia, drooling and subcutaneous emphysema of the neck.6 Occurrence of torticollis, cervical tenderness or neck swelling should alert the physician. Occasionally, an injury may lead to retropharyngeal abscess or pneumomediastinum,8 meningitis and brain abscess.9 None of the reported complications occurred in any of our patients, but we admitted all patients in order to observe for signs of impending complication. The serious nature of these complications has prompted investigators to develop their algorithms and management protocols.10 None of the studies have demonstrated any correlation between mechanism of injury or degree of injury with the potential for neurovascular complications. Most of the studies reviewed, advocate conservative management

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ENT with non-admission contingent on assurance of reliable adult supervision at home. Indicators prompting immediate re-evaluation include: fever, poor oral intake for more than 24 hours, drooling, difficulty in breathing, neck pain, vomiting, irritability, lethargy or excessive drowsiness and vision changes.8

3. Randall DA, Kang DR. Current management of penetrating injuries of the soft palate. Otolaryngol Head Neck Surg. 2006;135(3):356-60.

4. Younessi OJ, Alcaino EA. Impalement injuries of the oral cavity in children: a case report and survey of the literature. Int J Paediatr Dent. 2007;17(1):66-71.

However, studies have also advised admission and observation if anticipated follow-up is poor or social conditions warrant concern1 or if distance from the hospital is too much.8

5. Borges G, Bonilha L, Santos SF, Carelli EF, Fernandes YB, Ramina R, et al. Thrombosis of the internal carotid artery secondary to soft palate injury in children and childhood. Report of two cases. Pediatr Neurosurg.

2000;32(3):150-3.

CONCLUSION

6. Mains B, Nagle M. Thrombosis of the internal carotid artery due to soft palate injury. J Laryngol Otol.

1989;103(8):796-7.

In the developing world, with the constraints of unreliable supervision of adults at home, patients coming from far off distances and anticipated poor compliance of instructions, we feel that admission with observation or primary surgical intervention will avoid missing any serious complications.

7. Kaplan DM, Fliss DM, Peiser Y, Greenberg D, Leiberman A. Internal jugular vein thrombosis in a child due to a ‘pencil point injury’ of the palate. Int J Pediatr Otorhinolaryngol.

1998;44(2):183-7.

REFERENCES

8. Schoem SR, Choi SS, Zalzal GH, Grundfast KM. Management of oropharyngeal trauma in children.

Arch Otolaryngol Head Neck Surg. 1997;123(12): 1267-70.

1. Hellmann JR, Shott SR, Gootee MJ. Impalement injuries of the palate in children: review of 131 cases. Int J Pediatr Otorhinolaryngol. 1993;26(2):157-63.

9. Chang CJ, Huang LT, Lui CC, Huang SC. Oral wooden stick injury complicated by meningitis and brain abscess. Chang Gung Med J. 2002;25(4):266-70.

10. Raska GM, Cordova SW, Lema R, Goldwasser MS. 2. Takenoshita Y, Sasaki M, Horinouchi Y, Ikebe T, Kawano Y. Management of penetrating trauma to the soft palate: a Impalement injuries of the oral cavity in children. ASDC J Dent Child. 1996;63(3):181-4. case report. J Oral Maxillofac Surg. 2007;65(7):1279-85.

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Blocking Sweet Taste Receptors can Help Body Fight Off Sinus Infections Bitter taste receptors in the upper airway are a first-line of defense against sinus infections, but their ability to kill harmful toxins and pathogens is blocked when the sweet taste receptors are also stimulated. While glucose and other sugars are known to trigger these sweet taste receptors, researchers at the Perelman School of Medicine of the University of Pennsylvania have now shown amino acids can also have that effect. This new understanding could help pave the way toward new treatments for chronic sinus infections. The researchers published their findings in the journal Science Signaling.

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ENT

Angina Bullosa Hemorrhagica as a Presenting Feature of Malignant Hypertension: A Case Report VIKASDEEP GUPTA*, VANDANA SHARMA†, KULDEEP THAKUR‡, VIDHU SHARMA#

ABSTRACT A conscious and oriented 37-year-old female presented with a sudden onset small hemorrhagic lesion over the soft palate, which was diagnosed as angina hemorrhagica bullosa. Blood pressure was found to be 220/180 mmHg and there was presence of papilledema on funduscopic examination. Patient was diagnosed as a case of malignant hypertension, which was treated medically for hypertension and no local treatment was given. Lesion resolved and patient was free of symptoms after 2 weeks.

Keywords: Hemorrhagic lesion, soft palate, angina hemorrhagica bullosa, papilledema, funduscopic examination, malignant hypertension

B

adham suggested angina bullosa hemorrhagica (ABH) as the term for an oral mucosal blood blister that occurs without any evidence of blood dyscrasias or vesiculobullous disorders.1 Exact cause of ABH is still not determined, although most cases described in the literature seem to be associated with the long-term use of inhaled steroids, hypertension, consumption of hot beverages (thermal injury), mastication-related traumatic injuries, chronic renal failure, asthma, diabetes, rheumatoid arthritis, gastrointestinal disturbances and hyperuricemia, etc.2-7 This can help in further identifying the etiology of ABH as well as may enhance the knowledge of various presenting features of malignant hypertension, which should be ruled out in every case.

CASE REPORT A 37-year-old female patient presented to the ENT Department with complaints of foreign body sensation

*Senior Resident Dept. of ENT, PGIMS, Rohtak, Haryana †Eye Specialist, Civil Hospital, Dasuya, Punjab ENT Specialist, Mahatma Gandhi Medical Services Complex, Rampur, Himachal Pradesh ‡ENT Specialist Address for correspondence Dr Vikasdeep Gupta H. No. 156, Sector 14, Rohtak, Haryana E-mail: vdgupta88@gmail.com

noticed, more on swallowing. The symptoms appeared few hours ago and were sudden in onset. There was no history of bleeding from throat or respiratory distress.

There was no history of recent trauma or intake of hot beverages. There was no history of chronic disease or prolonged drug intake.

On examination, there was a single blood filled blister over the soft palate in the midline, dumbbell-shaped in appearance with regular margins. It measured about 3 cm in the long axis and about 1.5 cm in the maximum horizontal dimension. The blister was dark red in color, tense and nontender on palpation (Fig. 1). Surrounding mucosa was normal without any evidence of erythema or scarring. Indirect laryngoscopic examination was normal. Rest of the ENT examination did not reveal any abnormality. No hemorrhagic lesions were seen on the rest of the body. Oral hygiene was good.

Blood pressure (BP) was recorded to be 220/180 mmHg in the right arm in sitting position. Immediate fundus examination of the eye revealed bilateral papilledema suggestive of end organ damage due to raised BP. Routine blood investigations including hemoglobin, total leukocyte count, differential leukocyte count, peripheral smear, erythrocyte sedimentation rate (ESR), blood sugar, urea, creatinine and coagulation profile including platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR) showed values within normal limits. Rheumatoid arthritis factor was also within normal limits.

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ENT response to minor trauma.8 Weakening of the junction between epithelial and connective tissue can make nonkeratinized mucosa more susceptible to trauma. This can also play a role in development of submucosal blisters due to minor trauma.9 The above said theories lead to a speculation that trauma is the most common factor for development of ABH. Other authors have reported chronic use of inhaled steroids as the predisposing factor. Hypertension is implicated in the genesis of the lesion by some authors.10 Diabetes mellitus also seems to play a role. A case report has linked ABH to chronic renal failure.11 The exact etiology, however, remains unknown.

Figure 1. Hemorrhagic blister on the soft palate in the midline.

The patient was sent to the intensive care unit (ICU) where was admitted and BP was controlled. Patient was put on regular antihypertensives and was followed up for throat symptoms and lesion. Patient started noticing relief from throat symptoms after 4-5 days of starting treatment as blister started fading. The blister had completely resolved by 2 weeks after the control of BP with no subsequent scarring and the patient was free of symptoms.

Betadine mouth wash and instructions to maintain good oral hygiene and to take salt free semisolid/liquid diet was given. No other local treatment was given as the patient did not complain of any pain or odynophagia or any obstructing symptoms.

On the basis of the presenting complaints and appearance of the lesion and absence of blood dyscrasias or vesiculobullous disorders, a diagnosis of ABH was made in this case. Malignant hypertension appeared to be the cause for this sudden onset.

DISCUSSION ABH is believed to be an idiopathic condition. ABH is usually seen in middle-aged adults with no gender predilection.4 The chronic use of inhaled steroids affects collagen synthesis causing atrophy of the mucous epithelium and alters the synthesis of collagen reducing its content in the submucosa. Tissue elasticity may decrease with the maturation of these fibers. This leads to the poor support to the blood vessels present in the region leading to hemorrhage spontaneously or in

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The blisters are usually seen on the soft palate and may be present on the gingival mucosa or lateral border of the tongue. Multiple or recurrent lesions are uncommon.10 No treatment is indicated for the disorder as the blister ruptures and heals spontaneously within a week. However, surgical drainage may be considered if it is obstructing the airway.12 In our case of hemorrhagic blister over palate, the sudden rise in BP might have caused a day minor vessel in the palate to bleed, which formed a small blister. No specific local treatment was given in our case as there were no complaints of any pain or obstructive symptoms.

The blister healed spontaneously after the BP came to normal levels within 2 weeks. Patients was put to regular medication and follow-up. No similar complaints were present after 1 year of follow-up.

CONCLUSION This case is unique as no history of trauma or prolonged steroid inhalation was elicited. Only abnormality detected was a high BP (220/180 mmHg). The age of the presentation was also younger. The patient was not a known case of diabetes or hypertension. Therefore, the blister can be considered to have originated as a result of sudden rise in BP. This can help in further identifying the etiology of ABH. It has to be kept in mind that causes such as leukemias, thrombotic thrombocytopenic purpura (TTP), immune thrombocytopenic purpura (ITP) and other bleeding disorders must be ruled out before making a diagnosis of ABH. REFERENCES 1. Badham NJ. Blood blisters and the oesophageal cast.

J Laryngol Otol. 1967;81(7):791-803.

2. High AS, Main DM. Angina bullosa haemorrhagica: a complication of long-term steroid inhaler use. Br Dent J. 1988;165(5):176-9.

ENT 3. Kirtschig G, Happle R. Stomatopompholyx hemorrhagica.

J Am Acad Dermatol. 1994;31(5 Pt 1):804-5.

4. Hopkins R, Walker DM. Oral blood blisters: angina bullosa haemorrhagica. Br J Oral Maxillofac Surg. 1985;23(1):9-16.

5. Yamamoto K, Fujimoto M, Inoue M, Maeda M, Yamakawa N, Kirita T. Angina bullosa hemorrhagica of the soft palate: report of 11 cases and literature review. J Oral Maxillofac Surg. 2006;64(9):1433-6.

6. Domínguez JD, Rodríguez-Peralto JL, Iglesias L. Recurrent oral blood blisters. Arch Dermatol. 1999;135(5):593-4, 596-7.

8. Higgins EM, du Vivier AW. Angina bullosa haemorrhagica a possible relation to steroid inhalers. Clin Exp Dermatol.

1991;16(4):244-6.

9. Corson MA, Sloan P. Angina bullosa haemorrhagica: an unusual complication following crown preparation.

Br Dent J. 1996;180(1):24-5.

10. Horie N, Kawano R, Inaba J, Numa T, Kato T, Nasu D, et al. Angina bullosa hemorrhagica of the soft palate: a clinical study of 16 cases. J Oral Sci. 2008;50(1):33-6.

11. Shashikumar B, Reddy RR, Harish M. Oral hemorrhagic blister: an enigma. Indian J Dermatol. 2013;58(5):407.

12. Serra D, De Oliveira HS, Reis JP, Vieira R, Figueiredo A. 7. Curran AE, Rives RW. Angina bullosa hemorrhagica: Angina bullosa haemorrhagica: a disorder to keep in an unusual problem following periodontal therapy. mind. Eur J Dermatol. 2010;20(4):509-10.

J Periodontol. 2000;71(11):1770-3.

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Serial Measurements of Tumor Volume in Low-risk Papillary Thyroid Cancer to Detect Tumor Growth In patients undergoing active surveillance for low-risk papillary thyroid cancer measuring 1.5 cm or less, most cancers remained stable over several years of observation, as per a study reported August 31, 2017 in JAMA Otolaryngology-Head & Neck Surgery. The study suggests serial measurements of tumor volume to triage patients to observation versus surgery.

Breakthrough Technique for Spine and Thyroid Surgery A novel, less invasive technique may help clinicians to continuously assess laryngeal and vagus nerve function while patients are under general anesthesia during neurosurgery or otolaryngology procedures, suggests new research published in the July issue of Clinical Neurophysiology. The new technique makes use of a simple endotracheal tube, which simultaneously and continuously stimulates and monitors nerve responses.

Excise at Least Half of Parathyroid Gland to Reliably Rule Out Hyperfunction Researchers say that unless half of a parathyroid gland is biopsied during radio-guided parathyroidectomy, the 20% rule cannot reliably rule out the presence of a hyperfunctional parathyroid lesion. According to a small retrospective analysis of surgical data published online in JAMA Otolaryngology-Head & Neck Surgery, removal of half or more of the gland had 96.6% accuracy with gamma probe.

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An Interesting Cause of Hyperhidrosis and Hyperphagia – Acromegaly MOHAMED ILIYAS*, SUNDARAMURTHY†

ABSTRACT Hypersecretion of growth hormone (GH) before the fusion of epiphysis results in gigantism, while acromegaly results after the epiphyseal fusion. The average life expectancy of an acromegalic patient is 10 years less than the average population and the overall standardized mortality ratio is 1.48. The diagnosis is usually delayed by 6.6-10.2 years because of its indolent course. Early diagnosis and treatment can add a decade to their lifetime. We present the case of a young male with features of acromegaly, diagnosed and treated in our hospital.

Keywords: Acromegaly, gigantism, pituitary macroadenoma, growth hormone, insulin-like growth factor, macroglossia

A

cromegaly is a rare disease with an annual incidence of 3-4 cases/1 million due to hypersecretion of growth hormone (GH) from a pituitary tumor or an extrapituitary tumor like lymphoma or pancreatic islet cell tumor. Less commonly, it can be due to growth hormone-releasing hormone (GHRH) secreting tumors, usually carcinoids or small cell lung cancer. Pituitary adenomas are the most common cause of acromegaly. When the lesion is a pituitary GH - secreting somatotroph adenoma, acromegaly features are present. If the lesion is an acidophil stem cell adenoma secreting GH and prolactin, hyperprolactinemia features predominate and is frequently encountered in teenagers often causing gigantism.1 If the culprit lesion is a mixed mammosomatotroph tumor, both the features are present. GH cell carcinomas are very rare and should be suspected when extracranial metastases are present.

Carcinoids are the most common cause of acromegaly due to GHRH secreting tumors. Multiple endocrine neoplasia-1, familial acromegaly, Carney’s syndrome

*Assistant Professor Dept. of Internal Medicine Shri Sathya Sai Medical College and Research Institute, Chennai, Tamil Nadu †Professor Institute of Internal Medicine Rajiv Gandhi Government General Hospital and Madras Medical College Chennai, Tamil Nadu Address for correspondence Dr Mohamed Iliyas 1234, Madurapuri, Thuraiyur - 621 010, Tamil Nadu E-mail: dr.mohd.iliyas@gmail.com

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and McCune-Albright syndrome are the familial syndromes causing acromegaly.

CASE REPORT A 34-year-old male attended our Medical OPD with complaints of excessive sweating and increased appetite since 6 months. There was a history of excessive sleeping, easy fatigability, holocranial headache, increased frequency of micturition around 4 times in the night and breathlessness progressing from New York Heart Association (NYHA) Grade I to II. These symptoms started appearing one by one during the last 6 months. He noticed that his hands have become broad but attributed it to heavy work that he does. His shirt size had changed from 40 to 44 inches, footwear from 10 to 12 inches and brief from 90 to 100 cm. His wife complained that his voice had become hoarse since 5 months. There was no history of visual disturbance, vomiting, chest pain, leg swelling or change in personality. His sexual life was normal.

He had a road traffic accident 3 years back. There was contusion of right hypothalamus with intraventricular hemorrhage for which drainage was done. Splenectomy was done for splenic injury and hemoperitoneum.

On general examination, he had coarse facies, high-arched palate, macroglossia, prognathism, spade like fingers and broad feet (Figs. 1 and 2). His vitals were blood pressure (BP) - 130/90 mmHg, pulse rate - 80/min, respiratory rate - 14/min. His systemic examination was normal. Eye examination was done by ophthalmologists. Both eyes had congested bulbar

INTERNAL MEDICINE (8.17 lakh/mm3). Renal and liver function tests were normal. Serum insulin-like growth factor 1 (IGF-1) level was elevated, 841 ng/mL (normal: 115-307). Serum prolactin was mildly elevated, 18.65 ng/mL (normal: 2.1-17.7). Computed tomography (CT) brain was normal.

1.5 Tesla magnetic resonance imaging (MRI) brain with contrast showed a well-defined oval-shaped mass of size 2 Ă&#x2014; 1.6 cm lesion in the sellar region (Fig. 3). It was isointense on T1 and hypointense on T2 images with heterogeneous enhancement post-contrast. The lesion did not extend to suprasellar region or involve optic chiasma. These features were suggestive of pituitary macroadenoma.

Screening of other organs was done since acromegaly affects almost all organs. Echocardiography showed concentric left ventricular hypertrophy with normal ejection fraction (60%). Ultrasound (USG) of the abdomen showed left Grade IV hydroureteronephrosis.

CT abdomen showed left pelviureteric junction obstruction with gross hydroureteronephrosis (Fig. 4).

Figure 1. Acromegalic facies. Coarse skin, large fleshy nose, macroglossia and large mandible.

We suspected prior renal calculi. But his serum calcium (ionized - 4.2 mg/dL) and intact parathyroid hormone (37.97 pg/mL) were normal. USG of the neck showed diffuse nodular goiter confirmed by fine needle aspiration cytology. Thyroid function test was normal (free triiodothyronine [FT3] - 3.36 pg/mL, free thyroxine [FT4] - 1.20 ng/mL, thyroid-stimulating hormone

Figure 2. Paw hand. Massive hand with fat, cylindrical spatulate fingers with blunt tips.

conjunctiva, chemosis, proptosis, restricted abduction and adduction with normal fundus, color vision, field of vision. There was no diplopia on diplopia charting.

Hematological investigations revealed dimorphic anemia (hemoglobin [Hb] - 6.8 g/dL) with thrombocytosis

Figure 3. MRI brain. T1-weighted image - Sagittal section.

Well-defined isointense oval- shaped lesion of size 2 Ă&#x2014; 1.6 cm in the sellar region (arrow). Pituitary macroadenoma.

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INTERNAL MEDICINE centrally placed darkly staining nucleus arranged in cords, sheets and islands. Focal areas of rosette formation and separation of tumor cells by fibrovascular septae was present (Fig. 5). These features confirmed the lesion as pituitary adenoma. Postoperatively, his IGF-1 and GH levels decreased. He was discharged and is on regular follow-up.

DISCUSSION

Figure 4. CT abdomen. Hydroureteronephrosis of the left kidney due to pelviureteric junction obstruction (arrow).

Figure 5. HPE 40X magnification. Fairly uniform round to oval cells with eosinophilic cytoplasm and centrally placed darkly staining nucleus arranged in cords, sheets and islands with focal areas of rosette formation. Tumor cells are separated by fibrovascular septae. Features of pituitary adenoma.

[TSH] - 1.16 μIU/mL). Multiple endocrine neoplasia was ruled out by the above investigations.

Tablet cabergoline 0.5 mg twice a week was started as per endocrine surgeon’s advice. Two units of packed red blood cells (RBCs) were transfused. Team of endocrine and skull base surgeons resected the tumor by trans-nasal trans-sphenoidal endoscopic approach.

Histopathological examination showed fairly uniform round to oval cells with eosinophilic cytoplasm and

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Growth hormone secretion is increased by GHRH, ghrelin, fasting whereas somatostatin and food intake suppresses its release. The effects of GH are mediated through GH receptors in the cartilages and liver. GH leads to IGF-1. IGF-1 levels are highest during late adulthood and in pregnancy.

IGF-1 production is decreased in patients with hypothyroidism, hepatic disease, poorly controlled diabetes and in malnourished patients.2 IGF-1 and GH act dependently and independently to cause the features of hypersomatotropism. Acromegalics have characteristic features like coarse facies, frontal bossing, large fleshy lips and nose, macroglossia, prognathism, increased gap between lower incisors, spade like fingers.

At the time of diagnosis around 60% of the patients have hypertension, arrhythmia and valvular heart diseases, which causes concentric ventricular hypertrophy and diastolic heart failure.2 Our patient had concentric hypertrophy but didn’t progress to heart failure at the time of diagnosis. Heart failure is reversible with octreotide treatment while hypertension, and valvular regurgitation are not.2 Resting ECG can show ST-segment depression, T-wave abnormalities, conduction defects and arrhythmias in 50% of patients. Colon cancer risk is twice as common than in the general population hence screening by colonoscopy once in 3-5 years is advised.3 Our patient was not co-operative for the procedure; however, stool occult blood was negative. Obstructive sleep apnea, snoring and narcolepsy due to soft tissue deposition around the larynx, macroglossia and nasal polyps are present in more than 50% patients.4 Central sleep apnea associated with high GH and IGF-1 levels is also common. Voice changes are also common due to the fixation of vocal cords, laryngeal stenosis, tracheal calcification and cricoarytenoid joint arthropathy. Our patient had a deep voice, snoring and macroglossia.

Musculoskeletal manifestations are the most common features in acromegaly. Up to 70% patients have arthropathy in the form of joint swelling, hypermobility and cartilage thickening. Knee, elbow, shoulder, ankle hip and lumbosacral joints are commonly affected.

INTERNAL MEDICINE Kyphoscoliosis is common; our patient had kyphosis.

Carpal tunnel syndrome is seen in half of patients due to median nerve enlargement and its entrapment in the wrist. Osteophytes are commonly seen in the anterior aspects of vertebrae and in the phalangeal tufts mainly the distal phalanges giving an appearance of spade like fingers on X-ray. Hyperhidrosis and malodorous oily skin is present in 70% of patients and is an early sign.

Our patient sought medical attention for this, which helped us diagnose the pituitary lesion.

Increased glycosaminoglycan deposition and collagen production causes the typical coarse facies with skin wrinkles, nasolabial folds, fleshy nose, macroglossia, increased heel pad thickness. Heel pad thickness is measured in X-ray of the foot in a lateral view. The distance is measured between the lower most point of the calcaneum and the lower most point of the heel pad soft tissue shadow. If the measurement is >23 mm in males and >21 mm in females, the heel pad thickness is said to be increased. Phenytoin therapy, obesity and myxedema can also cause heel pad thickening.

Exophthalmos if present is frequently masked by frontal bossing. Skin tags if more than 3 in number in patients above 50 years of age is a marker of colonic adenomatous polyps not related to the GH and IGF-1 levels.

Impaired glucose tolerance and diabetes mellitus is very common because of the anti-insulin effects of GH. This is reversed after surgery or somatostatin analog therapy. Our patient was euglycemic. Around 30% of patients have co-existing hyperprolactinemia; our patient had mildly elevated prolactin. Hypogonadism is present in 50% of patients which is often reversible.

Thyroid dysfunction is quite common and may present with Grave’s disease, nodular or diffuse goiter, toxic or nontoxic goiter. Our patient had diffuse goiter with normal thyroid function test. Screening for multiple endocrine neoplasia type 1 (MEN1) syndrome was done but parathyroid hormone was within normal levels. Age, level of GH before and after treatment, IGF-1 levels, size of the tumor, degree of invasion and duration of symptoms before the diagnosis is made are important determinants of co-existing illnesses.2 Some important mortality determinants are high IGF-1 levels, GH level >2.5 μg/L, older age, cardiac disease, hypertension, inadequately replaced adrenocorticotropic hormone (ACTH)-dependent adrenal insufficiency and history of pituitary radiation.5 Younger age, shorter duration of the disease, GH levels <2.5 μg/L, absence of hypertension independently predict longer survival.6

The single best test to diagnose acromegaly is ageand sex-matched serum IGF-1 level. It is elevated in all patients with acromegaly distinguishing it from normal individuals.7 Our patient had a very high level of IGF-1. GH is secreted in a phasic manner in normal individuals with the lowest levels during the day often <2 μg/L, while in the night it can be as high as 30 μg/L.8 GH level is also influenced by sleep and food intake with a very short half-life (20 min). Hence, serum IGF-1 levels are preferred over GH levels.

However, in patients with equivocal IGF-1 levels, measurement of GH levels is additive. Oral glucose tolerance test (OGTT) is the most specific dynamic test. It is also the gold standard test to determine control of GH secretion post surgery.

OGTT is done by measurement of GH levels over 2 hours of ingestion of 75 g of glucose. GH levels ≥0.4 μg/L in OGTT is diagnostic of acromegaly. GH <1 μg/L signifies disease control.

MRI brain with contrast is the radiological investigation of choice. Information on size of the tumor along with compression and invasion of adjacent structures can be obtained. Even a tumour of 2 mm can be identified but it doesn’t differentiate functioning and nonfunctioning tumors. Macroadenoma (>1 cm) is seen in 75% patients. Other endocrine glands should be imaged as a part of routine work-up. ACROSCORE is a clinical tool developed for general practitioners and nonendocrinology specialists for easier identification of acromegaly. It classifies the patient into low-, mediumor high-risk of suspicion of acromegaly.

Surgical resection is the first management option for all acromegalics.9 The transphenoidal approach normalises IGF-1 and GH in >80% microadenomas and <50% macroadenomas. Recurrence or persistence of tumor is 6% in this approach. Conventional radiotherapy and stereotactic radiosurgery causes hypopituitarism in >50%, while normalizing IGF-1 and GH in only 30%. The somatostatin analogs (octreotide, lanreotide) shrinks the tumor by 50% by normalizing IGF-1 and GH in 70% of patients.

The GH receptor antagonist pegvisomant normalizes IGF-1 in >90% patients.2 Currently, this drug is preferred when other treatment modalities have failed, levels of IGF-1 (>900 ng/mL) are very high or whose glucose tolerance is worsened by somatostatin analogs.9 The dopamine agonist cabergoline is less commonly used nowadays because <15% normalization of IGF-1 and GH.

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INTERNAL MEDICINE REFERENCES 1. Maheshwari HG, Prezant TR, Herman-Bonert V, Shahinian H, Kovacs K, Melmed S. Long-acting peptidomimergic control of gigantism caused by pituitary acidophilic stem cell adenoma. J Clin Endocrinol Metab.

2000;85(9):3409-16.

2. Melmed S. Medical progress: Acromegaly. N Engl J Med. 2006;355(24):2558-73.

3. Renehan AG, Shalet SM. Acromegaly and colorectal cancer: risk assessment should be based on populationbased studies. J Clin Endocrinol Metab. 2002;87(4):1909; author reply 1909.

4. Rosenow F, Reuter S, Deuss U, Szelies B, Hilgers RD, Winkelmann W, et al. Sleep apnoea in treated acromegaly: relative frequency and predisposing factors. Clin Endocrinol (Oxf). 1996;45(5):563-9.

predict excess mortality in patients with acromegaly.

J Clin Endocrinol Metab. 2004;89(4):1613-7.

6. Holdaway IM, Rajasoorya RC, Gamble GD. Factors influencing mortality in acromegaly. J Clin Endocrinol Metab. 2004;89(2):667-74.

7. Stoffel-Wagner B, Springer W, Bidlingmaier F, Klingmüller D. A comparison of different methods for diagnosing acromegaly. Clin Endocrinol (Oxf).

1997;46(5):531-7.

8. Peacey SR, Toogood AA, Veldhuis JD, Thorner MO, Shalet SM. The relationship between 24-hour growth hormone secretion and insulin-like growth factor 1 in patients with successfully treated acromegaly: impact of surgery or radiotherapy. J Clin Endocrinol Metab.

2001;86(1):259-66.

9. Cook DM, Ezzat S, Katznelson L, Kleinberg DL, Laws ER Jr, Nippoldt TB, et al; AACE Acromegaly Guidelines 5. Ayuk J, Clayton RN, Holder G, Sheppard MC, Stewart PM, Task Force. AACE Medical Guidelines for Clinical Bates AS. Growth hormone and pituitary radiotherapy, Practice for the diagnosis and treatment of acromegaly. but not serum insulin-like growth factor-1 concentrations, Endocr Pract. 2004;10(3):213-25.

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Longer Duration of Sedentary Time Increases Risk of Death Not only total sedentary time (12 or more hours daily), but also longer and uninterrupted duration of sedentary time increase higher risk for death. Uninterrupted sedentary time of less than 30 minutes was associated with lower risk, according to a study published September 18, 2017 in the Annals of Internal Medicine.

Bismuth-based Quadruple Therapy Following H. pylori Eradication Failures A new study published in the Journal of Gastrointestinal and Liver Diseases assessed the efficacy of three-in-one capsules bismuth-based quadruple therapy in patients who failed one or more attempts of Helicobacter pylori eradication. This prospective, open-label, multicenter trial enrolled 208 consecutive, adults with persistent H. pylori infection, despite at least one standard therapy. All patients received a rescue quadruple therapy-three capsules, four times daily and esomeprazole 20 mg - one tablet, twice-daily, for 10 days. The results showed that overall, 180 patients were successfully cured from the infection. This accounted for 86.5% and 92.3% eradication rates at intention-to- treat analysis and at per protocol analysis, respectively. Cure rates were similar across patients who had failed one to three previous therapy attempts. However, the success rate declined to 67% in patients who had encountered four or more treatment failures. Compliance to therapy was good in 95.2% of patients, while in 5.3% cases the therapy was interrupted within 5 days due to side effects. A total of 46.6% patients complained of at least one side effect, of which nausea, diarrhea and vomiting were the most frequently reported. The results demonstrated that this bismuth-based quadruple therapy is highly effective as a rescue therapy for H. pylori eradication in clinical practice.

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INTERNAL MEDICINE

A Comparative Evaluation of Atorvastatin and Rosuvastatin Therapy on Serum Uric Acid Levels in Dyslipidemic Patients NIPUN HARISHCHANDRA PATIL*, AK KAPOOR†, HK SINGH‡, MALINI KULSHRESHTHA#, RAJIB KARMAKAR§

ABSTRACT Aim: The aim of the present study was to comparatively evaluate serum uric acid (SUA) levels following prolonged therapy with two potent statins in dyslipidemic patients. Material and methods: A prospective, randomized, interventional, openlevel, flexible dose, comparative clinical study of 1 year duration was conducted in dyslipidemic patients attending OPD of Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh. One hundred ten patients of both sexes were enrolled and were administered flexible doses of atorvastatin (AT) 20-40 mg/day or rosuvastatin (RS) 10-20 mg/day depending on clinical response. Besides, socio-demographic information, biochemical parameters inclusive of uric acid was measured. Results: Only 105 patients (53 AT and 52 RS group) completed the study. Baseline biochemical parameters were comparable in both the groups.

Repeat SUA levels at 3, 6 and 12 months showed a constant, steady, significant fall in SUA levels in both groups. The reduction of SUA level in AT group was 6.77-6.22 mg/dL and 6.9-6.52 mg/dL in RS group. Comparison of values of SUA between the two groups was also significant (p < 0.001) suggesting AT was more effective in lowering SUA levels. Conclusion: Our study observed a positive and significant reduction of SUA levels following administration of both AT and RS in therapeutic doses.

AT was found to be more effective than RS at the end of study in dyslipidemic patients.

Keywords: Dyslipidemic patients, serum uric acid, atorvastatin, rosuvastatin

D

yslipidemia is a well-recognized risk factor for the development of diseases associated with atherosclerosis including coronary heart disease (CHD) and stroke and is associated with more than 4 million deaths per year.1 Hence, cholesterollowering treatments, including statins (inhibitors of hydroxymethylglutaryl-coenzyme A reductase) have been recommended in national guidelines, since every 10% reduction in total cholesterol (TC) decreases the risk of coronary death by 15%.2,3 The updated Adult

*3rd Year Resident †Professor ‡Professor and Head Dept. of Pharmacology #Professor Dept. of Medicine §Ist Year Resident Dept. of Pharmacology Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh Address for correspondence Dr AK Kapoor Professor Rohilkhand Medical College and Hospital, Bareilly - 243 006, Uttar Pradesh E-mail: drakkapoor@rediffmail.com

Treatment Panel (ATP) III guidelines of 2004 were used for managing cholesterol. Besides, reduction in circulating low-density lipoprotein (LDL), statins also exhibit a number of pleiotropic effects such as augmenting endothelial function (upregulation of endothelial nitric oxide synthase, increase nitric oxide synthesis), stabilizing vulnerable plaques (decreased matrix metalloproteinase activity), inhibition of macrophage migration, phagocytosis/lipid uptake and foam cell formation (reduced vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin activity).4-6 Uric acid (UA) is the final product of purine metabolism.

DNA and RNA are degraded into purine nucleotides and bases, which are then metabolized by xanthine oxidase to xanthine and UA.7 The balance between the breakdown of purines via the action of xanthine oxidase and the rate of UA excretion controls the level of serum uric acid (SUA) in the body. Sustained hyperuricemia has putative adverse roles in cardiovascular diseases (CVDs). Further, large epidemiological studies support the hypothesis that UA independently influences CVD outcomes.8,9 SUA is considered as a useful biomarker

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INTERNAL MEDICINE for mortality in high-risk patients with acute coronary syndromes, heart failure and hypertension and in patients with type 2 diabetes.7,10 Further, SUA level is a powerful and independent predictor of cardiac and overall mortality in both sexes in patients with CHD or arterial hypertension.11-13 Malik et al14 observed that atorvastatin (AT) significantly improved endotheliumdependent vascular reactivity and that endothelial dysfunction preceeds the development of atherosclerosis.

A relation between elevated SUA level and stroke also has been shown in patients with (or without) CHD, with hypertension or diabetes mellitus.13,15 Despite high correlation of SUA with conditions such as hyperinsulinemia, hypertension, metabolic syndrome and renal function, a definitive causal role is yet to be established. It is also not clear whether strategies to reduce SUA will improve outcomes.7 Ndrepepa et al16 noted that SUA levels above 7.70 mg/dL were associated with increased mortality, independently of the effect of all traditional risk factors, other comorbid conditions and both insulin and diuretic therapy. These authors observed an independent role of SUA in predicting survival in type 2 diabetic patients.

Although, UA has beneficial antioxidant properties at a cellular level, yet UA increases both proliferative and proinflammatory actions and contributes to endothelial dysfunction.17 Additionally, UA may be a true mediator in the progression of kidney diseases.18

1.24, 2.94).15 Little is known about whether dyslipidemia causes an adverse effect on SUA levels, and if this can be reversed by statin treatment. Moreover, long-term effects of different statins on SUA has also not been extensively investigated and only sparse literature is available in respect to effects of rosuvastatin (RS) on SUA levels. Further, investigators in the field noted that the decrease in SUA levels might be an effect of certain statins as previous studies showed no change in SUA levels with simvastatin,20 pravastatin,21 lovastatin22 or fluvastatin.23 AIM The aim of the present study is to comparatively evaluate the effects of AT and RS on SUA levels in dyslipidemic patients with (or without) hypertension or diabetes on prolonged administration.

MATERIAL AND METHODS A prospective, randomized, interventional, open level, flexible dose, comparative clinical study of 1 year duration (November 2014 to October 2015) was undertaken amongst the dyslipidemic patients attending the OPD of Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh. Approval of study protocol was obtained from Institutional Ethical Committee. The study has been applied for registration with the clinical trial Registry of India (Ref No. 2016/09/012251).

However, the beneficial role of reducing UA levels on cardiovascular risk as well as progression of kidney diseases, is not well-established, though evidences suggest some potential beneficial effect of reducing UA levels in human beings.10

The participants were explained about the experimental protocol and those willing were enrolled for the study after obtaining informed consent from each participating subject, and one could withdraw without prejudice at any time.

Further, post hoc analyses of statin trial data suggest a significant reduction in vascular events with decreases in UA levels after adjustment for multiple risk factors, these findings may be treated as inconclusive and only hypothesis generating.19 There are no large clinical trials evaluating their benefits in improving survival in high-risk patients with CVD.10 It is worth noting that there is a strong genetic predisposition to SUA levels in humans with heritability estimates of up to 70%.10 In patients with essential hypertension, SUA in highest quartile was associated with increased cardiovascular event rate (hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.03, 3), cardiovascular mortality and allcause mortality (HR 1.63, 95% CI 1.02, 2.57).12 Similarly in diabetic patients, serum SUA concentration above the median (295 Âľmol/L-1) have been associated with near double an increased risk of stroke (HR 1.91, 95% CI

A total of 110 patients (AT 55 and RS 55) of 18-65 years, of both genders, of all socioeconomic classes and diagnosed as dyslipidemic (as per the ATP III National Cholesterol Education Program [NCEP] guidelines) comprised the sample size. Both newly diagnosed as well as those dyslipidemic patients suffering from Stage I hypertension and/or uncomplicated type 2 diabetes mellitus were enrolled. The patients were assigned a reference number on first come first serve basis. Simple randomization was done, the odd numbers were allotted AT and even numbers RS.

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Flexible dose schedule of both the drugs were used, AT 20-40 mg/day and RS 10-20 mg/day depending upon evaluation of the clinical condition and response by the consulting physician, though initially lower doses were administered. After 6 weeks of treatment dose of statin was up-titrated (AT 40 mg/d, RS 20 mg/d) if

INTERNAL MEDICINE the treatment goal was not achieved. No other lipidlowering therapy was given to patients except test drugs during the study period.

All patients were advised regarding the lifestyle changes, dietary modifications and light exercises and were emphatically told that they have to take the prescribed medicine for at least 1 year (study period) despite adequate control. The exclusion criteria included subjects with history of any other acute or chronic disease that would affect the study variables, significant renal disease and diabetic nephropathy, significant liver diseases, pregnant or lactating females and those using oral contraceptives, CVDs like heart failure, valvular heart disease, uncontrolled hypertension, etc., and patients with known hypersensitivity to statins.

Predesigned, structured questionnaire was used for recording sociodemographic information, medical history and lifestyle habbits like smoking, alcohol intake and sedentary habbits and history of antihypertensive/ antidiabetic medications used, if any. Height, weight (for body mass index [BMI]), waist-to-hip ratio and blood pressure (BP) were also recorded. Baseline routine investigations and preliminary clinical examination was conducted on all subjects to rule out exclusion criteria.

RESULTS Results were reported as per CONSORT (CONsolidated Standards of Reporting Trials) 2010 statement (Fig. 1).

Two hundred fifty-four patients were assessed for eligibility based on the deranged lipid profiles, of which 110 patients met the inclusion criteria. Of the 110 patients enrolled in the study, 55 each in AT and RS group, only 105 patients 53 in AT group and 52 in RS group completed the study. Mean age of patients in AT group was 45.89 ± 11.107 (mean ± SD) years and 47.6 ± 10.331 in RS group. The p-value was 0.406 showing that the two groups were comparable. Male:female (M:F) ratio was 0.64:1 (43 males and 67 females) depicting predominance of females. Sixty-five patients belonged to urban area and 45 from rural area, U:R ratio was 1.44:1, p-value 0.121 between the groups indicated that distribution of patient’s locality between the two groups was evenly matched. Majority of cases belonged to lower middle socioeconomic class i.e., 44/110 (AT = 25, RS = 19), 19 patients were of upper class and 38 patients belonged to lower middle class. Of 110 cases, 52 were vegetarian and 58 nonvegetarian, p = 0.702 reflected that the two groups were comparable.

Table 1 shows that there were 25 smokers (AT = 9, RS = 16), p-value not significant (p = 0.097) and 27 patients were alcoholics (AT = 13, RS = 14). Regarding concurrent illnesses present, 37 were diabetic (AT = 19, RS = 18) and 53 were hypertensive (AT = 31, RS = 22).

Table 2 depicts the metabolic parameters namely BMI and waist-to-hip ratio in the two groups. These were also comparable as p values were not statistically significant.

Assessed for eligibility (n = 254) Excluded (n = 144) yyNot meeting inclusion criteria (n = 124) yyRefused to participate (n = 18) yyOther reasons (n = 12)

Enrollment

Randomized (n = 110) Allocation yyAllocated to intervention yyTablet AT 20 mg (n = 55) yyReceived allocated intervention (n = 55) yyDid not receive allocated intervention (n = 0)

yyAllocated to intervention yyTablet RS 10 mg (n = 55) yyReceived allocated intervention (n = 55) yyDid not receive allocated intervention (n = 0) Follow-up

yyLost to follow-up (n = 0) yyDiscontinued intervention (n = 2) (due to adverse drug event)

yyLost to follow-up (n = 2) (did not report for follow-up) yyDiscontinued intervention (n = 2) (1 due to adverse event and 1 due to high cost of therapy) Analysis

yyAnalyzed (n = 53) yyExcluded from analysis yy(n = 0)

yyAnalyzed (n = 52) yyExcluded from analysis yy(n = 0) (give reasons)

Figure 1. CONSORT: Transparent reporting of trials.

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INTERNAL MEDICINE Table 1. Concurrent Illnesses and Substance Abuse AT

RS

χ2 value

P value

Smokers (n = 25)

9 (36%)

16 (64%)

2.751

0.097

Alcoholics (n = 27)

13 (48.1%)

14 (51.9%)

0.002

0.962

Diabetes (n = 37)

19 (35.8%)

18 (34.6%)

0.18

0.895

Hypertension (n = 53)

31 (58.5%)

22 (42.3%)

2.750

0.097

Variables

*P < 0.05 = Significant, p < 0.001 = Highly significant, p > 0.05 = Not significant.

Table 2. Metabolic Parameters at Baseline Variables BMI

(kg/m2)

Waist-to- hip ratio (cm) *P < 0.05 = Significant,

#p

AT (n = 55)

RS (n = 55)

't' value

P value

26.97 ± 3.37

26.57 ± 3.37

0.518

0.606

0.92 ± 0.078

0.128

0.899

0.92 ± 0.076 < 0.001 = Highly significant,

#p

> 0.05 = Not significant.

Table 3. Baseline Biochemical Parameters Biochemical parameters

AT (n = 55)

RS (n = 55)

't' value

P value

TC (mg/dL)

216.1132 ± 23.46901

218.9038 ± 23.8934

−0.601

0.549$

TGs (mg/dL)

214.42 ± 71.3391

223.087 ± 76.0804

−0.597

0.552$

LDLs (mg/dL)

127.21 ± 13.3798

126.4904 ± 14.0834

0.265

0.792$

HDLs (mg/dL)

37.6604 ± 4.9257

38.7442 ± 5.3443

−0.478

0.634$

Fasting blood sugar (mg/dL)

142.484 ± 61.3899

134.378 ± 44.9533

1.175

0.336$

HbA1c (%)

6.508 ± 1.0224

6.496 ± 1.5893

0.044

0.965$

Blood urea (mg/dL)

31.981 ± 9.500

29.365 ± 6.6245

1.634

0.105$

Serum creatinine (mg/dL)

0.9789 ± 0.2364

0.9706 ± 0.2772

0.501

0.618$

SGPT (IU)

30.811 ± 7.6083

31.365 ± 8.5636

−0.351

0.727$

*P <0.05 = Significant, #p <0.001 = Highly significant, $p >0.05 = Not significant.

Table 4. Mean Serum Uric Acid Values Visits

AT

RS

't' value

P value

Baseline

6.7773 ± 0.6336

6.9954 ± 0.5649

−0.6542

0.0687$

3 months

6.5432 ± 0.5986

6.8234 ± 0.4896

−1.2654

0.0127*

6 months

6.3251 ± 0.5663

6.6874 ± 0.7701

−2.2366

<0.001#

12 months

6.2234 ± 0.7896

6.5234 ± 0.5698

−3.6548

<0.001#

*P < 0.05 = Significant, #p < 0.001 = Highly significant, $p >0.05 = Not significant.

Table 3 shows biochemical parameters at the baseline in the patients of the two groups namely fasting lipid profile, (TC, triglycerides [TGs], LDL cholesterol and high-density lipoprotein [HDL]), glycemic parameters (fasting blood sugar and glycated hemoglobin [HbA1c]), blood urea, serum creatine and serum glutamicpyruvic transaminase (SGPT) were estimated and these parameters were comparable as p values were not significant. Table 4 shows the baseline values of mean

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SUA in the two groups and the effects of the study drugs at 3, 6 and 12 months on mean SUA. SUA values in both the groups steadily decreased from the first follow-up at 3 months and a continued sustained fall was noted at 6 months and at 12 months. The comparisons in values of SUA between the two groups were also statistically significant (p < 0.001). AT was observed to be more effective than RS at the end of study in therapeutic doses.

INTERNAL MEDICINE DISCUSSION Uric acid is a breakdown product of ingested and endogenously synthesized purines, which are then metabolized via the action of xanthine oxidase to xanthine and UA.7 These latter steps are irreversible and the action of xanthine oxidase leads to generation of superoxide anions and is one of the principal sources of reactive oxygen species (ROS) in the human vasculature.7,24 The molecular effects and importance of ROS in CVD has already been extensively reviewed.25,26 Superoxide anions once formed can inactivate NO, leading to formation of peroxynitrite, which is also a strong oxidant. This inhibits endothelial-dependent vasorelaxation, limits favorable effects of NO on platelet aggregation and vascular smooth muscle proliferation and causes oxidation of DNA and lipids, all factors integral to development of atherosclerosis.27 Increased UA concentrations may reflect increased xanthine oxidase activity, which may directly contribute to the development of atherosclerotic disorders and predispose to more severe vascular events.7 UA may also increase oxygenation of LDL and may have a causative role in the development of hypertension.28 UA has proinflammatory effects on vascular cells and adipocytes, and may function as an antioxidant.29 UA has antioxidant activity and that concentrations may rise after ischemic insult. Moreover, in healthy human volunteers, UA administration has been shown to increase serum antioxidant capacity.30 Conversely, UA can also function as a pro-oxidant, either by generating radicals during its degradation or by stimulating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.31 Several drugs are known to lower UA either by increasing UA excretion (uricosuric drugs), block the final step in UA production via xanthine oxidase inhibition or lead to UA breakdown (rasburicase).7 Interestingly, three drugs known to reduce cardiovascular mortality have also been shown to reduce serum UA. Apart from fenofibrate and losartan, statin therapy also lowers serum UA.7,32 Decreased serum level of UA by drugs is mostly attributable to their uricosuric action.

A total of 110 drug naĂŻve dyslipidemic patients conforming to NCEP ATP III guidelines were enrolled, of these 5 patients (2 in AT and 3 in RS group) dropped out owing to irregular compliance probably because of higher cost of medicine (particularly RS) or poor awareness that despite adequate control one has to take medicine almost throughout their life to prevent recurrence or because of adverse events.

Regarding socio-demographic features, mean age of patients in both groups were evenly matched. There was a preponderance of females, urban inhabitants, nonvegetarians, literates and lower-middle class socioeconomic group.

One hundred five patients who completed the study were investigated for biochemical parameters inclusive of effect on UA due to AT and RS. In the present study, both AT and RS caused beneficial effects on lipid profile such as decreased TC, LDL and TGs and a lesser increase in HDL (data not shown). Our observations are in line with previous studies.

Little is known about the effect of dyslipidemia on SUA levels and less is known about the comparative effects of statin treatment on them. The present study was primarily designed to compare the effects of two lipidlowering agents on SUA levels in dyslipidemics. We have observed that both AT and RS caused a constant and steady statistically significant decreased in mean SUA at 3, 6 and at 12 months. The steady fall in SUA levels is more marked with AT as compared to RS (p < 0.001) in usual therapeutic doses. Our observations are in line with those of Ogata et al32 who too observed that both AT and RS decreased SUA levels but pitavastatin did not lower UA. AT has been shown to lower UA by other investigators too. This is possibly because of decreased UA production.33 Milionis et al34 observed that high dose of AT (40 mg/d) significantly decreased SUA levels although the underlying mechanisms remain speculative. Moutzouri et al35 observed RS (10 mg/d) similarly exhibits a UA lowering effect.

Statin therapy has been shown to lower SUA and that the decrease in SUA levels might be an effect of certain statins only.7,32 This is not a class effect since simvastatin, pravastatin, lovastatin, and fluvastatin did not lower SUA levels.20-23 A fall in SUA has been mirrored in other studies of statin therapy, but typically in association with improvements in serum creatinine.

In the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study,36 AT was associated with a fall in UA (by 8.2%), whereas SUA increased in those patients allocated to the placebo group (by 3.3%).

After adjustment for risk factors, each 60 Âľmol/L-1 reduction in SUA was associated with a reduction in vascular event rates (HR 0.76, 95% CI 0.62, 0.89).

It has been shown that AT treatment to NCEP targets for LDL, not only inhibits SUA increase, but also significantly reduces SUA levels. Although a decreased SUA represents a further beneficial effect, but cannot be

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INTERNAL MEDICINE assumed to explain some of AT effects. Furthermore, in the present study both AT and RS caused a significant reduction in SUA levels. We also noted that reduction in SUA was more marked in patients with an elevated baseline SUA levels.

Athyros et al36 observed that in structured-care group, a reduction in SUA (and adjusted serum creatinine) levels was seen as early as treatment Week 6. This may be caused by a direct effect of AT on renal function (possibly because of increased renal blood flow induced by improved endothelial function). We could not comment on this aspect as in our study, the first follow-up was at 3 months. The authors also noted that the effect of AT on SUA level is dose-dependent as greater doses of AT reduced SUA levels more than lower doses (p = 0.025).

SUA is a marker of oxidative stress and is being considered as an independent risk factor for CVD.7 It has also been shown that elevated SUA levels are powerful and independent predictor of cardiac and overall mortality in both sexes in patients with CHD9 or arterial hypertension. Though a clear pathophysiological role for UA in the development CVD has yet to be singled out, data to support detrimental and prothrombotic effects on platelet and endothelial function are available, post hoc analyses suggest that some of the beneficial effects of proven treatments for CVD may be due to changes in SUA concentrations.

There is wealth of epidemiological, animal and now clinical data to suggest that strategies to lower UA will not only be beneficial but will improve outcomes.7 Further, a relation between SUA levels and stroke has also been demonstrated in patients with or without CHD, arterial hypertension or diabetes mellitus. Large epidemiological studies support the hypothesis that UA independently influences cardiovascular outcomes.8,9 Further, post-hoc analyses of statin trial data suggest a significant reduction in vascular events with a decrease in UA levels after adjustment for multiple risk factors.19 CONCLUSION Reduction in SUA levels is not a class effect of statins.

Our study identified positive and significant reduction in SUA levels following prolonged therapy with two potent, widely used statins namely AT and RS. Since, uric acid may be an independent risk factor for CVD and that SUA is associated with cardiovascular mortality, the reduction in UA levels by statin therapy probably may cast a beneficial effect though well-designed large randomized controlled trial to test the efficacy and effectiveness of pharmacological intervention reducing

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SUA to improve outcomes are the need of hour.

However, post-hoc analyses suggest that some of the beneficial effects of proven treatments for CVD may be due to changes in SUA concentrations.

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6. Koh KK. Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability. Cardiovasc Res. 2000;47(4):648-57.

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15. Lehto S, Niskanen L, Rönnemaa T, Laakso M. Serum uric acid is a strong predictor of stroke in patients with non-insulin-dependent diabetes mellitus. Stroke.

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16. Ndrepepa G, Braun S, King L, Cassese S, Tada T, Fusaro M, et al. Prognostic value of uric acid in patients with Type 2 diabetes mellitus and coronary artery disease. Clin Sci (Lond). 2013;124(4):259-68.

17. Filiopoulos V, Hadjiyannakos D, Vlassopoulos D. New insights into uric acid effects on the progression and prognosis of chronic kidney disease. Ren Fail.

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18. Kang DH, Nakagawa T, Feng L, Watanabe S, Han L, Mazzali M, et al.A role for uric acid in the progression of renal disease. J Am Soc Nephrol. 2002;13(12):2888-97.

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22. Gardner SF, Schneider EF, Granberry MC, Carter IR. Combination therapy with low-dose lovastatin and niacin is as effective as higher-dose lovastatin. Pharmacotherapy.

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23. L öcsey L, Asztalos L, Kincses Z, Balázs G. Fluvastatin (Lescol) treatment of hyperlipidaemia in patients with renal transplants. Int Urol Nephrol. 1997;29(1):95-106.

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28. Dyer AR, Liu K, Walsh M, Kiefe C, Jacobs DR Jr, Bild DE. Ten-year incidence of elevated blood pressure and its predictors: the CARDIA study. Coronary Artery Risk Development in (Young) Adults. J Hum Hypertens.

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29. Waring WS, McKnight JA, Webb DJ, Maxwell SR. Uric acid restores endothelial function in patients with type 1 diabetes and regular smokers. Diabetes. 2006;55(11): 3127-32.

30. Waring WS, Webb DJ, Maxwell SR. Systemic uric acid administration increases serum antioxidant capacity in healthy volunteers. J Cardiovasc Pharmacol.

2001;38(3):365-71.

31. Santos CX, Anjos EI, Augusto O. Uric acid oxidation by peroxynitrite: multiple reactions, free radical formation, and amplification of lipid oxidation. Arch Biochem Biophys. 1999;372(2):285-94.

32. Ogata N, Fujimori S, Oka Y, Kaneko K. Effects of three strong statins (atorvastatin, pitavastatin, and rosuvastatin) on serum uric acid levels in dyslipidemic patients.

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33. Kakafika A, Tsimihodimos V, Elisaf M. Effect of atorvastatin on serum uric acid levels. Atherosclerosis.

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34. Milionis HJ, Kakafika AI, Tsouli SG, Athyros VG, Bairaktari ET, Seferiadis KI, et al. Effects of statin treatment on uric acid homeostasis in patients with primary hyperlipidemia. Am Heart J. 2004;148(4):635-40.

35. Moutzouri E, Liberopoulos EN, Florentin M, Liamis G, Elisaf MS. Effects of statin monotherapy versus statin plus ezetimibe combination on serum uric acid levels. J Cardiovasc Pharmacol Ther. 2013;18(1):13-8.

36. Athyros VG, Elisaf M, Papageorgiou AA, Symeonidis AN, Pehlivanidis AN, Bouloukos VI, et al; GREACE Study Collaborative Group. Effect of statins versus untreated dyslipidemia on serum uric acid levels in patients with coronary heart disease: a subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Am J Kidney Dis. 2004;43(4): 25. Hamilton CA, Miller WH, Al-Benna S, Brosnan MJ, Drummond RD, McBride MW, et al. Strategies to reduce 589-99.

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Every citizen of India should have the right to accessible, affordable, quality and safe heart care irrespective of his/her economical background

Sameer Malik Heart Care Foundation Fund An Initiative of Heart Care Foundation of India E-219, Greater Kailash, Part I, New Delhi - 110048 E-mail: heartcarefoundationfund@gmail.com Helpline Number: +91 - 9958771177

“No one should die of heart disease just because he/she cannot afford it” About Sameer Malik Heart Care Foundation Fund

Who is Eligible?

“Sameer Malik Heart Care Foundation Fund” it is an initiative of the Heart Care Foundation of India created with an objective to cater to the heart care needs of people.

Objectives Assist heart patients belonging to economically weaker sections of the society in getting affordable and quality treatment.

Raise awareness about the fundamental right of individuals to medical treatment irrespective of their religion or economical background.

Sensitize the central and state government about the need for a National Cardiovascular Disease Control Program.

Encourage and involve key stakeholders such as other NGOs, private institutions and individual to help reduce the number of deaths due to heart disease in the country.

To promote heart care research in India.

All heart patients who need pacemakers, valve replacement, bypass surgery, surgery for congenital heart diseases, etc. are eligible to apply for assistance from the Fund. The Application form can be downloaded from the website of the Fund. http://heartcarefoundationfund.heartcarefoundation. org and submitted in the HCFI Fund office.

Important Notes The patient must be a citizen of India with valid Voter ID Card/ Aadhaar Card/Driving License.

The patient must be needy and underprivileged, to be assessed

by Fund Committee.

The HCFI Fund reserves the right to accept/reject any application for financial assistance without assigning any reasons thereof.

The review of applications may take 4-6 weeks.

All applications are judged on merit by a Medical Advisory Board who meet every Tuesday and decide on the acceptance/rejection of applications.

The HCFI Fund is not responsible for failure of treatment/death of patient during or after the treatment has been rendered to the patient at designated hospitals.

To promote and train hands-only CPR.

Activities of the Fund Financial Assistance

The HCFI Fund reserves the right to advise/direct the beneficiary to the designated hospital for the treatment.

Financial assistance is given to eligible non emergent heart patients.

Apart from its own resources, the fund raises money through donations, aid from individuals, organizations, professional bodies, associations and other philanthropic organizations, etc.

The financial assistance granted will be given directly to the treating hospital/medical center.

After the sanction of grant, the fund members facilitate the patient in getting his/her heart intervention done at state of art heart hospitals in Delhi NCR like Medanta – The Medicity, National Heart Institute, All India Institute of Medical Sciences (AIIMS), RML Hospital, GB Pant Hospital, Jaipur Golden Hospital, etc. The money is transferred directly to the concerned hospital where surgery is to be done.

The HCFI Fund has the right to print/publish/webcast/web post details of the patient including photos, and other details. (Under taking needs to be given to the HCFI Fund to publish the medical details so that more people can be benefitted).

The HCFI Fund does not provide assistance for any emergent heart interventions.

Check List of Documents to be Submitted with Application Form Passport size photo of the patient and the family A copy of medical records

Drug Subsidy

Identity proof with proof of residence

The HCFI Fund has tied up with Helpline Pharmacy in Delhi to facilitate

BPL Card (If Card holder)

patients with medicines at highly discounted rates (up to 50%) post surgery.

Details of financial assistance taken/applied from other sources (Prime Minister’s Relief Fund, National Illness Assistance Fund Ministry of Health Govt of India, Rotary Relief Fund, Delhi Arogya Kosh, Delhi Arogya Nidhi), etc., if anyone.

Income proof (preferably given by SDM)

The HCFI Fund has also tied up for providing up to 50% discount on imaging (CT, MR, CT angiography, etc.)

Free Diagnostic Facility

Free Education and Employment Facility

The Fund has installed the latest State-of-the-Art 3 D Color Doppler EPIQ 7C Philips at E – 219, Greater Kailash, Part 1, New Delhi.

HCFI has tied up with a leading educational institution and an export house in Delhi NCR to adopt and to provide free education and employment opportunities to needy heart patients post surgery. Girls and women will be preferred.

This machine is used to screen children and adult patients for any heart disease.

Laboratory Subsidy HCFI has also tied up with leading laboratories in Delhi to give up to 50% discounts on all pathological lab tests.

About Heart Care Foundation of India

Help Us to Save Lives

The Foundation seeks support, donations and contributions from individuals, organizations and establishments both private and governmental in its endeavor to reduce the number of deaths due to heart disease in the country. All donations made towards the Heart Care Foundation Fund are exempted from tax under Section 80 G of the IT Act (1961) within India. The Fund is also eligible for overseas donations under FCRA Registration (Reg. No 231650979). The objectives and activities of the trust are charitable within the meaning of 2 (15) of the IT Act 1961.

Heart Care Foundation of India was founded in 1986 as a National Charitable Trust with the basic objective of creating awareness about all aspects of health for people from all walks of life incorporating all pathies using low-cost infotainment modules under one roof.

HCFI is the only NGO in the country on whose community-based health awareness events, the Government of India has released two commemorative national stamps (Rs 1 in 1991 on Run For The Heart and Rs 6.50 in 1993 on Heart Care Festival- First Perfect Health Mela). In February 2012, Government of Rajasthan also released one Cancellation stamp for organizing the first mega health camp at Ajmer.

Objectives Preventive Health Care Education Perfect Health Mela Providing Financial Support for Heart Care Interventions Reversal of Sudden Cardiac Death Through CPR-10 Training Workshops Research in Heart Care

Donate Now...

Heart Care Foundation Blood Donation Camps The Heart Care Foundation organizes regular blood donation camps. The blood collected is used for patients undergoing heart surgeries in various institutions across Delhi.

Committee Members

Chief Patron

President

Raghu Kataria

Dr KK Aggarwal

Entrepreneur

Padma Shri, Dr BC Roy National & DST National Science Communication Awardee

Governing Council Members Sumi Malik Vivek Kumar Karna Chopra Dr Veena Aggarwal Veena Jaju Naina Aggarwal Nilesh Aggarwal H M Bangur

Advisors Mukul Rohtagi Ashok Chakradhar

Executive Council Members Deep Malik Geeta Anand Dr Uday Kakroo Harish Malik Aarti Upadhyay Raj Kumar Daga Shalin Kataria Anisha Kataria Vishnu Sureka

This Fund is dedicated to the memory of Sameer Malik who was an unfortunate victim of sudden cardiac death at a young age.

Rishab Soni

HCFI has associated with Shree Cement Ltd. for newspaper and outdoor publicity campaign HCFI also provides Free ambulance services for adopted heart patients HCFI has also tied up with Manav Ashray to provide free/highly subsidized accommodation to heart patients & their families visiting Delhi for treatment.

http://heartcarefoundationfund.heartcarefoundation.org

NEUROLOGY

Functional Neuroimaging in Psychiatry KRISHAN KUMAR*, RAJNISH KUMAR†

ABSTRACT Functional neuroimaging has rapidly developed as a powerful tool in cognitive neuroscience and, in recent years, has seen widespread application in psychiatry. Although such studies have produced evidence for abnormal patterns of brain response in association with some pathological conditions, the core pathophysiologies remain unresolved. Although imaging techniques provide an unprecedented opportunity for investigation of physiological function of the living human brain, there are fundamental questions and assumptions, which remain to be addressed. We consider the difficulties that accompany the most frequent application of these techniques—an attempt to identify responses of the brain to changing tasks or contexts—and explore how these responses are affected by psychiatric illness. These are critical issues. If they cannot be addressed, functional imaging approaches must confine their ultimate aims to diagnosis and accept that they will never clarify etiology. If the questions remain unanswered, the techniques, no matter how complex their technical advances, will inevitably produce ambiguous findings. (1) Has the psychiatric disorder under study been appropriately specified? (2) Has the chosen task enabled a clear and unambiguous manipulation of the psychological processes that we wish to study? (3) How may we interpret changes in brain activations in the patient group.

Keywords: Functional neuroimaging, psychiatry, electroencephalography, magnetic resonance imaging and positron emission tomography

S

ince, the development of first functional brain imaging technique used in human beings by Seymour S Kety in 1948 functional neuroimaging has advanced in such a way that today it provides the crucial link between clinical features of several psychiatric disorders and their corresponding dysfunctional brain systems. By showing the various stages in the cascade from neuronal activity to behavior, functional neuroimaging scores over the conventional structural neuroimaging as the latter points out only the details of structures of brain without offering any implication they have on behavior. Functional neuroimaging quite rightly, therefore, is considered the spearhead of a neuropsychiatric perspective.

Today functional neuroimaging is used in research purposes. Though limited by cost, it can also be used

*Clinical Psychologist †Consultant Neurologist Computational Neuroscience and Neuroimaging Centre National Brain Research Center, Manesar, Haryana Address for correspondence Dr Krishan Kumar Clinical Psychologist Computational Neuroscience and Neuroimaging Centre National Brain Research Center, Manesar, Haryana E-mail: keshusony@rediffmail.com

as an important diagnostic aid. Moreover, investigation like transcranial magnetic stimulation offers the advantage of its use as an efficacious intervention technique as well.

With the advances in technology, various devices for detecting more specific functional aspects came up.

Now to select a suitable mode of investigation we have plenty of options to choose from e.g., positron emission tomography (PET), single-photon emission computed tomography (SPECT), xenon enhanced computed tomography (CT), functional magnetic resonance imaging (fMRI) to detect blood flow and perfusion; magnetic resonance spectroscopy (MRS), PET to gain information about metabolism; SPECT and PET for ligands and neuroreceptor imaging and lastly electroencephalography (EEG), magnetoencephalography (MEG) and transcranial magnetic stimulation (TMS) for electrophysiology.

Surprisingly, unlike the measurement of brain structure measurement of brain function has not been used much extensively in clinical practice. Its main application has been in research, though clinicians opine that alterations in brain function must at some level underlie all disorders in psychiatry. So, in the near future, it can be expected that functional neuroimaging will gain popularity among the clinicians and will gain the status of an essential rather than optional mode of investigation.

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NEUROLOGY FUNCTIONAL NEUROIMAGING TECHNIQUES

Positron Emission Tomography Positron emission tomography (PET) is named from its use of positron emitting isotopes to image brain functioning. Positron emitting isotopes are very short lived radioactive entities including oxygen 15 (15O), nitrogen 13 (13N), carbon 11 (11C) and fluorine 18 (18F).

The radioactive isotopes are incorporated into specific molecules to study cerebral metabolism, blood flow and neuroreceptors. Most commonly used are (15O) water for cerebral blood flow studies or (18F) fluorodeoxyglucose (FDG) to image metabolism.1,2 Radioactive agents are intravenously injected into the subject, whose head is positioned within a radiation detector. The radioactive isotope decays within the brain, releasing a positron.

The positron travels a short distance and collides with an electron, resulting in the emission of two photons that travel at 1800 to each other at the speed of light.

The photons are detected at the opposite sides of the head simultaneously, and the location of the emitting positron can thus be calculated.1 Advantages Used extensively to understand normal brain functioning, to image neurotransmitter and their receptor, and cerebral blood flow. It has greater spatial resolution than SPECT. Only PET can measure cerebral glucose metabolism. Because of shorter half-life of tracer, PET studies can often be conducted multiple times in a day.

Single-photon Emission Computed Tomography Single-photon emission computed tomography (SPECT) also uses radioactive compounds to image brain activity. Like PET, SPECT derives its name from the type of radioisotope involved, compounds that produce only one photon per disintegration. The radioisotopes are readily available from commercial sources. This makes SPECT available in most clinical centers. However, because SPECT imaging depends on a single-photon being released, its spatial resolution is less than that of PET. Advantages It produces both quantitative and qualitative measures of cerebral blood flow. It may be beneficial in diagnosing dementing illnesses, and is more affordable than PET.

Functional Magnetic Resonance Imaging Functional magnetic resonance imaging (fMRI) couples the exquisite spatial resolution of structural MRI with

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the ability to image areas related to neural activity. It does this noninvasively, without the use of radioactive agents. When a localized region of brain tissue becomes active, it uses oxygen and glucose and produces certain metabolic byproducts. In these areas of increased neural activity, the metabolism and blood flow increase with the increased energy demands. The cerebrovascular physiology of the brain is such that local blood flow and volume increases to supply the needed fuel and remove the metabolic waste products. Although the exact mechanism remains to be determined, many scientists believe that the supply of oxygen is much greater than what neurons utilize. This results in an actual increase in the concentration of oxygenated hemoglobin compared with deoxygenated hemoglobin in areas of neural activity. Oxygenated hemoglobin is less paramagnetic and has increased intensity (looks brighter) compared with deoxygenated hemoglobin on images created with T2- weighted pulse sequences. fMRI uses this blood oxygen level dependent (BOLD) effect to image changes in neural activity.3 In fMRI measures of activation are always relative as they do not directly assess absolute changes in blood flow. So, cognitive tests are given which serves as probes to activate specific neural network.

Advantages Because fMRI requires no radiation and can be completely noninvasive, a participant can be imaged multiple times. It also removes ethical constraints about imaging children and adolescent with psychiatric illnesses. fMRI is performed in standard, clinically available 1.5 Tesla, magnetic resonance scanner and so is a readily available mode of investigation.

Magnetic Resonance Spectroscopy Magnetic resonance spectroscopy (MRS) is performed in the same scanners as structural and fMRI. However, by altering the scanning parameters, the signal represents chemical entities from brain areas. The response of an atom in a magnetic field is characteristic, based on the number and nature of its subatomic particles, as well as its unique molecular environment. Spectra are obtained that are characteristic for nuclei within certain molecules.4 This principle is employed in MRS to study the concentration of brain metabolites. Typically, spectra are obtained from a number of nuclei, including 1H, 13C, 23Na, 7Li and 31P. In psychiatry, investigators are primarily using 1H and MRS. Proton (1H) spectroscopy can distinguish N- acetylaspartate (NAA), creatine and phosphocreatine,

31P

NEUROLOGY and phosphatidylcholine. Signals can be obtained from glutamate, gamma-aminobutyric acid (GABA), lactate and inositol phosphates, although these signals may be difficult to adequately resolve.5 NAA is found in neurons and is absent in most glial cell lines. Decreases in NAA may reflect a diminished number or density of neurons; NAA levels decrease proportionate to the brain loss in neurodegenerative disorders.6,7 Creatine and phosphocreatine are important energy substrates, and phosphatidylcholine is an important component of cell membranes.5 MRS with 31P detects the relative tissue concentrations of certain phosphorous metabolites, including those involved in energy and phospholipid metabolism.8 Resonances are obtained from the precursors and breakdown products of membrane phospholipids (phosphomonoesters and phosphodiesters, respectively), which uncover potential abnormalities in membrane turnover. To reflect energy metabolism, 31P MRS senses phosphocreatine, adenosine triphosphate, adenosine diphosphate and inorganic orthophosphate; intracellular pH can also be assessed.9 Advantages Able to measure concentration of some drugs in the brain including lithium and fluoxetine.

Magnetoencephalography Reading of brain electromagnetic activity is the basis of MEG. All electrical sources generate magnetic field.

Electrical sources within the brain have been modeled as electrical dipoles consisting of assemblies of neurons oriented in tangential (i.e., parallel to the skull) or radial (i.e., perpendicular to the skull) direction. MEG utilizes a device called superconducting quantum interference device (SQUID) magnetometer to detect these magnetic fields within the brain. This is a super cooled detection coil that is extremely sensitive to low intensity magnetic fields generated by dipoles within the brain.

Advantage Over EEG ÂÂ

SQUID need not be in contact with the scalp and it is insensitive to the effects of muscle tension and activity.

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Relatively unaffected by the interposed structures like skull, scalp.

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Detects sources deep within the brain.

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Relatively unaffected by surrounding fields.

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Better temporal resolution.

Electroencephalography A method of recording graphically the electric activity of the brain, particularly the cerebral cortex, by the means of electrodes attached to the scalp. The conventional EEG parameters are obtained from averaged EEG power spectra, based on periods of time and broad fixed frequency band for a specific lead. This approach of averaging of EEG signal masks the dynamic and temporal structure of EEG, leading to complicated data interpretation.

Technical advancement of EEG equipment in the last three decades has also facilitated quantitative analysis of EEG data. Quantitative EEG, also known as neurometrics or brain mapping, is a method of paperless recording using computer-based instrumentation. There are various advantages compared to conventional EEG including storage, acquisition, quantification, automatic spike detection and automatic event detection.

Quantitative EEG has provision for making changes in the recorded parameters, such as montage, filter.

Spectral Analysis In this technique, a series of segments (epochs) of EEG data (commonly 1-4 seconds in length) are processed through Fourier transformation to calculate the energy (power) in the signal that can be accounted for by a series of sinusoidal waveform of different amplitudes and frequencies. It represents state of neuronal activity in the brain.

Coherence or Synchronization It measures synchronized brain electrical activity from different regions within an individual which reflects both the structural and functional connections between brain areas. A decrease in coherence between two regions presumably indicates a decrease in their functional connection and vice-versa. Used for assessing anatomical/functional binding and metabolism in brain.

Evoked Potentials In this paradigm, electrical activity is recorded while the subjects are exposed to repetitive visuals (i.e., flashes of light or pattern), auditory (i.e., clicks or tones) or other stimuli (i.e., electrical stimulation of the skin). A computer averages the response to time locked, repeated stimuli, thus enhancing the signal evoked by the stimuli while averaging out other brain activity unrelated to the stimuli. The resulting display is a voltage waveform of the average response potentials.

These potentials appear as a series of positive and negative waveforms occurring at specific time intervals following a stimulus and are labeled according to their

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NEUROLOGY polarities (P for positive, N for negative) and latencies from time of the stimulus (in milliseconds). Used to assess rapidity and level of processing of brain.

Transcranial Magnetic Stimulation Transcranial magnetic stimulation (TMS) refers to an in vivo technique of delivering magnetic pulses to the cortex with a handheld stimulating coil, which is applied directly to the head. The equipment necessary for delivering TMS consists of two parts: a stimulator, which generates brief pulses of strong electrical currents whose frequency and intensity can be varied, and a stimulation coil connected to the stimulator. TMS stimulates the cortex focally and painlessly by creating a time-varying magnetic field. This localized pulsed magnetic field over the surface of the head induces electrical currents in the brain, which then depolarizes underlying superficial neurons.

TMS methods have been applied in a number of ways to probe the function of various aspects of the normal and abnormal brain in human subjects. ÂÂ

Cortical stimulation

ÂÂ

Cortical and regional connectivity

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Cortical plasticity

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Cognition.

NEUROIMAGING FINDINGS IN MAJOR PSYCHIATRIC ILLNESSES

Psychotic Disorders Schizophrenia PET and SPECT Studies ÂÂ

ÂÂ

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During the resting state: The first functional cerebral abnormality reported in older schizophrenic patients was a reduction in frontal blood flow or hypofrontality.10 This findings spawned a number of studies; patient populations have ranged from acutely ill, never medicated adolescents to patients receiving long-term medication. Hypofrontality is an inconsistent finding and probably depends on many factors.1,11-17 In fact, some investigators find hyperfrontality in unmedicated schizophrenic patients.18 Several PET studies implicate basal ganglia dysfunction in schizophrenia.19-21 During cognitive tasks: By imaging participants during the performance of tasks, cerebral activity patterns reflect a state with less variability due to random, task independent thought processes.

Schizophrenic individual invariably show

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dysfunction within frontoparietal temporal networks regardless of the task used.22-31 fMRI Studies Overall studies have reported reduced limbic activation in the schizophrenia for given cognitive task.32,33 MRS Studies 31P

MRS has been used to investigate membrane components and high energy phosphate compounds in the left dorsolateral prefrontal cortex (DLPFC). of drug naive patients with first episode schizophrenia, patients with chronic schizophrenia and healthy control subjects. All patients with schizophrenia, whether acute, drug naive or chronic, showed decreased levels of phosphomonoesters, building blocks for cell membranes.9,34 However, other groups have reported increased phosphodiesters even in chronic patients.35 In 1H MRS studies schizophrenic patients showed reduced NAA in mesial temporal lobe and DLPFC.7,36-40 EEG Studies Numerous qualitative studies indicate abnormal conventional EEG findings in 20-60% of schizophrenic patients.41,42 Evaluation of EEG and qEEG literature on schizophrenia is complicated by the evident heterogeneity of the illness. Most often, the reported abnormalities have been delta and/or theta excesses in frontal areas.43-48 and decreased mean frequency and lower power in the alpha band.42,44,49,50 and increased beta power.51-53 Increased anterior coherence also has often been reported.54 In this institute Agarwal and Nizamie55 found a significantly less interhemispheric gamma coherence across all brain area in schizophrenics and further Bandopadhayaya and Nizamie56 found more so in temporal area.

ERP Studies The P300 ERP, a positive deflection occurring approximately 300 msec after the introduction of a stimulus, is regarded as a putative biological marker of risk for schizophrenia.57,58 The P300 amplitudes are smaller in patients with schizophrenia and is one of the most replicated electrophysiological findings.59,60 Latency of P300 was prolonged and value was maximum in left central (C3) and frontal region in drug naïve and drug free schizophrenics.61 Abnormalities in the N400 amplitude in schizophrenia have been reported.62-64 Investigators suggest that individuals with schizophrenia do not use the context of the preceding portion of the sentence and fill in responses

NEUROLOGY to phrases based on the immediately preceding word rather than the whole sentence or passage.

Mood Disorders PET and SPECT Studies Studies revealed decreased blood flow and metabolism in subgenual prefrontal cortex (SGPFC)65 in bipolar depressed patients. Whereas manic patients showed increased blood flow in SGPFC;66,67 and basal ganglia.66,68 fMRI Studies During motor performance, manic bipolar patients had significantly higher activation in right globus pallidus compared with bipolar depressed patients.69 During Stroop task, manic patients showed decreased right ventral prefrontal cortical activation, whereas depressed patient showed an area of increased activation compared with euthymic patients.70 During verbal fluency task, bipolar patients had increased prefrontal cortical activation compared with healthy controls.71 Because of wide variability of cognitive task employed comparison of fMRI studies are inevitably hampered.

MRS Studies MRS studies have reported elevated choline concentrations in the striatum of bipolar patients.67 Decreased NAA in the DLPFC was found in bipolar children and adolescents with parental bipolar disorder,72 in bipolar adults73 and in manic patients.

Davanzo et al74 and Cecil et al75 found a nonsignificant elevation in myo-inositol concentration in bipolar children compared with healthy subjects, suggesting that elevated myo-inositol may be a biological marker for early onset affective disorder.

Using MRS to examine medication effect, Moore et al76 reported a decrease in anterior cingulated myoinositol following lithium treatment. Lithium has also been shown to increase NAA in frontal, temporal, parietal and occipital lobes of bipolar patients, which has been interpreted to suggest that lithium may be neuroprotective.77,78 EEG Studies The incidence of abnormal conventional EEG findings in mood disorders appears to be substantial, ranging from 20% to 40%41,79-81 higher in: 1) manic than depressed patients, 2) female than male bipolar patients and 3) nonfamilial cases with late-age onset. EEG studies report that small sharp spikes and paroxysmal events

are often found, especially on the right hemisphere.82 There is broad consensus in qEEG studies that increases in alpha or theta power, as well as asymmetry and hypocoherence in anterior regions, appear most often in unipolar depressed patients.83-89 Bipolar patients often display decreased alpha,86,90,91 but increased beta activity.91-93 Together, these studies support a model of bipolar disorder that involves dysfunction within subcortical (striatal thalamic) prefrontal networks and the associated limbic modulating regions (amygdala, midline cerebellum).

Functional Imaging in Personality Disorders Schizotypal Personality Disorders SPECT study by Trestman et al94 revealed greater increase in blood flow to DLPFC during cognitive task.

PET studies show asymmetry in striatal metabolism95 and lower glucose metabolism in anterior cingulate.96 This finding suggest abnormal striated function in schizotypal personality disorder, which reflects a particular form of dopaminergic dysfunction in schizophrenia spectrum illness.

Borderline Personality Disorders Goyer et al97 examined regional cerebral metabolic rates of glucose (rCMRG) in patients with personality disorders; they found higher glucose metabolism in the prefrontal cortex, lower metabolism in inferior portions of the frontal cortex, the posterior cingulated and the left parietal area.

Antisocial Personality Disorders A study by Intrator98 utilizing SPECT found that antisocial personality disorder (ASPD) had more ventral occipital and less temporoparietal cortical activation than normal with the affective task. Thus, this study provides support for the hypothesis that patients with ASPD respond abnormally to stimuli with aversive emotional significance.

Anxiety Disorders Panic Disorders PET studies revealed abnormal asymmetry in orbitofrontal and hippocampal region.99,100 MRS studies showed increased brain lactate levels in patients with panic disorder.101 Another study focusing on frontal lobe revealed phosphocreatine asymmetry with levels on the left greater than those on the right.102 qEEG showed paroxysmal activity in temporal lobe.103

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NEUROLOGY PTSD PET study showed that increased activity in amygdala, orbitofrontal cortex, insular cortex, anterior temporal pole and anterior cingulated cortex occurs in subjects of PTSD.104,105 Though Bremner et al106 reported deactivation in medial prefrontal cortex in similar population.

Obsessive Compulsive Disorders PET Studies Major PET studies found elevated metabolism, or regional cerebral blood flow (rCBF) in the orbitofrontal cortex107-109 or thalamus.108,110 There was significant decrease in glucose metabolism in these areas after treatment with clomipramine,111 fluoxetine112 and paroxetine.113 SPECT Studies Baseline SPECT studies have found that patients with obsessive-compulsive disorder (OCD) have increased rCBF in frontal cortex114,115 and decreased rCBF in basal ganglia specially caudate nucleus.116,117 Elevated HMPAO uptake in OCD patients decreased significantly after treatment with fluoxetine118 and clomipramine.115 MRS Studies Bartha et al119 found significantly lower relative level of NAA in the left and right striatum of patients with OCD compared with healthy control subjects.

EEG Studies Increased theta activity has been reported in OCD.120,121 Sarkar and Sinha122 carried out 1st qEEG study to validate fronto-subcortical dysfunction hypothesis and found increased theta coherence in OCD patients as compared to normal controls. To summarize, these studies consistently indicate elevated activity in the orbitofrontal cortex in patients with OCD, with less consistent abnormalities in the caudate nucleus, which decreases with the treatment.

Substance Use Disorders Alcohol PET and SPECT Studies Alcoholics showed decreased metabolism in prefrontal, parietal and temporal cortices123; increased metabolism in frontal regions during detoxification.124 Significantly lower benzodiazepine distribution was seen in frontal, anterior cingulate and cerebellar cortices.125 MRS Studies Measures of visibility of brain alcohol in vivo vary widely ranging from 21% to 100%.126-129 NAA/choline

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ratio thought to represent neuronal reserve were reduced in frontal, thalamic and cerebellar areas.130 EEG Studies Among numerous qEEG studies, there is a consensus of increased beta relative power in alcoholism.131-135 ERP studies suggest a frontal lobe function anomaly in alcoholics.136 Cannabis PET and SPECT Studies Studies showed increased regional metabolism in the cerebellum during acute administration of THC, though chronic use showed increased metabolism in the orbitofrontal cortex and cingulated gyrus.137,138 EEG Studies Increased alpha power, especially in anterior regions, has been reported in withdrawal, as well as after acute exposure to cannabis.139,140 Opiates PET and SPECT Studies Acute intake of morphine reduced global metabolism by 10% and by about 5-15% in telencephalic areas and the cerebellar cortex.141 Another study revealed significant increase in regional cerebral blood flow in cingulated, orbitofrontal and medial prefrontal cortices and caudate nuclei.142 EEG Studies Increased alpha and decreased delta and theta have been reported in cocaine users during withdrawal.143-147

Child Psychiatric Disorder Autism PET and SPECT Studies Studies have shown temporal and frontal lobe hypoperfusion148,149 and abnormal temporal cortex activation during auditory test.150,151 fMRI Studies Increased activity in the bilateral inferior temporal gyrus, right thalamus, left superior temporal gyrus and left peristriate visual cortex has been found in subjects with autism, but not is healthy controls, when they process facial features (identity) and facial expressions (emotion).152-154 Ring et al155 and Luna et al156 investigated executive function in autism, found dysfunctional integration of the DLPFC, posterior cingulated cortex and parietal cortex.

NEUROLOGY Recently, it was found that the language deficits in autism were subtended by anomalies in the dentatothalamo-prefrontal pathway and reverse dominance in the right hemisphere.157 MRS Studies Studies have found evidence of decreases synthesis and increased degradation of prefrontal cortical membrances.158 and reduced concentration of NAA in the amygdala, hippocampus, cingulate, cerebellum and wernicked area159-162 in subjects with autism.

EEG Studies A variety of EEG abnormalities may be seen in autistic disorder, including diffuse and focal spikes, paroxysmal spike and wave patterns, multifocal spike activity and a mixed discharge. The prevalence of EEG abnormalities in autistic disorder (in the absence of a clinical seizure disorder) ranges from 10% to 83% and depends on the number of recordings and the nature of the sample obtained.163 EP Studies Auditory brainstem evoked potentials in autistic disorder indicates no evidence of abnormalities in the auditory brainstem pathways. However, abnormalities of cognitive potentials, particularly the auditory P300 (which represents the brainâ&#x20AC;&#x2122;s processing of sensory stimuli) have been demonstrated in autistic disorder.

This presumably reflects abnormalities in higher auditory processing and neural pathways.163 On the basis of these findings, it has been suggested that structural and biochemical abnormalities in neural network involving the fronto-temporo-parietal cortex, limbic system and cerebellum underlie the pathophysiology of autism.

Attention-deficit/Hyperactivity Disorder PET and SPECT Studies One of the fundamental underlying dysfunction in attention-deficit/hyperactivity disorder (ADHD) is thought to be within the dopamine system. Doughtery et al164 in a SPECT study found a 70% increase in dopamine transporter density in the straitum of adults with ADHD. Another PET study by Ernst et al165 showed a 48% increase of DOPA accumulation in the right midbrain of children with ADHD. These studies indicate that overproduction of dopamine in the midbrain could be related to increased reuptake of dopamine in the stratum.

fMRI Studies Bush et al166 on testing attention in a group of adult ADHD patients found that they failed to activate the cognitive/attention division of the anterior cingulated gyrus. Similarly, Rubia et al167 and Vaidya et al168 have shown a failure of right prefrontal cortex activation during response inhibition paradigm in boys with ADHD versus normal controls.

EEG Studies A large percentage of children with attention deficit problems (more than 90%) show qEEG signs of cortical dysfunction, the majority displaying frontal theta or alpha excess, hypercoherence and a high incidence of abnormal interhemispheric asymmetry.169,170 Dementia Alzheimerâ&#x20AC;&#x2122;s disease.

SPECT Studies Studies have shown a temporoparietal hypoperfusion that is typically asymmetric.171,172 Not all patients with AD show temporoparietal hypoperfusion but AD can be accompanied by a great variety of perfusion patterns, depending on cognitive findings or the severity of illness.173 PET Studies Like typical hypoperfusion perfusion patterns visualized by SPECT, PET studies demonstrate a reduced cortical oxygen consumption or glucose metabolism, which is most pronounced and often asymmetrical in temporoparietal areas.174 The observed metabolic changes are correlated with test performance, the severity of illness and duration of illness.175 EEG Studies Studies show decrease of mean frequency176 of the dominant occipital activity of the alpha: theta ratio and an increase of relative177 or absolute theta power, whereas delta power increases in later stages of illness.178 WHERE WE STAND NOW? With the advent, functional neuroimaging raised hopes of providing the master key to unlock the even unsolved mystery of etiology of psychiatric disorders.

But, in reality we are left stranded with bunch of research reports mostly reproving and strengthening earlier theories and hypothesis, respectively. There is

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NEUROLOGY as yet no definitive and unambiguous evidence that any psychiatric brain imaging measure can provide a comprehensive and clearly incremental improvement to the existent approach to the treatment or even diagnosis of psychiatric illness. Does a pattern of imaging findings reflect a diagnostic entity or is it peculiar to a particular symptom profile? Does inconsistency within a diagnostic or symptom based grouping reflect state related psychological phenomena, or underlying etiological differences, perhaps seen at the level of the genotype? Clearly, the difficulties are highly complex and will not be addressed by any single approach to experimental design but rather by the accumulation of data sets in which the correlations of brain activity with phenotypic and genotypic variables are examined.

It has been possible, for example, to combine functional imaging with molecular genetics and developmental neurobiology. Such an approach, capitalizing on the identification of specific genetic mutations and cooccurring behavioral deficits, may offer the precision that imaging studies require. This evolving alliance along with cognitive neuroscience may in near future identify neural networks and heralds a new era of knowledge about healthy brain function, the mechanism of disease, underlying etiology, unimagined innovations in therapeutic intervention and efficacious strategies for prevention.

FUTURE DIRECTIONS ÂÂ

To employ tasks on which performance of the patient and control group is matched.

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Correlation studies should be hypothesis driven.

It would be an improvement if a hypothesis made were based on past data, for example that temporal lobe abnormality might contribute to auditory hallucination because temporal lobe epileptics experience such symptoms.

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Longitudinal investigations could help to resolve whether neuropathological changes are related to neurodevelopmental or neurodegenerative process, or an interaction of the two. Investigations with children and younger populations will be necessary to confirm neurodevelopmental theories and to demonstrate interactions with normal developmental processes.

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To consider the need to obtain information about baseline or resting state of human brain.

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To extend future studies beyond the receptor and neurotransmitter to look into second messenger system in the brain.

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Application of synergistic approach i.e., using different neuroimaging modalities complementarily

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to get more rewarding information to unravel the major issues in clinical neuroscience.

To integrate regional brain activity data with knowledge of underlying pharmacological mechanisms.

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American Psychiatric Press Review of Psychiatry. Vol. 10, Washington, DC: American Psychiatric Press; 1991. pp.

24-59.

2. Nadeau SE, Crosson B. A guide to the functional imaging of cognitive process. Neuropsychiatry Neuropsychol Behav Neurol. 1995;8:143-62.

3. Kwong KK, Belliveau JW, Chesler DA, Goldberg IE, Weisskoff RM, Poncelet BP, et al. Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation. Proc Natl Acad Sci U S A. 1992;89(12):5675-9.

4. McClure RJ, Kanfer JN, Panchalingam K, Klunk WE, Pettegrew JW. Magnetic resonance spectroscopy and its application to aging and Alzheimer's disease.

Neuroimaging Clin N Am. 1995;5(1):69-86.

5. Narayana PA, Jackson EF. Image-guided in vivo proton magnetic resonance spectroscopy in human brain.

Current Science 1991;61(5):340-51.

6. Maier M. In vivo magnetic resonance spectroscopy.

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138. Mathew RJ, Wilson WH, Coleman RE, Turkington TG, DeGrado TR. Marijuana intoxication and brain activation in marijuana smokers. Life Sci. 1997;60(23):2075-89.

139. Struve FA, Straumanis JJ, Patrick G, Price L. Topographic mapping of quantitative EEG variables in chronic heavy marihuana users: empirical findings with psychiatric patients. Clin Electroencephalogr. 1989;20(1):6-23.

140. Struve FA, Straumanis JJ, Patrick G. Persistent topographic quantitative EEG sequelae of chronic marihuana use: a replication study and initial discriminant function analysis. Clin Electroencephalogr. 1994;25(2):63-75.

141. London ED, Broussolle EP, Links JM, Wong DF, Cascella NG, Dannals RF, et al. Morphine-induced metabolic changes in human brain. Studies with positron emission tomography and [fluorine 18]fluorodeoxyglucose. Arch Gen Psychiatry. 1990;47(1):73-81.

142. Firestone LL, Gyulai F, Mintun M, Adler LJ, Urso K, Winter PM. Human brain activity response to fentanyl imaged by positron emission tomography. Anesth Analg.

1996;82(6):1247-51.

143. Alper KR, Chabot RJ, Kim AH, Prichep LS, John ER. Quantitative EEG correlates of crack cocaine dependence.

Psychiatry Res. 1990;35(2):95-105.

144. Alper KR, Chabot R, Prichep LS, et al. Crack cocaine dependence: discrimination from major depression using qEEG variables. In: Maurer K (Ed.). Imaging of the Brain in Psychiatry and Related Fields. Berlin: Springer-Verlag; 1993. pp. 289-93.

145. Cornwell A, Roemer RA, Jackson P, Dewart D. Paroxysmallike EEG abnormalities associated with chronic polydrug abuse. Biol Psychiatry 1994;35(9):692-3.

146. Prichep LS, Alper KR, Kowalik S, Merkin H, Tom M, John ER, Rosenthal MS. Quantitative electroencephalographic characteristics of crack cocaine dependence. Biol Psychiatry. 1996;40(10):986-93.

147. Roemer RA, Cornwell A, Jackson P, Dewart D. Quantitative EEG measures: correlations with lifetime exposure to cocaine, alcohol, and marijuana in chronic polydrug. Biol Psychiatry. 1994;35:624-5.

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162. Friedman SD, Shaw DW, Artru AA, Richards TL, Gardner J, Dawson G, et al. Regional brain chemical alterations in young children with autism spectrum disorder.

Neurology. 2003;60(1):100-7.

149. Zilbovicius M, Boddaert N, Belin P, Poline JB, Remy P, Mangin JF, et al. Temporal lobe dysfunction in childhood autism: a PET study. Positron emission tomography. Am J Psychiatry. 2000;157(12):1988-93.

163. Volkmar J. Prevasive developmental disorder. In: Sadock BJ, Sadock VA. Comprehensive Textbook of Psychiatry.

Philadelphia, USA: Lippincott William and Wilkins; 2005.

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150. MĂźller RA, Behen ME, Rothermel RD, Chugani DC, Muzik O, Mangner TJ, et al. Brain mapping of language and auditory perception in high-functioning autistic adults: a PET study. J Autism Dev Disord. 1999;29(1):19-31.

164. Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ. Dopamine transporter density in patients with attention deficit hyperactivity disorder.

Lancet. 1999;354(9196):2132-3.

151. Boddaert N, Zilbovicius M. Functional neuroimaging and childhood autism. Pediatr Radiol. 2002;32(1):1-7.

152. Critchley HD, Daly EM, Bullmore ET, Williams SC, Van Amelsvoort T, Robertson DM, et al. The functional neuroanatomy of social behaviour: changes in cerebral blood flow when people with autistic disorder process facial expressions. Brain. 2000;123(Pt 11):2203-12.

153. Schultz RT, Gauthier I, Klin A, Fulbright RK, Anderson AW, Volkmar F, et al. Abnormal ventral temporal cortical activity during face discrimination among individuals with autism and Asperger syndrome. Arch Gen Psychiatry. 2000;57(4):331-40.

154. Ogai M, Matsumoto H, Suzuki K, Ozawa F, Fukuda R, Uchiyama I, et al. fMRI study of recognition of facial expressions in high-functioning autistic patients.

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155. Ring HA, Baron-Cohen S, Wheelwright S, Williams SC, Brammer M, Andrew C, et al. Cerebral correlates of preserved cognitive skills in autism: a functional MRI study of embedded figures task performance. Brain.

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156. Luna B, Minshew NJ, Garver KE, Lazar NA, Thulborn KR, Eddy WF, et al. Neocortical system abnormalities in autism: an fMRI study of spatial working memory.

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165. Ernst M, Zametkin AJ, Matochik JA, Pascualvaca D, Jons PH, Cohen RM. High midbrain [18F]DOPA accumulation in children with attention deficit hyperactivity disorder.

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166. Bush G, Frazier JA, Rauch SL, Seidman LJ, Whalen PJ, Jenike MA, et al. Anterior cingulate cortex dysfunction in attention-deficit/hyperactivity disorder revealed by fMRI and the Counting Stroop. Biol Psychiatry.

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167. Rubia K, Overmeyer S, Taylor E, Brammer M, Williams SC, Simmons A, et al. Hypofrontality in attention deficit hyperactivity disorder during higher-order motor control: a study with functional MRI. Am J Psychiatry.

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169. Marosi E, Harmony T, SĂĄnchez L, Becker J, Bernal J, Reyes A, et al. Maturation of the coherence of EEG activity in normal and learning-disabled children.

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171. Goldenberg G, Podreka I, Suess E, Deecke L. The cerebral localization of neuropsychological impairment in Alzheimer's disease: a SPECT study. J Neurol.

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173. McMurdo ME, Grant DJ, Kennedy NS, Gilchrist J, Findlay D, McLennan JM. The value of HMPAO SPECT scanning in the diagnosis of early Alzheimer's disease in patients attending a memory clinic. Nucl Med Commun.

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OBSTETRICS AND GYNECOLOGY

Sheehan’s Syndrome: A Case Report SHIKHA SINGH*, REKHA RANI†, DIBYA SINGH‡

ABSTRACT Sheehan's syndrome is postpartum hypopituitarism caused by necrosis of the pituitary gland, which usually result of severe hypotension or shock caused by massive hemorrhage during or after delivery. Patients with Sheehan's syndrome have varying degrees of anterior pituitary hormone deficiency, the basic event seems to be an infarct in the anterior pituitary due to decreased blood volume. Enlargement of pituitary gland, small sella size, disseminated intravascular coagulation and autoimmunity have been suggested to play a role in its pathogenesis. We report a case of a 26-year-old para 1 female who presented with amenorrhea since past 7 years. She gave a history of vaginal delivery at home followed by heavy bleeding for which she was managed conservatively along with 3 units of blood transfusion at a local hospital. She was thoroughly investigated and she was diagnosed to be suffering from Sheehan's syndrome. She was managed by cyclical hormone replacement therapy with positive outcome. Her menses have become regular with normal flow and duration and she is now planning for infertility treatment.

Keywords: Sheehan's syndrome, postpartum pituitary necrosis, intrapartum or postpartum hemorrhage, hormone replacement, growth hormone deficiency

S

heehan’s syndrome, first described by Sheehan in 1937,1 is postpartum hypopituitarism caused by intrapartum or postpartum hemorrhage.

The damage to pituitary tissue may require lifelong hormone replacement.

Pituitary damage unrelated to pregnancy is called Simmonds’ disease.2 In a study of 1,034 symptomatic adults, Sheehan’s syndrome was found to be the sixth most frequent etiology of growth hormone deficiency, being responsible for 3.1% of cases (vs. 53.9% due to a pituitary tumor).3 Although the pathogenesis of Sheehan’s syndrome is not clear, the basic event is infarct in the anterior pituitary due to decreased blood volume.4 It is not clear whether this infarct is due to vasospasm, thrombosis or a vascular compromise.

Pituitary volume increases twofold during pregnancy.

This is due to hyperplasia of prolactin secreting cells from elevated estrogen secretion. Enlarged pituitary

*Assistant Professor †Lecturer ‡Junior Resident Dept. of Obstetrics and Gynecology SN Medical College, Agra, Uttar Pradesh Address for correspondence Dr Shikha Singh 23, Jaipur House, Agra - 282 010, Uttar Pradesh E-mail: drshikhasingh.shikha@gmail.com

gland may be compressing the blood vessels supporting it or there may be a predisposition in pregnant women compared with nonpregnant women or these two conditions may concur. Pituitary gland doesn’t have ability to regenerate. Scar tissue substitutes the necrotic cells. Presence of 50% of pituitary gland suffices the maintenance of normal functions.4 Partial or total hypopituitarism develops with necrosis of 70-90%.5 We report our experience in diagnosing and managing a case of Sheehan’s syndrome.

CASE REPORT A 26-year-old para 1 female presented with amenorrhea for 7 years. There was history of vaginal delivery at home followed by heavy bleeding for 2 days, for which she was admitted to some local hospital managed conservatively along with 3 units of blood transfusion.

She did not resume her menses for 5 years post-delivery and did not breastfeed her baby due to insufficient milk production. In 2010, she took advice from some local practitioner and got investigated. Her serum prolactin level was 0.63 mg/dL, triiodothyronine (T3) - 0.25 mg/dL, thyroxine (T4) - 1.30 mg/dL, thyroid-stimulating hormone (TSH) - 2.13 mg/dL and estradiol - 23.92 pg/mL. She was prescribed many medications but did not resume her menses at all. She became hopeless and left treatment. Two years after this treatment failure, she presented to us with same complaints and additionally with cold intolerance for 2 years.

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OBSTETRICS AND GYNECOLOGY On general examination, she was thin built of short stature (height 142 cm) with weight of 46 kg; pulse rate was 88/min and blood pressure (BP) was 132/86 mmHg with mild pallor. Her facial skin was dry, rough, discolored and few fine wrinkles were seen. Her systemic examination was within normal limits. Per speculum examination was within normal limits.

Her cold intolerance and lethargy improved and skin texture was better. Earlier she was hopeless with the treatment but after having positive results she is willing for infertility treatment. She will be planned for infertility treatment in future.

On per vaginal examination, uterus was anteverted, hypoplastic, mobile, nontender, bilateral adnexa were clear and nontender. She was again investigated and results were:

Known as postpartum pituitary necrosis, diagnosis of Sheehan’s syndrome is based upon medical history of the patient, clinical findings, detection of low level of pituitary and target gland hormones and visualizing partial or complete empty sella by imaging procedures.

Sheehan’s syndrome is one of the leading causes of hypopituitarism in developing countries.6,7

ÂÂ

Free T3 (FT3) - 0.40 pmol/L

ÂÂ

Free T4 (FT4) - 0.50 pmol/L

ÂÂ

TSH - 2.130 µIU/mL

ÂÂ

Serum prolactin - 0.48 ng/mL

ÂÂ

Growth hormone - 4.15 µIU/mL.

Blood picture of our patient showed - hemoglobin - 9.8 gm%, total leukocyte count (TLC) - 4,500/dL, differential leukocyte count (DLC) - P74L26, platelet count - 2,80,000/dL, GPB - normocytic normochromic mild anisocytosis, no HP seen. Lipid profile was triglyceride - 112 mg%, cholesterol - 159 mg%, high-density lipoprotein (HDL) 45%, low-density lipoprotein (LDL) - 91 mg%, very lowdensity lipoprotein (VLDL) - 23 mg%.

On USG → Hypoplastic uterus was found. Ovaries were within normal limits. No adnexal mass was noted.

Magnetic resonance imaging (MRI) was done, which showed partially empty sella suggestive of pituitary necrosis. Dynamic pituitary tests could not be done due to financial constraints of the patient.

All her investigations were suggestive of Sheehan’s syndrome. She was prescribed cyclical hormones in the form of ethinyl estradiol 0.05 mg o.d. (Day 1 to Day 21) and norethindrone acetate 5 mg b.i.d. (Day 16 to Day 25) and referred to Medicine Department for other supplementary hormonal therapy. There she was advised tablet prednisolone - 20 mg o.d., levothyroxine 50 µg o.d. for 1 month.

After 1 month, she resumed her menses with average flow and duration. Meanwhile hormonal doses were changed, she was kept on tablet prednisolone 10 mg for 15 days f/b 7.5 mg. Dose of levothyroxine was increased to 75 µg for 1 month. Estrogen and progestins were continued in the same dose. She again had her menses at an average interval, flow and duration. After 2 months of treatment, her thyroid profile was FT3 - 3.33 pmol/L (within normal limit), FT4 - 10.37 pmol/L (within normal limits) and TSH - 1.770 µIU/mL (within normal limits).

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DISCUSSION

Pituitary insufficiency in Sheehan’s syndrome may be in the form of partial or complete hormone insufficiency.8 Symptoms and signs of Sheehan’s syndrome are generally due to insufficient levels of hormones secreted from the anterior pituitary. The skin is dry, pale and light-colored and face is wrinkled. Axillary and pubic hair decrease and amenorrhea develops as a result of insufficiency of gonadotropins. Thyioid gland is shrunk as thyroid stimulation is ceased. Sufficient milk cannot be produced because of hypoprolactinemia.9 The patients with Sheehan’s syndrome usually are presented to emergency services due to situations such as “coma of hypothyroidism, adrenal insufficiency, hypoglycemia and hyponatremia following a serious stressful event”.10 Hyponatremia is the most common electrolyte disorder in Sheehan’s syndrome. It develops due to volume depletion, cortisol insufficiency, hypothyroidism and probably syndrome of inappropriate antidiuretic hormone secretion (SIADH). It may merge in postpartum period as well as several years after delivery.10-13 Anemia may develop in Sheehan’s syndrome due to cortisol deficiency, hypothyroidism and hypogonadism.14 Sheehan’s syndrome patient may present with hyperlipidemia due to hypothyroidism and growth hormone insufficiency.

It is believed that functions most frequently affected in Sheehan’s syndrome are prolactin and growth hormone secretion. However, the secretion of other hormones may also be affected adversely. In our patient, prolactin level was very low.

In regard to basal hormone levels, our patient had low T3, T4 and normal TSH level. This suggested that situation was secondary to hypothyroidism. Studies show that sella volume of patient with Sheehan’s syndrome are smaller than normal controls.15,16 Our patient had partially empty sella on MRI.

OBSTETRICS AND GYNECOLOGY Sheehan’s syndrome may be acute or chronic, it’s acute form is rare. Sheehan’s syndrome diagnosis is usually made several years after the postpartum bleeding. The interval may be as long as 15-20 years.9 Our patient was diagnosed much earlier with disease duration of 7 years.

6. Dash RJ, Gupta V, Suri S. Sheehan’s syndrome: clinical profile, pituitary hormone responses and computed sellar tomography. Aust N Z J Med. 1993;23(1):26-31.

CONCLUSION

8. Haddock L, Vega LA, Aguiló F, Rodríguez O. Adrenocortical, thyroidal and human growth hormone reserve in Sheehan’s syndrome. Johns Hopkins Med J. 1972;131(2):80-99.

Sheehan’s syndrome is more common in rural parts of our country. Considering the duration of disease, one may conclude that diagnosis and treatment are delayed. This may be originating from natural course of disease and also because of delay in diagnosis. Though rare but also it is frequently missed because of lack of awareness on the part of treating clinician. So keeping in mind, a women coming in postpartum period with history if heavy bleeding during or after child birth, signs and symptoms suggestive of deranged hormonal profile should be investigated for early diagnosis and treatment of Sheehan’s syndrome.

REFERENCES 1. “Postpartum necrosis of the anterior pituitary”, by H.L. Sheehan, Journal of Pathology and Bacteriology, vol. 45, pp. 189-214, 1937. Am J Obstet Gynecol. 1971;111(6):851.

2. Pituitary (Hypoestrogenic Amenorrhea). In: First Aid for the Obstetrics and Gynecology Clerkship. p. 226.

3. Abs R, Bengtsson BA, Hernberg-Stâhl E, Monson JP, Tauber JP, Wilton P, et al. GH replacement in 1034 growth hormone deficient hypopituitary adults: demographic and clinical characteristics, dosing and safety. Clin Endocrinol (Oxf). 1999;50(6):703-13.

4. Kovacs K. Sheehan syndrome. Lancet. 2003;361(9356): 520-2.

7. Ozbey N, Inanc S, Aral F, Azezli A, Orhan Y, Sencer E, Molvalilar S. Clinical and laboratory evaluation of 40 patients with Sheehan’s syndrome. Isr J Med Sci. 1994;30(11):826-9.

9. De Groot LJ. Textbook of Endocrinology. 2nd Edition, Philadelphia, Pa: Saunders; 1989. pp. 431-2.

10. Kageyama Y, Hirose S, Terashi K, Nakayama S, Komatsuzaki O, Fukuda H. A case of postpartum hypopituitarism (Sheehan’s syndrome) associated with severe hyponatremia and congestive heart failure. Jpn J Med. 1988;27(3):337-41.

11. Shoji M, Kimura T, Ota K, Ohta M, Sato K, Yamamoto T, et al. Cortical laminar necrosis and central pontine myelinolysis in a patient with Sheehan syndrome and severe hyponatremia. Intern Med. 1996;35(5):427-31.

12. Umekawa T, Yoshida T, Sakane N, Kondo M. A case of Sheehan’s syndrome with delirium. Psychiatry Clin Neurosci. 1996;50(6):327-30.

13. Boulanger E, Pagniez D, Roueff S, Binaut R, Valat AS, Provost N, et al. Sheehan syndrome presenting as early post-partum hyponatraemia. Nephrol Dial Transplant.

1999;14(11):2714-5.

14. Bayram F, Ünlühızarcı K, Keleştimur F. A retrospective investigation of the patients with Sheehan’s syndrome seen in Erciyes University Medical School Hospital during the last 7 years. Tur JEM. 1996;6(3):279-91.

15. Bakiri F, Bendib SE, Maoui R, Bendib A, Benmiloud M. The sella turcica in Sheehan’s syndrome: computerized tomographic study in 54 patients. J Endocrinol Invest.

1991;14(3):193-6.

5. Aron DC, Finding JW, Tyrell BJ. Hypothalamus and pituitary. In: Greenspan FS, Strewler GJ (Eds.). Basic and 16. Sherif IH, Vanderley CM, Beshyah S, Bosairi S. Sella size Clinical Endocrinology. 5th Edition, Stanford CT, USA: and contents in Sheehan’s syndrome. Clin Endocrinol (Oxf). 1989;30(6):613-8.

Appleton & Lange; 1997. pp. 95-156.

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...Cont'd from page 468 174. Salmon E, Sadzot B, Maquet P, Degueldre C, Lemaire C, Rigo P, et al. Differential diagnosis of Alzheimer's disease with PET. J Nucl Med. 1994;35(3):391-8.

175. Kwa VI, Weinstein HC, Posthumus Meyjes EF, van Royen EA, Bour LJ, et al. Spectral analysis of the EEG and 99m-Tc-HMPAO SPECT-scan in Alzheimer's disease. Biol Psychiatry. 1993;33(2):100-7.

176. Brenner RP, Ulrich RF, Spiker DG, Sclabassi RJ, Reynolds CF 3rd, Marin RS, Boller F. Computerized EEG spectral analysis in elderly normal, demented and depressed

subjects.

Electroencephalogr 1986;64(6):483-92.

Clin

Neurophysiol.

177. Coben LA, Danziger WL, Berg L. Frequency analysis of the resting awake EEG in mild senile dementia of Alzheimer type. Electroencephalogr Clin Neurophysiol.

1983;55(4):372-80.

178. Prichep LS, John ER, Ferris SH, Reisberg B, Almas M, Alper K, et al. Quantitative EEG correlates of cognitive deterioration in the elderly. Neurobiol Aging. 1994;15(1):8590. Erratum in: Neurobiol Aging 1994;15(3):391.

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OBSTETRICS AND GYNECOLOGY

An Unusual Case of Uterine Anomaly, Surgically Corrected with a Fruitful Pregnancy At Last SUMITRA YADAV*, ANITA SINGH†, NIYATI JAIN‡

ABSTRACT Fusion anomalies of uterus results in a variety of uterine shapes which cause increased incidence of miscarriage, poor fetal growth, malpresentation and abnormal placental adherence in such cases. Prevalence of uterine anomalies in general population is 7-8%. We are presenting a case report of a 20-year-old P0 patient who presented with acute abdomen. Ultrasonography revealed a hemorrhagic cyst. On laparotomy, it was found to be unicornuate uterus with hematometra in the noncommunicating arm.

She was subjected to surgical correction which led to a bicornuate uterus and thereafter she was conceive twice successfully.

Keywords: Fusion anomalies of uterus, unicornuate uterus, bicornuate uterus, hematometra, surgical correction

F

usion anomalies of the uterus results in a variety of uterine shapes which cause increased incidence of miscarriage, poor fetal growth, malpresentation and abnormal placental adherence in such cases.1-3 Prevalence of uterine anomalies in general population is 7-8%. Now, because of better availability of diagnostic modalities like transvaginal sonography, hysterosalpingography and laparoscopy, better detection of such anomalies is possible.4 Reproductive outcomes can be improved with early diagnosis and proper surgical correction. We are reporting a case of unicornuate uterus with a noncommunicating horn which after surgical correction became a bicornuate and resulted in successful pregnancy outcome.

CASE REPORT A 20-year-old married female was admitted with acute abdominal pain and vomiting for 1 day in MY Hospital, Indore on May 2008. As per patient, her menses lasted for 1 day only. Her ultrasonography (USG) showed a cyst of size 7.47 × 4.17 cm in right adnexal region with internal echo and absent right-sided kidney. Color

*Associate Professor †Senior Resident ‡3rd Year PG Student MY Hospital and MGM Medical College, Indore, Madhya Pradesh Address for correspondence Dr Sumitra Yadav 30, Nayapura, Aerodrome Road, Indore, Madhya Pradesh - 452 005 E-mail: drsumitrayadav@yahoo.co.in

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Doppler showed acute hemorrhage in right ovary.

Emergency laparotomy was done. Intraoperatively, there was a globular swelling on left side, which was connected to uterus (Figs. 1 and 2). Uterus was small of about 4 × 3 cm with tubes and ovary on right side only. So, it was diagnosed to be a unicornuate uterus having noncommunicating horn with hematometra (Fig. 3). Hematometra was drained and the unicornuate uterus surgically corrected to a bicornuate uterus by modified Strassman’s method. Her cervical os was pin-pointed and dilation was done. On follow-up, her menstrual history showed that her cycles now lasted for 5-6 days with good flow as compared to previous scanty menses. Hysterosalpingography showed bicornuate uterus with 2 separate cavities.

Cervix was common and seen in continuation of right horn with patent fallopian tube.

Figure 1. Globular swelling on left side.

OBSTETRICS AND GYNECOLOGY delivered. She conceived second time after 1 year and a male baby of 2.26 kg with maturity of around 36 weeks was delivered through emergency LSCS and this time tubectomy was also done.

DISCUSSION Developmental failure of one mullerian duct while the other develops normally results in unicornuate uterus5 and accounts for approximately 20% of mullerian duct anomalies. A unicornuate uterus may be isolated, manifested in 35% patients, although it is usually associated with variable degree of a rudimentary horn.

A rudimentary horn without endometrium is seen in 33% of cases and that with endometrium is seen in 32%. A rudimentary horn is designated communicating if there is communication with the endometrium of contralateral horn (10%) and noncommunicating, if there is no such communication (22%).

Figure 2. Globular swelling connecting to uterus.

CONCLUSION Various studies show that it is better to remove rudimentary horn with hematometra.6 In this case report, an experimental surgery has been done in which rudimentary horn with hematometra after drainage was joined with a small uterus that resulted in a fruitful pregnancy.

REFERENCES Figure 3. Unicornuate uterus having noncommunicating

horn.

1. Propst AM, Hill JA 3rd. Anatomic factors associated with recurrent pregnancy loss. Semin Reprod Med. 2000;18(4):341-50.

2. Patton PE, Novy MJ. Reproductive potential of the anomalous uterus. Semin Reprod Endocrinol. 1988;6: 217-33.

Outcome She conceived after 1½ years and her last menstrual period was 20th October 2009 with expected delivery date 27th July 2010. She was admitted at 32 weeks with complaint of backache. She was kept on tocolytics and given decadron. After 1 month of ward admission, she had pain in lower abdomen and persistent tachycardia.

She finally landed up in emergency lower segment cesarean section (LSCS) on 20th June 2010. A female baby of 1.5 kg with maturity around 35 weeks was

3. Heinonen PK. Unicornuate uterus and rudimentary horn.

Fertil Steril. 1997;68(2):224-30.

4. Carrington BM, Hricak H, Nuruddin RN, Secaf E, Laros RK Jr, Hill EC. Müllerian duct anomalies: MR imaging evaluation. Radiology. 1990;176(3):715-20.

5. Buttram VC Jr, Gibbons WE. Müllerian anomalies: a proposed classification. (An analysis of 144 cases). Fertil Steril. 1979;32(1):40-6.

6. Rock John A, Jones Howard W III. TeLinde’s Operative Gynaecology. 10th Edition, 575 (Andrews and Johnes).

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473

MEDILAW

Consent for Diagnostic Procedure cannot be Extended to Therapeutic Procedure

My GP referred me to a gynaecologist, who did a hysterectomy, even though I had given my consent only for a diagnostic laparoscopy.

Proceed Consent given for a diagnostic procedure cannot be extended to a therapeutic procedure in the absence of an emergency.

Lesson: In the landmark Samira Kohli vs Dr Prabha Manchanda & Anr on 16 January, 2008 Appeal (civil) 1949 of 2004, the Supreme Court of India held “19. …in Medical Law, where a surgeon is consulted by a patient, and consent of the patient is taken for diagnostic procedure/ surgery, such consent cannot be considered as authorisation or permission to perform therapeutic surgery either conservative or radical (except in life-threatening or emergent situations). Similarly, where the consent by the patient is for a particular operative surgery, it cannot be treated as consent for an unauthorised additional procedure involving removal of an organ, only on the ground that such removal is beneficial to the patient or is likely to prevent some danger developing in future, where there is no imminent danger to the life or health of the patient.”

who got her discharged against medical advice and without clearing the bill.

CASE SUMMARY ÂÂ

May 9, 1995: The patient ‘X’, an unmarried woman aged 44 years, consulted Dr ‘A’ complaining of prolonged menstrual bleeding for 9 days. An ultrasound was done and after examining the report, patient was advised to come back the next day for laparoscopy to make an affirmative diagnosis.

ÂÂ

May 10, 1995: Patient was admitted to the clinic and laparoscopy was done under general anaesthesia.

While the patient was still in the OT and under anaesthesia, consent for hysterectomy was taken from the mother. Abdominal hysterectomy and bilateral salpingo-oophorectomy was done by Dr ‘A’.

ÂÂ

May 15, 1995: Patient left the clinic without settling the bill.

ÂÂ

May 23, 1995: Dr ‘A’ filed a complaint with the Police alleging threat from the patient’s friend,

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ÂÂ

May 31, 1995: Patient filed a complaint against the doctor alleging negligence and unauthorised removal of her reproductive organs.

ÂÂ

June 6, 1995: A legal notice was issued by the doctor to the patient demanding Rs. 39,325/- as fees.

ÂÂ

January 19, 1996: Patient filed a complaint before the National Consumer Disputes Redressal Commission (NCDRC) claiming compensation of Rs. 25 lakhs from Dr ‘A’ alleging negligence and that removal of her uterus and both ovaries was “unlawful, unauthorised and unwarranted”. “She claimed compensation “for loss of reproductive organs, loss of opportunity to become a mother, diminished matrimonial prospects, loss of vital body organs, irreversible body damage as well as for pain and emotional trauma.”

MEDILAW ÂÂ

November 19, 2003: NCDRC dismissed the complaint and decided in favor of the doctor. The Commission held that “the patient had voluntarily gone to the clinic for treatment … the hysterectomy had been done with adequate care and caution and the surgical removal of uterus, ovaries etc. was necessitated as the appellant was found to be suffering from endometriosis (Grade IV), and if they had not been removed, there was likelihood of the lesion extending to the intestines and bladder and damaging them.”

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Patient filed an appeal in the Supreme Court against this decision of the NCDRC.

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January 11, 2008: The Supreme Court delivered judgement in favour of the patient.

procedure will not be valid for conducting some other treatment procedure... The only exception to this rule is where the additional procedure though unauthorised, is necessary in order to save the life or preserve the health of the patient and it would be unreasonable to delay such unauthorised procedure until patient regains consciousness and takes a decision.

(iv) There can be a common consent for diagnostic and operative procedures where they are contemplated. There can also be a common consent for a particular surgical procedure and an additional or further procedure that may become necessary during the course of surgery.

(v) The nature and extent of information to be furnished by the doctor to the patient to secure the consent need not be of the stringent and high degree … but should be of the extent which is accepted as normal and proper by a body of medical men skilled and experienced in the particular field...”

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The legal notice issued by Dr ‘A’, wherein the patient had been asked to pay a sum of Rs. 39,325/- towards the bill amount “also makes it clear that the appellant was not admitted for conducting hysterectomy or bilateral salpingo-oophorectomy, but only for diagnostic purposes.” The Court also pointed out an erroneous statement in the notice, which said that the video recording of the procedure was shown to the mother and both the patient and her mother were informed that because of the extensive lesion, which became evident only after diagnostic laparoscopy, “more extensive surgery was preferable”. “When the laparoscopy and video recording was made, the appellant was already unconscious. Before she regained consciousness, AH-BSO was performed removing her uterus and ovaries.” So, the statement in the legal notice was factually incorrect.

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“40. The consent form shows that the appellant gave consent only for diagnostic operative laparoscopy, and laparotomy if needed... It does not amount to consent for AH-BSO surgery removing the uterus and ovaries/fallopian tubes.

If the appellant had consented for AH-BSO then the consent form would have given consent for “diagnostic and operative laparoscopy. Laparotomy, hysterectomy and bilateral salpingo-oophorectomy, if needed.”

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Dr ‘A’ submitted that the consent given by the mother for the additional procedure should be regarded as a valid consent. In response, the Court said: “The appellant was neither a minor, nor mentally challenged, nor incapacitated. When a patient is a competent adult, there is no question of someone else giving consent on her behalf. There was no medical

SOME SALIENT COURT OBSERVATIONS ÂÂ

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“14. Consent in the context of a doctor-patient relationship, means the grant of permission by the patient for an act to be carried out by the doctor, such as a diagnostic, surgical or therapeutic procedure. Consent can be implied in some circumstances from the action of the patient. Except where consent can be clearly and obviously implied, there should be express consent.

There is, however, a significant difference in the nature of express consent of the patient, known as ‘real consent’ in UK and as ‘informed consent’ in America...”

The Court also summarised the principles relating to consent.

“32. (i) A doctor has to seek and secure the consent of the patient before commencing a ‘treatment’ (the term ‘treatment’ includes surgery also). The consent so obtained should be real and valid, which means that: the patient should have the capacity and competence to consent; his consent should be voluntary; and his consent should be on the basis of adequate information concerning the nature of the treatment procedure, so that he knows what is consenting to.

(ii) The ‘adequate information’ to be furnished by the doctor (or a member of his team) who treats the patient, should enable the patient to make a balanced judgement as to whether he should submit himself to the particular treatment as to whether he should submit himself to the particular treatment or not. This means that the Doctor should disclose (a) nature and procedure of the treatment and its purpose, benefits and effect; (b) alternatives if any available; (c) an outline of the substantial risks; and (d) adverse consequences of refusing treatment... (iii) Consent given only for a diagnostic procedure, cannot be considered as consent for therapeutic treatment. Consent given for a specific treatment

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MEDILAW emergency during surgery… The respondent ought to have waited till the appellant regained consciousness, discussed the result of the laparoscopic examination and then taken her consent for the removal of her uterus and ovaries. In the absence of an emergency and as the matter was still at the stage of diagnosis, the question of taking her mother’s consent for radical surgery did not arise. Therefore, such consent by mother cannot be treated as valid or real consent…Further a consent for hysterectomy, is not a consent for bilateral salpingooophorectomy.” ÂÂ

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“48. We find that the Commission has, without any legal basis, concluded that “the informed choice has to be left to the operating surgeon depending on his/her discretion, after assessing the damage to the internal organs, but subject to his/her exercising care and caution”. It also erred in construing the words “such medical treatment as is considered necessary for me for__.” in the consent form as including surgical treatment by way of removal or uterus and ovaries.”

A diagnosis of endometriosis was made after diagnostic laparoscopy, which is managed either conservatively or by hysterectomy depending on the patient’s age and stage of the disease. The Court observed: “52… worldwide studies show that most hysterectomies are conducted unnecessarily by Gynaecologists demonstrates that it is considered as a favoured treatment procedure among medical fraternity, offering a permanent cure. Therefore respondent cannot be held to be negligent, merely because she chose to perform radical surgery in preference to conservative treatment. This finding however has no bearing on the issue of consent which has been held against the respondent. The correctness or appropriateness of the

treatment procedure, does not make the treatment legal, in the absence of consent for the treatment.” ÂÂ

“54. In view of our finding that there was no consent by the appellant for performing hysterectomy and salpingooophorectomy, performance of such surgery was an unauthorised invasion and interference with appellant’s body which amounted to a tortious act of assault and battery and therefore a deficiency in service... This is a case of respondent acting in excess of consent but in good faith and for the benefit of the appellant… On the facts and circumstances, we consider that interests of justice would be served if the respondent is denied the entire fee charged for the surgery and in addition, directed to pay Rs. 25,000 as compensation for the unauthorised AHBSO surgery to the appellant.”

FINAL JUDGEMENT The Supreme Court cancelled the NCDRC order and partly allowed the patient’s claim for compensation as follows: “If the respondent has already received the bill amount or any part thereof from the appellant (either by executing the decree said to have been obtained by her or otherwise), the respondent shall refund the same to the appellant with interest at the rate of 10% per annum from the date of payment till the date of re-payment. The Respondent shall pay to the appellant a sum of Rs. 25,000/as compensation with interest thereon at the rate of 10% per annum from 19.11.2003 (the date of the order of Commission) till date of payment. The appellant will also be entitled to costs of Rs. 5,000 from the respondent.”

REFERENCE

1. Samira Kohli vs Dr. Prabha Manchanda & Anr on 16 January, 2008 Appeal (civil) 1949 of 2004.

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CONFERENCE PROCEEDINGS

ADA-PAMS: Clinical Update in Diabetes-2017 MANAGEMENT OF THYROID DISORDERS IN PREGNANCY

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What was humanity’s original, natural diet?

Analyzing the available “knowledge,” scientific/ religious/cultural/empirical/diet book/infomercials or I-know-best secret tips from health magazines data, I feel at best we can make an educated guess about what our ancestors ate.

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What is perfect “diet”? There have been arguments for eating exclusively organic, vegetarian, raw, Paleo, low-fat, low-carb foods, etc. Such arguments, scientific or otherwise, raise the following questions: How can one particular diet be good for the entire world? How to decide that eating a particular plan is the best? Is there a one-size-fits-all diet? We are still groping in semi darkness for the right answer for these questions.

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SURTHRIVAL: Our bodies need different diets and foods at different stages of our lives. The main purpose of food was for survival of the species but in evolutionary context it is required to thrive as a species. Survival + Thrive = SURTHRIVAL.

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When we look at what we eat from an ecological point, there are important differences between diets like environmental damage, animal cruelty, scientific issues - the amount of fat, complex carbohydrate and protein for optimal health and longevity.

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The perpetual debaters can be divided into two main camps: Paleo and Vegan.

Dr Subramanian Kannan, Bengaluru ÂÂ

Associations between overt hypothyroidism and materno-fetal outcomes: Pre-eclampsia and gestational hypertension; placental abruption; nonreassuring fetal heart rate tracing; preterm delivery, including very preterm delivery (before 32 weeks); low birth weight; increased rate of cesarean section; perinatal morbidity and mortality; postpartum hemorrhage.

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Serum TSH reference range determinations should take into account iodine intake, TPO positivity and according to some studies, BMI.

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Analysis of TSH and free T4 “set point” in pregnant women showed that reductions in free T4 were observed only when serum TSH was >4.8 mU/L.

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Algorithm of management: Patients with subclinical hypothyroidism (SCH),

at any period of gestation: Treat as per guidelines, with L-thyroxine. Do not consider MTP.

Patients with overt hypothyroidism (OH), beyond

20 weeks gestation: Treat as per guidelines, with L-thyroxine. Do not consider MTP.

Patients with OH, below 20 weeks gestation:

Treat as per guidelines, with L-thyroxine. If conception has occurred without difficulty, and OH is severe, take a final decision after discussing all aspects with the patient. MTP cannot be recommended at present unless there is a request from the patient.

Paleo (or “caveman”) diet - consume foods that

our hunter-gatherer ancestors ate: meat, fish, eggs, vegetables, and fruit. Grains, legumes, sugars, processed foods and most dairy products are forbidden.

Vegan diet - vegetables, fruits, grains, nuts and

NEO PALEO DIET – GIMMICK OR (HOLY) GRAIL: BALANCED VIEW Dr MA Shekar, Bengaluru ÂÂ

“Paleolithic diet” is about foods consumed by our ancestors, who lived from around 7,50,000 years ago up until 10,000 years ago, “the hunter-gatherer Caveman” of Paleolithic era.

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“Neo Paleolithic diet” is a current day lifestyle based on dietary and exercise lessons from our Paleolithic ancestors, but using successful ethnographic and anthropological studies and research data.

seeds—and prohibits anything that comes from an animal.

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The foundational principles of both diets—Real whole, fresh food in its natural state, free of processed ingredients, refined carbohydrates and additives—are the same. Both Paleo and Vegan diet can provide health benefits.

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PEGAN diet: The best parts of both diets distilled into one diet. Essentially, it’s a Paleo, which includes more vegetables, but unlike the Vegan diet, animal products are included. The ratio of

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CONFERENCE PROCEEDINGS animal products to vegetable products may vary from 75:25 to 60:40. ÂÂ

A simple, pragmatic way of understanding diet for surthrival is to address three questions: When to eat? What to eat? How much to eat?

The answer to each question is based on geographic, seasonal, ethnic, region-specificity of people and foods.

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There are more questions than answers when we try to discuss diet but I am impressed by this quote: “Science compared every Diet and the Winner is Real whole, fresh Food.”

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HCQ inhibits insulin degradation.

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Anti-inflammatory action of HCQ: Inhibits cytokine production - Reduces C-reactive protein (CRP) levels; inhibits prostaglandin synthesis; inhibits leukocyte activation and migration.

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HCQ improves insulin sensitivity and plasma adiponectin levels.

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HCQ: Treatment of T2DM–HCQ decreases HbA1c levels; HCQ improves glucose tolerance and LDL-C levels; insulin sparing effect - Daily insulin dose had to be reduced by an average of 30% when patients were under insulin with HCQ therapy; it is effective in controlling fasting blood sugar (FBS), postprandial blood sugar (PPBS) and HbA1c.

It reduces total cholesterol (TC), LDL-C and triglycerides; HCQ doesn’t cause hypoglycemia and has good tolerability.

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Cardiovascular protection: Effective in reducing the risk of incident CVD in rheumatoid arthritis patients; patients with dyslipidemia when treated with FDC of atorvastatin and HCQ showed reduction in TC, LDL-C and non–high-density lipoprotein cholesterol (non–HDL-C); oral HCQ is effective in reducing postoperative deep venous thrombosis in legs.

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HCQ is contraindicated during hypersensitivity, retinopathy, pregnancy and long-term therapy in children.

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Retinopathy is very uncommon, if the recommended daily dose is not exceeded.

TRANSITION FROM INSULIN INFUSION TO S/C INSULIN Dr Anjali Bhatt, Pune When to do it?

Stable blood glucose levels <180 mg/dL for at least 4-6 hours with <2 U/hr. Resolution of acidosis in diabetic ketoacidosis (DKA). Hemodynamically stable without use of vasopressors. Stable nutrition plan.

Stable IV drip rates (low variability).

Transition may be challenging in High pre-admission HbA1c. High variability of blood glucose in the 24 hours preceding transition. Drip rate >2 U/hr. On corticosteroids.

How to do it with practical tips?

Step 1: Calculating the total daily dose (TDD) of insulin. Step 2: Determining the insulin to be used and distribution of the TDD. Step 3: Adjusting insulin regimen for maintenance.

INTRODUCTION TO INFLAMMATION AND DIABETES Dr SR Aravind, Bengaluru

Miscellaneous ÂÂ

Inflammation is the principal link for various diseases such as rheumatoid arthritis, prediabetes, diabetes and atherosclerosis.

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Inflammation is one of the environmental risk factors for diabetes.

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Prediabetes can be predicted by measuring adiponectin levels.

The Drug Controller General of India (DCGI) approved hydroxychloroquine (HCQ) as an adjunct to exercise and diet to improve glycemic control in patients with diabetes who are under SU and metformin combination (Dose 400 mg/d).

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Mechanisms linking inflammation and diabetes: Higher leukocyte counts precede and predict risk of T2DM and CVD; increased cytokines.

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Inflammation is associated with acquired insulin resistance and acquired b-cell dysfunction.

HCQ differs from chloroquine by the presence of a hydroxyl group at the end of the side chain. This makes it more suitable for chronic diseases.

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Key mechanisms regulating inflammation in diabetes: Hyperglycemia and elevated free fatty acids; glucotoxicity and lipotoxicity might also

Transition in stress hyperglycemia. Transition in patients still NPO. Transition in patient on tube feeding.

Giving IV and S/C insulin together.

ANTI-INFLAMMATORY APPROACHES IN DIABETES: FOCUS ON HYDROXYCHLOROQUINE Dr AG Unnikrishnan, Pune ÂÂ

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CONFERENCE PROCEEDINGS exert oxidative stress and endoplasmic reticulum stress; obesity is associated with alterations in gut microbiome; angiotensin II has been shown to induce expression of chemokine MCP-1 and IL-6, leading to impaired mitochondrial function and insulin secretion, as well as increased b-cell apoptosis.

CHANGING PARADIGMS IN T2DM – FROM PREVENTION TO TREATMENT OF PREDIABETES Dr Leigh Perreault, Colorado Diabetes risk calculator is a simple tool for detecting undiagnosed diabetes and prediabetes. Reversion to normal glucose regulation is associated with a significantly reduced risk of future diabetes.

Diabetes risk during Diabetes Prevention Program Outcomes Study (DPPOS) was 56% lower for participants who had returned to normal glucose regulation vs. those who consistently had prediabetes.

Achieving normal glucose regulation prevents diabetes over the long-term.

The Satiety and Clinical Adiposity—Liraglutide Evidence in Nondiabetic and Diabetic Individuals (SCALE) study revealed that once-daily subcutaneous liraglutide, as an adjunctive therapy to diet and exercise, was associated with clinically meaningful weight loss in overweight or obese patients, with reductions in glycemic variables and multiple cardiometabolic risk factors, as well as improvements in health-related quality-of-life.

Prevention of diabetes prevents composite microvascular disease. The Swedish Obese Subjects (SOS) study showed that bariatric surgery has a great impact on reduction of microvascular disease in prediabetes. Weight loss in prediabetes reduces longterm incidence of CV mortality.

CARDIOVASCULAR OUTCOME TRIALS – DIFFERENCES AMONG GLP-1 RAS Dr Leigh Perreault, Colorado ÂÂ

CVOTs in diabetes have revealed benefits of SGLT2i and some GLP-1 RAs on CVD. SGLT2i prevent CVD; GLP-1 RAs are safe and some may prevent CVD.

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Differences in CVD outcomes within the GLP-1 class may be a function of study population, trial design or duration.

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Nevertheless, structural differences between exendin-4-based vs. human recombinant

GLP-1 RAs yield differences in A1c reduction, body weight and BP. ÂÂ

Additional pleiotropic differences are likely to be discovered.

THE HEART FAILURE STORY IN DIABETES Dr Allison Goldfine, Boston Diabetes and heart failure are highly coprevalent.

Diabetes contributes to disease progression in heart failure and is associated with worse prognosis.

Standard heart failure therapies should be instituted in heart failure patients with diabetes. The neprilysinangiotensin receptor inhibitor sacubitril/valsartan may improve glycemia in patients with T2DM and heart failure with reduced ejection fraction (HFrEF). There is an unmet need to optimize glucose-lowering and heart failure treatments in patients with diabetes.

CVOT trials showed that DPP-4i are safe to use in patients with T2DM and CVD/risk.

SGLT2i may be preferred for patients with T2DM and heart failure requiring glycemic intensification.

The EMPA-REG trial revealed that empagliflozin improves CV outcomes and death from any cause.

Canagliflozin reduces CV and heart failure events in T2DM. APPROACH TO HYPERTHYROIDISM Dr Pramila Kalra, Bengaluru Thyrotoxicosis is a clinical state that results from inappropriately high thyroid hormone action in tissues generally due to inappropriately high tissue thyroid hormone levels.

Hyperthyroidism is a form of thyrotoxicosis due to inappropriately high synthesis and secretion of thyroid hormone(s) by the thyroid. It could be a potential etiology of many of the complaints with which the patients present to different departments. The patients can present with weight loss, tremors, palpitations, eye symptoms like proptosis and redness. They can also present with atrial fibrillation, congestive heart failure, tremors, hepatitis and hyperglycemia. Females can also present with infertility and menstrual irregularities.

All patients with known or suspected hyperthyroidism should undergo a comprehensive physical examination, including measurement of pulse rate, BP, respiratory rate and body weight. Also, thyroid size; presence or absence of thyroid tenderness, symmetry and nodularity; pulmonary, cardiac and neuromuscular

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CONFERENCE PROCEEDINGS function and presence or absence of peripheral edema, eye signs or pretibial myxedema should be assessed.

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Interruption of glucagon action leads to a-cell proliferation and hyperplasia.

Early recognition in children and adolescents is very important to optimize growth and development.

The presentation in old age can be with apathetic hyperthyroidism.

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Lowering glucagon is beneficial (GLP-1 RA and DPP-4i).

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Some agents work despite raising glucagon (SGLT2i).

The Tc-99m pertechnetate scan helps to differentiate between causes of thyrotoxicosis associated with increased uptake (e.g., Graves’ disease and toxic multinodular goiter) and decreased or absent uptake (e.g., thyroiditis and iatrogenic thyrotoxicosis). In patients with thyroid nodules, ultrasound imaging with Thyroid Imaging, Reporting and Data System (TIRADS) classification helps in deciding further management.

Fine-needle aspiration cytology (FNAC) should be done for suspicious nodules and cold nodules.

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Glucagon receptor antagonism lowers blood glucose in T2DM.

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New approaches for glucagon replacement: Bihormonal pumps and intranasal glucagon.

CONCENTRATED INSULINS: NICHE OR MAINSTREAM?

INITIAL COMBINATIONS WITH OAHS: TIME TO LOWER THE BAR? Dr Allison Goldfine, Boston ÂÂ

T2DM is a complex and progressive disease.

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Combination therapy is commonly required.

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Currently, the treatment paradigm is “treat until fail” then up-titrate therapies. There may be advantages to early combination approaches to multiple components that contribute to disease.

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Combinations have some therapeutic advantages: Lower doses of drugs with greater efficacy than higher dose monotherapy; lower doses of drugs in FDCs reduce risk of adverse events that are more likely to occur with higher doses of monotherapy; reduced numbers of pills/medications permitting simplified dosing regimens, improving adherence and it improves 23% when switching from loose to combination FDC; FDCs may be less costly than free combinations of the agents.

Dr Vijay Negalur, Thane ÂÂ

Concentrated insulin is entering the mainstream in diabetes therapy.

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Insulin pens have eliminated many dosing challenges for patients.

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U500 regular: lower volume, BID/TID provides basal effect.

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U300 glargine: longer-acting, flatter, but less potent.

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U200: degludec and lispro interchangeable with U100.

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These insulins offer additional features that will benefit our patients. Switching from one basal insulin to another requires attention to the type of insulin being used.

GLUCAGON AND THE α-CELL – MORE IMPORTANT IN DIABETES THAN WE THOUGHT? Dr Alvin C Powers, Nashville, USA ÂÂ

480

Glucagon: Sensitively and rapidly stimulates hepatic glucose production; impacts glucose uptake by the liver; contributes to postprandial hyperglycemia and glycogen storage; critical contributor to increased glucose production in exercise, infection and fasting; first-line of defense against hypoglycemia; lost in type 1 diabetes; relative or absolute glucagon excess contributes to the metabolic phenotype of type 1 and type 2 diabetes.

Indian Journal of Clinical Practice, Vol. 28, No. 5, October 2017

THE EMR AND MOBILE APPS: DO THEY MAKE A DIFFERENCE? Dr Jothydev Kesavadev, Kerala New generation electronic medical records (EMR) and interactive mobile apps are generating a wave of excitement in diabetes care and research.

Diabetes care fails in the majority primarily because of nonadherence to medications, lifestyle advices and physician visits. Coaching and 24x7 live interactive chats via mobile apps enhances confidence and continuous education.

Bot-enabled customized diet advices, glycemic patterns, remote intervention alerts, etc., will soon become a reality. friendly, customizable apps are designed owning an ordinary smartphone.

analysis of on red flag Cheap, user for anybody

CONFERENCE PROCEEDINGS SGLT2i VS. GLP-1 RA – WHICH SHOULD BE EARLIER IN CARE? FOR GLP-1 RA Dr Vageesh Ayyar, Bengaluru ÂÂ

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Characteristics of an ideal antidiabetic agent: Control fasting and postprandial hyperglycemia; should not produce hypoglycemia; should be effective in once a day dosing or less frequent dosing; should not produce hyperinsulinemia and/or weight gain; should not interact with other drugs; should reduce CV risk; should address pathophysiology; pleotrophism.

Dulaglutide AWARD program: HbA1c reduction noted across all the AWARD trials (AWARD 1, 2, 3, 4, 5 and 6) at primary endpoint.

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LEAD trials: Liraglutide reduces both FPG and PPG.

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Liraglutide reduces visceral body fat.

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Liraglutide, in combination with metformin, presents a low risk of hypoglycemia.

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When glucose levels approach normal values, insulin levels decrease. When glucose levels approach normal values, glucagon levels rebound.

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GLP-1 analogs enhance glucagon secretion in hypoglycemic conditions.

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LEAD 4 trial: Significant increases in C-peptide and homeostasis model assessment (HOMA) of b-cell function and significant decreases in the proinsulin-to-insulin ratio occurred with liraglutide vs. placebo.

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Liraglutide had lower rates of CV events and death from any cause compared to placebo.

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Both the classes are likely similar in efficacy, lowering A1c by ~1-1.5%.

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The HbA1c reduction, weight reduction and reduction in hypoglycemia is similar for the two classes.

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When it comes to reduction in SBP, SGLT2i score over GLP-1 RA.

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A multicenter, double-blind, placebo-controlled trial revealed a higher rate of retinopathy events with liraglutide than with placebo.

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In terms of prevention of micro- and macrovascular complications, SGLT2i score over GLP-1 RA.

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Canagliflozin, was found to be a cost-effective treatment vs. liraglutide for patients inadequately controlled with metformin monotherapy.

Canagliflozin represented good value for money compared to GLP-1 RA.

INTERPRETATION OF THYROID FUNCTION TESTS Dr KM Prasanna Kumar, Bengaluru ÂÂ

TSH is a good screening test to assess thyroid function in an outpatient setting. If TSH is abnormal, the diagnosis is confirmed with thyroid hormone levels.

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Screening for thyroid diseases, especially those at high risk, is cost-effective as up to 20% of those with subclinical thyroid disease may turn to clinical thyroid disease.

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Timing and choosing the right thyroid test is the best approach in understanding the meaning of the results.

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Screening with TSH alone has best results in healthy individuals – Use with free T4 levels in patients with other illnesses, suspected central hypothyroidism, changing thyroid status.

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Interpretation of abnormal TSH always in relation to FT4 and clinical status.

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Watch out for routine spoilers like drugs, pregnancy.

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Close liaison with biochemists and laboratory technicians.

SGLT2i VS. GLP-1 RA – WHICH SHOULD BE EARLIER IN CARE? FOR SGLT2i Dr Samit Ghosal, Kolkata ÂÂ

We treat T2DM to: Target HbA1c + No weight gain (preferably weight loss) + No hypoglycemia + Reduction in SBP + Prevent or retard microvascular complications +

SGLT2i VS. GLP-1 RA – WHICH SHOULD BE EARLIER IN CARE? BALANCED Dr JJ Mukherjee, Kolkata

Prevent or retard macrovascular complications. ÂÂ

Selection of treatment for T2DM should be patient specific.

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Currently, there are no head-to-head studies evaluating GLP-1 RA vs. SGLT2i.

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Before initiation of treatment, one should consider the patient preferences, cost-effectiveness, required HbA1c reduction to achieve goal, potential adverse effects and comorbid medication conditions.

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CONFERENCE PROCEEDINGS ÂÂ

Selection of class of drugs for treatment of T2DM should be patient specific.

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Both SGLT2i and GLP-1 RA are effective secondline treatments, exhibit positive effects on body weight changes and are associated with minimal risk of hypoglycemia.

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No head-to-head clinical studies on evaluating GLP-1 RA vs. SGLT2i are available.

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SGLT2i match with GLP-1 RAs for HbA1c reduction and weight loss in patients with diabetes.

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SGLT2i are preferable for achieving reduction in systolic BP compared to GLP-1 RAs.

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SGLT2i are favored over GLP-1 RAs in reduction of micro- and macrovascular complications.

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In real world practice, interest in the combination of GLP-1 RA and SGLT2i therapy is high because, they are cardioprotective and probably work via different mechanisms of action.

INDIAN CIRCADIAN GLUCOSE PATTERNS ARE DIFFERENT

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MANAGEMENT OF THYROID ASSOCIATED OPHTHALMOPATHY Dr Rajesh Rajput, Rohtak ÂÂ

Natural history of thyroid associated ophthalmopathy (TAO): Mild to moderate disease – spontaneous improvement in 30%; complete normalization is less likely in view of permanent structural changes.

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TAO – General treatment objectives: Target modifiable risk factors, especially smoking; restoration and maintenance of euthyroidism; assess need for treatment of ophthalmopathy; decide on the mode of treatment; Goals – Symptom relief; Correction of anatomical, functional and cosmetic impairments.

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Predictors of worsening TAO after radioiodine: Pretreatment biochemical severity of hyperthyroidism (T3 >5 nmol/L); post-treatment TSH levels (delayed treatment of hypothyroidism); preexisting active eye disease; smoking; high TBII levels.

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Radioiodine is not associated with deterioration of Graves’ ophthalmopathy (GO) in patients with minimally active eye disease when postradioiodine hypothyroidism is prevented.

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Choice of treatment based on eye status

Dr G Vijaya Kumar, Chennai ÂÂ

Circadian rhythms can influence: Sleep-wake cycles; hormone release; body temperature; other important bodily functions.

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Abnormal circadian rhythms have also been associated with diabetes, obesity, depression, bipolar disorder, etc.

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Different body functions rise and fall over a 24-hour period based on Circadian rhythms.

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T2DM may develop because of disturbance of Circadian rhythms due to – shift work, sleep loss, nocturnal lifestyle.

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Asian Indian diabetics are different as compared to other ethnicities – Epigenetic factors (Thrifty Gene); higher glycemic response; younger age of onset; diabetogenic diet; high insulin resistance; high PPG throughout HbA1c range.

The Asian Indian diet is typically high in carbohydrates.

Pathological DP – If the body doesn’t produce enough insulin, blood sugar levels can rise. This may cause high blood sugar in the morning (before eating).

Ocular involvement

Degree of activity

Treatment

Nonsevere

Active

Supportive measures

Nonsevere

Inactive

Supportive measures

Severe

Active

High-dose glucocorticoids Orbital radiotherapy Orbital decompression

Severe

Inactive

Orbital decompression Eye muscle surgery Eyelid surgery

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Nonsevere ophthalmopathy management

Sign/symptom

Therapeutic measures

Photophobia

Sunglasses Artificial tears and ointments

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Dawn phenomenon (DP) – normal rise in blood sugar as a person’s body prepares to wake up.

Foreign body sensation Eyelid retraction; increased intraocular pressure

Beta blocking eye drops

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Physiological DP – In the early morning hours, hormones cause the liver to release large amounts of sugar into the bloodstream. For most people, the body produces insulin to control the rise in blood sugar.

Lagophthalmos

Nocturnal taping of the eyes

Mild diplopia

Prisms

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Management of severe thyroid ophthalmopathy – established treatment: Glucocorticoids; orbital irradiation; rehabilitative surgery.

CONFERENCE PROCEEDINGS

53rd Annual Meeting of the European Association for the Study of Diabetes (EASD 2017) but the choice for a second-line drug is less clear. Thiazolidinediones or Sulfonylureas and Cardiovascular Accidents. Intervention Trial (TOSCA.IT) was a multicenter, randomized, pragmatic clinical trial that compared the longterm effects of pioglitazone vs. sulfonylureas, given in addition to metformin, on cardiovascular events in patients with T2DM.

THE IMPACT OF INTENSIFIED MULTIFACTORIAL INTERVENTION IN T2DM AND MICROALBUMINURIA PATIENT ON RISK OF HEART FAILURE Congestive heart failure is a common, fatal and often forgotten complication of T2DM. The aetiology of heart failure in diabetic patient is multifactorial and can be classified into primary (metabolic/diabetic) and secondary (ischemic).

In Steno-2 study, multifactorial intensified intervention for 7.8 years in patients with T2DM and microalbuminuria reduced the risk of atherosclerotic CVD. This study analyzed the impact of intensified multifactorial intervention on risk of heart failure with 21.9 years of follow-up in T2DM patients with microalbuminuria. The study included 160 T2DM patients with microalbuminuria and were randomized into conventional or intensified, multifactorial target driven interventions which involve both behavioral and pharmacological approaches including RAS-inhibition.

After 7.8 years, study continued as an observational follow-up study and all patients were recommended treatment similar to intensive therapy group. Heart failure hospitalization was recorded, log-rank test was used to compare event rates and Cox regression adjusted for age and sex analyzed time to event.

Total 10 intensive therapy patients vs. 19 patients from conventional therapy were hospitalized for heart failure. The unadjusted hazard ratio was 0.39 (0.18-0.84, p = 0.017) in the intensive group compared to conventional group. While, the HR adjusted for age and sex was 0.37 (0.17-0.81, p = 0.013) and death in the end point kept signal stable with HR 0.50 (0.33-0.75, p = 0.001). The coexisting atherosclerotic coronary disease was more frequent in conventional group as compared to intensified group. The intensified multifactorial intervention in T2DM and microalbuminuria patients reduced the risk of hospitalization for heart failure and importantly decreased secondary (ischemic) heart failure.

COMPARATIVE BENEFITS OF ADD-ON PIOGLITAZONE AND SULFONYLUREA WITH METFORMIN IN T2DM: THE TOSCA.IT STUDY ÂÂ

Currently metformin is the recommended firstline drug for glycemic control in type 2 diabetes,

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This study included 3,028 T2DM patients aged from 50-75 years, inadequately controlled with metformin monotherapy (2-3 g/day) between Sep 18, 2008 and Jan 15, 2014. The patients were stratified in two groups to add-on pioglitazone (n = 1,535; 15-45 mg) or a sulfonylurea (n = 1,493, 5-15 mg glibenclamide, 2-6 mg glimepiride or 30-120 mg gliclazide).

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The primary outcome assessed was a composite of first occurrence of all-cause death, nonfatal myocardial infarction, nonfatal stroke or urgent coronary revascularization, assessed in the modified intention-to-treat population.

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Pioglitazone does not decrease the all-cause or CVD death but provides CVD (atherosclerotic) benefits.

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Fewer patients had hypoglycemia in the pioglitazone group (148 [10%]) than in the sulfonylureas group (508 [34%], p < 0·0001).

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The primary outcome was achieved in 105 patients (1.5 per 100 person-years) in pioglitazone group and 108 (1.5 per 100 person-years) in sulfonylureas group (HR 0.96, 95% CI 0.74-1·26, p = 0.79).

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Both the group had moderate weight gain (<2 kg, on average) while, the rate of heart failure, bladder cancer and fractures were not significantly different between treatment groups.

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In TOSCA.IT study, the incidence of cardiovascular events was similar with sulfonylureas (mostly glimepiride and gliclazide) and pioglitazone as add-on treatments to metformin. These are easily available and cost-effective treatment; with respect to efficacy and adverse events pioglitazone was associated with fewer hypoglycemic events.

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CONFERENCE PROCEEDINGS HOSPITALIZATION FOR HEART FAILURE AND DEATH IN PATIENT WITH/WITHOUT PRIOR CVD IN NEW USERS OF SGLT2i: A CVD-REAL STUDY ÂÂ

T2DM patients with CVD on sodium glucose co-transporter 2 inhibitor (SGLT2i) have shown reduction in cardiovascular death and hospitalization for heart failure (HHF).

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This study used clinical practice data from 2012-2016 and compared HHF and death in patient with/without prior CVD or heart failure in new users of SGLT2i vs. other glucose-lowering drugs (oGLD).

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HHF and deaths were collected via medical records, medical claims, electronic health and death records, and national register; hazard ratio (HR) for HHF, death and the composite endpoint (HHF or death) was calculated as average.

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Overall, 306,156 patients with >150,000 person year (PY) (1,00,947 PY for SGLT2i; 89,208 PY for oGLD) and 950 new HHF events were analyzed.

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SGLT2i was associated with significant lower rates of HHF with/without prior CVD (HR 0.69;95% CI 0.59-0.80) compared with oGLD (HR 0.55, 95% CI 0.34-0.88).

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Similarly, death and composite endpoint was significantly lower for SGLT2i when compared to oGLD, irrespective of heart failure or CVD.

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SGLT2i was associated with significant reduction in HHF and death vs. oGLD in both with/without prior CVD or heart failure patients, which shows the beneficial effect of SGLT2i over broad range of patient population with T2DM.

systolic blood pressure and BMI at baseline and background therapy as covariate. ÂÂ

Time-to-next therapy - CANA’s (n = 1,143) time-tonext therapy was longer compared to GLP1-RA, DPP-4i.

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Adjusted hazard ratio (HRs, 95% CI) vs. CANA ranged from 1.43 (1.20-1.70) (sitagliptin; n = 17,777) and 1.76 (1.47-2.11) (saxagliptin; n = 4,531) for DPP4i (p < 0.001); from 1.43 (1.20, 1.71) (liraglutide, n = 4,933) and 1.84 (1.52, 2.23) (exenatide; n = 1,254) for GLP-1 RA (p < 0.001); and from 1.20 (1.00, 1.44) (p = 0.048, dapagliflozin; n = 5,821) and 1.20 (0.80, 1.81) (p = 0.38, empagliflozin; n= 317) for SGLT2i.

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CANA treatment had longer time on treatment before a change in therapy vs. other AHA, which reflects better effectiveness and/or tolerability.

ASSOCIATION OF INSULIN RESISTANCE AND IRON OVERLOAD IN T2DM PATIENT ÂÂ

Iron plays a significant role in physiological processes such as redox balance, inflammation, and mitochondrial respiratory metabolism; while alteration in iron homeostasis leads to insulin resistance and diabetes. The present study investigated the relationship and molecular mechanism between iron overload and IR in human skeletal muscle cells and muscle biopsies from patients with T2DM.

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The study analyzed iron metabolism, related protein levels such as tranferrin receptor 1 (TfR1), heavy chain ferritin (FTH), light chain ferritin (FTL) and divalent metal transporter 1 (DMT1).

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Treatment of human skeletal muscle with palmitate had increased level of TfR1 and FTH, while iron regulatory protein 1 was not increased.

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The muscle biopsies of T2DM patients showed increased level of TfR1, FTH, FTL and DMT1 in comparison to normal subjects.

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The intracellular labile iron pool increased in palmitate induced IR skeletal muscle cells.

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Knockdown of TfR1 using SiRNA in human skeletal muscle cells provided protection against palmitateinduced IR and also preserved intracellular iron pool.

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The treatment of iron (FeSo4 and FeCL3) in human skeletal muscle cells stimulated phospo-JNK and phosp-p38 and significantly induced mitochondrial dysfunction.

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The chemical iron chelator deferoxamine recovered

COMPARATIVE BENEFITS OF CANAGLIFLOZIN WITH OTHER HYPERGLYCEMIC AGENTS ÂÂ

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The retrospective data was used to analyze the pattern of change in therapy for patients with type 2 diabetes mellitus (T2DM) treated with the sodium glucose co-transport 2 inhibitor (SGLT2i) canagliflozin (CANA) vs. other hypoglycemic agents.

The study included T2DM patients from Clinical Practice Research Datalink (n = 46,349), who were initiated on glucagon-like peptide 1 receptor agonist (GLP1-RA), dipeptidyl peptidase-4 inhibitor (DPP-4i) or SGLT2i from the period 2012 to 2015.

Kaplan-Meier analysis and multivariate Cox proportional hazards regression was used to analyze time-to-next therapy, with age, sex, Hb1Ac,

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CONFERENCE PROCEEDINGS mitochondrial dysfunction and palmitate-induced IR in human skeletal muscle cells. ÂÂ

Iron overload in skeletal muscle cell induces mitochondrial dysfunction and IR through TfR1, similarly reducing the intracellular iron content protected against IR. Hence, the strategy is to block iron overload for preventing IR and diabetes.

APOJ: A NOVEL HEPATOKINE ÂÂ

The relationship of liver and skeletal muscle cells is vital for glucose homeostasis and the responsible factors are hepatokines, liver derived proteins which regulates glucose metabolism and insulin sensitivity in skeletal muscle. The study aimed to determine the physiological role of apolipoprotein J (ApoJ) in regulation of glucose metabolism and insulin sensitivity and to determine weather the ApoJ → LRP2 pathway is key signaling for insulin action in skeletal muscle.

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The study used mice lacking ApoJ (in liver or muscle) and LRP2 (in muscle) for glucose metabolism and insulin sensitivity; cultured muscle C2CI2 for interaction of IR with LRP2 and insulin induced endocytosis.

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The study estimated glucose (1 g/kg) and insulin (0.75 units/kg) tolerance, glucose stimulated insulin secretion (1 g/kg), glucose uptake in peripheral tissue, insulin stimulated signaling event (10 U/kg), endocytosis, insulin stimulated signaling events and in situ proximity ligation assay was performed.

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Liver is the primary organ for production and transporting ApoJ to metabolically active organs such as muscle.

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The mice lacking LRP2 gene, showed elevated levels of ApoJ in serum but decreased levels in muscle, which indicates that ApoJ is used in muscle via LRP2.

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Selective deletion of hepatic ApoJ or muscle LRP2 leads to systemic insulin resistance and glucose intolerance by suppressing insulin induced signal transduction and glucose uptake in skeletal muscle.

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On the cell surface of muscle, insulin drives the physical interaction between IR and LRP2 and the complex of LRP2 and IR undergoes coendocytosis, which is essential step in insulin signaling in muscle.

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However, absence of hepatic ApoJ or muscle LRP2, leads to disruption of insulin stimulated IR-LRP2 interaction.

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ApoJ is a novel hepatokine required for insulin mediated glucose metabolism through LRP2dependent mechanism, coupled with IR system.

Hence, ApoJ → LRP2 is a novel signaling pathway for central maintenance of normal glucose homeostasis and insulin sensitivity.

ROLE OF COGNITIVE BEHAVIORAL GROUP THERAPY IN OBESE DIABETIC PATIENTS ÂÂ

The study investigated whether group CBT would prevent weight regain in patients with both obesity and type 2 diabetes, who had lost weight by following a very low-calorie diet, in the prevention of weight regain (POWER) trial.

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The initial 8-week very low-calorie diet (750 kcal/ day based on meal replacements) resulted in 158 patients losing at least 5% of initial body weight, all the patients had a body mass index of greater than 27 kg/m2 (mean around 36 kg/m2), and half were female.

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These participants were randomized to the active group CBT (n = 83) or usual care (n = 75) and underwent regular checkups, diabetic nurse, dietitian, and 5 group meetings for measurements.

While, the intervention arm comprised an additional 17 group CBT sessions over one and a half years, and diet during the follow-up period involved slow reintroduction of healthy normal eating habits.

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The follow-up was 2 years, and primary outcomes comprised body weight at 2 years, and weight regain from randomization over the followup period. Secondary outcomes were waist circumference, HbA1c, insulin dose, lipids, depression, and anxiety.

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During the initial very low-calorie diet, patients lost around 10% of their body weight, but unfortunately after 2 years there was no difference in weight regain between the control and the intervention groups.

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In the CBT group, weight regain was 4.0 kg vs.

4.7 kg in the control arm; between-group difference was only -0.7 kg (CI 95%, -3.1 to 1.6).

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Perhaps medication had a role here as 2/3rd of type 2 diabetic patients were on insulin therapy which is known for weight gain and maybe these patients have too many other challenges for group CBT to work.

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After 2 years, it was found that subjects had lost 5% of their weight (initial weight loss was 10%) and had a lower waist circumference and depression score.

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CONFERENCE PROCEEDINGS ÂÂ

Participants were previously adhered to an 8-week very low-calorie diet and lost around 10% of their body weight. However, adding the CBT to usual care over the following 2 years had no effect on preventing weight regain nor in controlling cardiovascular risk factors and indicators of psychological well-being.

FAT SCORE AS A PREDICTOR OF POOR WEIGHT LOSS AFTER SURGERY ÂÂ

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A novel and easy-to-use score that measures fibrosis in human subcutaneous adipose tissue (scAT) can help to identify patients who are poor responders to Roux-en-Y gastric bypass (RYGB) weight-loss surgery, which will help for more personalized follow-up care.

The FAT score was used to characterize 183 biopsy specimens from severely obese patients who had received RYGB surgery and had complete followup data of 1 year after surgery.

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The study showed that the most severe fibrosis scores before surgery were associated with a poorer weight-loss response of three to four times the risk.

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After 1 year of bariatric surgery, patients with a high FAT score (≥2), after adjustment for age, diabetes status, hypertension, interleukin-6 level, and percentage fat mass, had an odds ratio of 3.6 (p = 0.003) of being a poor responder.

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Poor responder lost an average 22.7% of body weight compared with 35.6% in good responders, corresponding to an average difference of 17 kg.

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The FAT score is based on a semi-quantitative evaluation of perilobular and pericellular fibrosis and is easily measured and reproducible and showed significant relationship between the total scAT fibrosis and the amount of fibrosis (p < 0.001).

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Specifically severely obese subjects with a fibrosis score of adipose tissue (FAT) score of at least 2 prior to bariatric surgery showed the greatest risk of poor response after the operation.

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AROUND THE GLOBE

News and Views Ministry of Health Adjudged Best for ‘Swachhta Pakhwada’

Febuxostat Prevents Flares in Patients with Early Gout

The Ministry of Health and Family Welfare has been adjudged as the best department for its contribution during Swachhta Pakhwada, an Inter-Ministry Initiative of Swachh Bharat Mission of Ministry of Drinking Water and Sanitation. The Health Ministry observed the Swachhta Pakhwada from 1st to 15th February, 2017. The award was presented to the Ministry on 2nd October, 2017, the third anniversary of Swachh Bharat Mission. Shri CK Mishra, Secretary (HFW) received the award on behalf of the Ministry… (Press Information Bureau, Ministry of Health and Family Welfare, October 3, 2017).

Urate-lowering therapy with febuxostat for 2 years improved MRI synovitis, reduced gout flares and improved serum uric acid control with no major safety concerns in patients with early gout, according to a study reported October 4, 2017 in the journal Arthritis & Rheumatology.

WHO Scales up Response to Plague in Madagascar The World Health Organization (WHO) is rapidly scaling up its response to an outbreak of plague in Madagascar that has spread to the capital and port towns, infecting more than 100 people in just a few weeks. The Government of Madagascar has confirmed that the death of a Seychellois national was due to pneumonic plague. The basketball coach died in hospital in Antananarivo on Wednesday (September 27), while visiting the island nation for a sports event.

Health authorities are tracing people with whom he came into contact in recent days and who may have become exposed to the illness. Once identified, they will be given antibiotics to prevent infection as a precautionary measure. The incident brings the death count to 21 since the outbreak was identified in late August; at least 114 people have been infected. Plague is endemic to Madagascar, where around 400 cases of–mostly bubonic-plague are reported annually.

Contrary to past outbreaks, this one is affecting large urban areas, which increases the risk of transmission…

(WHO, October 1, 2017).

Black Tea may also Help with Weight Loss A new study published October 4, 2017 in the European Journal of Nutrition has shown that black tea may also promote weight loss and other health benefits by changing bacteria in the gut. The ratio of intestinal bacteria was altered in the animal study, with a decrease in the percentage of bacteria associated with obesity and increase in the bacteria associated with lean body mass.

Supervised High Intensity Exercise Improves Functional Performance in Postmenopausal Women with Low Bone Mass A study published October 4, 2017 in the Journal of Bone and Mineral Research study has found that only 30 minutes twice a week of closely supervised high intensity resistance and impact training improved functional performance and enhanced indices of bone strength in otherwise postmenopausal women with low to very low bone mass, without adverse effects.

Night Shift Work may Increase Risk of Obesity Night shift work was associated with a 29% increased risk of becoming obese or overweight, in particular abdominal obesity than other obesity types. Permanent night workers had a higher risk than rotating shift workers. These observations from a meta-analysis has been published October 4, 2017 in the journal Obesity Reviews.

Low-dose Estradiol Cream Efficacious in Vulvovaginal Atrophy Low-dose estradiol vaginal cream (0.003%) applied three times in a week is an effective and well-tolerated treatment for dyspareunia due to vulvovaginal atrophy, according to results of a phase III trial published online September 18, 2017 in the journal Menopause.

Vulvovaginal irritation and itching and dryness also improved.

2017 Nobel Prize in Physiology or Medicine Announced The 2017 Nobel Prize in Physiology or Medicine has been awarded to Jeffrey C Hall, PhD of the University of Maine, Orono; Michael Rosbash, PhD of Brandeis University, Waltham, Massachusetts and Michael W Young, PhD of Rockefeller University, New York

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AROUND THE GLOBE City “for their discoveries of molecular mechanisms controlling the circadian rhythm”.

5. Routine thyroid ultrasounds in children who have simple goiters or autoimmune thyroiditis.

India Registers Significant Decline in Infant Mortality Rate

Skipping Breakfast Associated with Hardening of the Arteries

India has registered a significant decline in infant mortality rate (IMR). According to the SRS Bulletin released recently, IMR of India has declined by three points (8% decline), from 37 per 1,000 live births in 2015 to 34 per 1,000 live births in 2016, compared to two points decline last year. Not only this, India also recorded a major drop in birth cohort, which has for the first time come down to below 25 million. India has registered 90,000 fewer infant deaths in 2016 as compared to 2015. The total number of estimated infant deaths have come down from 9,30,000 (9.3 lakhs) in 2015 to 8,40,000 (8.4 lakhs) in 2016. According to the SRS Bulletin the gender gap in India for child survival is reducing steadily. The gender difference between female and male IMR has now reduced to <10%, giving a major boost to the ‘Beti Bachao Beti Padhao’ scheme of the Government… (Press Information Bureau, Ministry of Health and Family Welfare, September 29, 2017).

Skipping breakfast is associated with an increased risk of atherosclerosis, according to new research published October 2, 2017 in the Journal of the American College of Cardiology. Along with study participants who skipped breakfast, atherosclerosis was also more common in those who ate low-energy breakfasts vs. breakfast consumers. These participants also had higher prevalence of cardiometabolic risk markers.

One Hour of Exercise a Week can Prevent Depression Even small amounts of exercise can protect against depression, with mental health benefits seen regardless of age or gender, suggests a study published October 3, 2017 in the American Journal of Psychiatry. People who reported doing no exercise at all at baseline had a 44% higher risk of developing depression than those who reported exercising 1-2 hours a week.

AAP New List of Endocrine-related Tests as Part of the Choosing Wisely Campaign

Fluoride Exposure During Pregnancy Affects Cognitive Function in Children According to a study published September 19, 2017 in the journal Environmental Health Perspectives, higher prenatal exposure to fluoride, as assessed by higher levels of maternal urinary fluoride, was associated with lower scores on tests of cognitive function in the offspring at age 4 and 6-12 years.

Sustained Disease Remission Associated with Lower Infection Rates in RA Patients Lower disease activity in patients with rheumatoid arthritis (RA) is associated with lower serious infection rates. A study reported in the journal Arthritis Care & Research has found that compared with patients in sustained remission (Clinical Disease Activity Index [CDAI] score of 2.8 or lower), those with low disease activity, or a CDAI score between 2.8 and 10, had a 69% higher risk of serious infections.

Health Services Must Stop Leaving Older People Behind

3. Routine vitamin D screening in otherwise healthy children, including those who are overweight or obese.

The World Health Organization (WHO) has called for a new approach to providing health services for older people. On the International Day of the Older Person, WHO highlighted the role of primary care and the contribution community health workers can make towards keeping older people healthier longer.

The Organization also emphasized the importance of integrating services for different conditions. “By the year 2050, 1 in 5 people in the world will be aged 60 and older,” says Dr Tedros Adhanom Ghebreyesus, Director-General of WHO. “It’s our goal to ensure that all older people can obtain the health services they need, whoever they are, wherever they live.”

4. Thyroid function and/or insulin levels tests in children with obesity.

WHO’s new Guidelines on Integrated Care for Older People recommend ways community-based services

The American Academy of Pediatrics (AAP) has released a new list of five endocrine-related tests that should prompt careful discussion between parents and physicians.

1. Hormone tests for children with pubic hair and/or body odor but no other signs of puberty.

2. Screening tests to detect chronic disease or endocrine disorders in healthy children growing at or above the 3rd percentile with a normal growth rate.

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AROUND THE GLOBE can help prevent, slow or reverse declines in physical and mental capacities among older people. The guidelines also require health and social care providers to coordinate their services around the needs of older people through approaches such as comprehensive assessment and care plans…(WHO, September 29, 2017).

Vascular Inflammation in Psoriasis Increases Risk of Heart Attacks and Stroke Patients with psoriasis are at a higher risk of developing heart attacks and strokes due to vascular inflammation, says a study reported in the October 2017 issue of the Journal of the American Academy of Dermatology. Vascular inflammation was significantly associated with disease duration and the risk increased 1.0% per additional year of the disease duration.

Study Shows Efficacy of Once-daily Raltegravir in Patients with HIV-1 Infection Results from the phase III ONCEMRK study show that once-daily regimen of 1,200 mg raltegravir in combination with tenofovir disoproxil fumarate and emtricitabine is effective in patients with previously untreated HIV-1 infection. The study is reported online September 11, 2017 in The Lancet HIV.

Study Shows Gender Differences in Association of TSH Levels to Papillary Thyroid Cancer

of Nutrition (NIN) in Hyderabad, which works under the aegis of Indian Council of Medical Research (ICMR), Union Ministry of Health and Family Welfare.

The report, “Diet and nutritional status of urban population and prevalence of obesity, hypertension, diabetes and its associated noncommunicable diseases”, was released on the occasion of NIN Foundation Day function.

The report is based on a comprehensive urban nutrition survey carried out by the National Nutrition Monitoring Bureau (NNMB) during 2015-16. The NNMB was established in 1972 by the ICMR. According to the report, “The prevalence of diabetes among men and women (after adjustment of age) was 22% and 19%, respectively.” “It was significantly associated with overweight and obesity, physical inactivity, hyperlipidemia (an abnormal increase in the levels of fats, including cholesterol, in the blood),” it said. The prevalence of tobacco smoking among men was 16%, while alcohol consumption was observed in 30% men, the report said. A total of 1.72 lakhs “subjects” from 16 states in the country were covered for their socio-demographic status while carrying out the survey, it said… (PTI, September 27, 2017).

EU Approves Marketing of Dupilumab for Atopic Dermatitis

A study published in the August 2017 issue of the journal Cancer Epidemiology, Biomarkers & Prevention has reported a significantly higher risk of papillary thyroid cancer associated with thyroid-stimulating hormone (TSH) levels below the normal range among women and with TSH levels above the normal range among men.

The European Commission has granted marketing authorization to dupilumab (Dupixent, Samofi and Regeneron), a human monoclonal antibody, for adults with moderate-to-severe atopic dermatitis, to be used with or without topical corticosteroids. Dupilumab will be available in a premixed syringe for biweekly injection.

Prophylactic Antibiotics Reduce UTIs in Children Undergoing VCUG

Frequent Sauna Bathing Keeps BP Under Control

Treating children with antibiotics before and after they undergo a voiding cystourethrogram (VCUG) reduces their risk of urinary tract infections (UTIs), suggest a study reported online August 30, 2017 in the Archives of Disease in Childhood.

Prevalence of Hypertension Higher in Men than Women in the Country The prevalence of hypertension among urban men and women in the country was 31% and 26%, respectively, a new study has found. While the prevalence of hypertension among urban men and women was maximum in Kerala (31-39%), it was lowest in Bihar (16-22%), according to a report by the National Institute

Findings of a study published September 29, 2017 in the American Journal of Hypertension show that the risk of developing high blood pressure (BP) was nearly 50% lower among men who had a sauna 4-7 times a week as compared to men who had a sauna only once a week.

Eat Carbohydrate Last to Check Postprandial Glucose Rise in Type 2 Diabetes People with type 2 diabetes who ate carbohydrate first, followed 10 minutes later by protein and vegetables showed higher increase in their postprandial blood sugar levels compared to those who ate protein and vegetables first, followed 10 minutes later by carbohydrate. These findings were reported online September 1, 2017 in BMJ Open Diabetes Research and Care.

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AROUND THE GLOBE Enteral Nutrition is Preferred Over Parenteral Nutrition in Patients with Severe Pancreatitis

Duration of Stored RBCs does not Affect Mortality in Critically Ill Patients

According to a meta-analysis published online September 13, 2017 in the European Journal of Clinical Nutrition, compared with parenteral nutrition, enteral nutrition is associated with lower rates of overall mortality and multiple organ failure in patients with severe pancreatitis in an intensive care unit. The study recommends enteral nutrition as the preferred route of nutrition for critically ill patients with severe acute pancreatitis.

Transfusing critically ill patients with the freshest available red cells, rather than with standard-issue (oldest available) red cells, provides no clinically meaningful benefits, according to the results of the TRANSFUSE trial published online September 27, 2017 in the New England Journal of Medicine. The age of transfused red cells did not affect 90-day mortality among critically ill patients included in the study.

Hypofractionated Radiation Therapy is Effective in Breast Cancer Following Mastectomy According to a new research presented September 25, 2017 at the American Society for Radiation Oncology (ASTRO) 2017 Annual Meeting in San Diego, hypofractionated radiation therapy (HFRT) delivered in fewer fractions over a shorter period was comparable in effects to conventional fractionated radiation therapy in post-mastectomy patients with breast cancer.

Expectant Mother’s Elevated BP Raises Child’s Risk of Obesity When expectant mothers have elevated blood pressure during pregnancy, it may raise their children’s risk of developing childhood obesity, according to a study published September 27, 2017 in the Journal of Clinical Endocrinology & Metabolism.

Among women who were hypertensive during the second trimester, their children were 49% more likely to be overweight or obese than children of mothers who had lower BP. While children of women with high BP during the third trimester were 14% more likely to be overweight or obese.

NIH Clinical Center Provides One of the Largest Publicly Available Chest X-ray Datasets to Scientific Community The National Institute of Health (NIH) Clinical Center recently released over 1,00,000 anonymized chest X-ray images and their corresponding data to the scientific community. The release will allow researchers across the country and around the world to freely access the datasets and increase their ability to teach computers how to detect and diagnose disease.

Ultimately, this artificial intelligence mechanism can lead to clinicians making better diagnostic decisions for patients.

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A New Fast-acting Insulin Option for Treatment of Diabetes in Adults A new faster-acting (within 2.5 minutes), mealtime version of insulin aspart (Fiasp, Novo Nordisk) for the treatment of type 1 and type 2 diabetes in adults by the US Food and Drug Administration (FDA). It also contains niacinamide to increase speed of the initial insulin absorption. Available as a prefilled delivery device and in a vial, Fiasp is to be administered at the beginning of a meal or within 20 minutes after starting a meal.

SO2S Study Findings Against Routine Use of Low-dose Oxygen in Nonhypoxic Patients with Acute Stroke Findings of the Stroke Oxygen Study (SO2S) published in the September 26, 2017 issue of JAMA show no improvement in outcomes with the routine use of prophylactic low-dose oxygen in nonhypoxic patients with acute stroke. In the study, the prophylactic use of low-dose oxygen supplementation did not reduce death or disability at 3 months.

Elimination of Dog-transmitted Rabies by 2030 Targeted The total elimination of dog-transmitted human rabies by 2030 has been called for in a joint statement by the World Veterinary Association (WVA) and World Medical Association (WMA). The two organizations have joined forces to mark World Rabies Day on September 28 in collaboration with the “Rabies: Zero by 30” campaign of Global Alliance for Rabies Control (GARC).

Rabies claims the lives of an estimated 60,000 people each year, mainly affecting poorer people and children between the ages of 5 and 15. About 97% of these deaths can be attributed to bites from dogs. But notifications and reporting of animal bites are generally not required in the countries in which these bites occur most commonly, leading to unreliable data on animal bites.

AROUND THE GLOBE The WVA and WMA say that the global and endemic nature of rabies can also be attributed to a general lack of awareness of preventive measures, such as wound washing after bites, poor knowledge of proper postexposure prophylaxis (PEP) through vaccination, lack of administration of immunoglobulins and an irregular supply of anti-rabies vaccine and immunoglobulin, particularly in primary healthcare facilities. Lack of affordability of vaccines and immunoglobulin is also a contributing factor.

International and national vaccine manufacturers produce enough vaccine annually to deliver approximately 28 million rabies human PEP treatments in dog rabies-enzootic countries of Africa, Asia and the Eastern Mediterranean region, preventing nearly 98% of human rabies deaths. Unfortunately, easier access to rabies vaccine, particularly in urban centres of Africa and Asia, has been accompanied by an increasing proportion of PEP (up to 70%) being administered to people who are not at high risk of developing rabies.

WVA President, Dr Johnson Chiang said: “Rabies control is a multidisciplinary and multidimensional activity.

Participation and effective intersectoral cooperation among medical and veterinary professionals from government and academic institutions, civic and local bodies, national and international nongovernmental organizations, and animal welfare organizations is essential.”

WMA President, Dr Ketan Desai added: “If dogtransmitted rabies is to be eliminated, strengthening legislation concerning pet ownership, reducing the population of stray and unowned free-roaming dogs, broadly implementing dog vaccination programs, and provision of early rabies diagnostic facilities and adequate post-exposure healthcare are prerequisites.

Dog-transmitted rabies elimination is an ideal opportunity to move the ‘One Health’ concept forward” (WMA, September 27, 2017).

A New Treatment for HR+/HER2- Advanced or Metastatic Breast Cancers The US Food and Drug Administration (FDA) has approved verzenio (abemaciclib) to treat adult patients who have hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer that has progressed after taking therapy that alters a patient’s hormones (endocrine therapy). It is to be administered in combination with fulvestrant, an endocrine therapy, after the cancer had grown on endocrine therapy. It is also approved to be given on its own, if patients

were previously treated with endocrine therapy and chemotherapy after the cancer had spread (metastasized).

Intrapartum Fever may Increase Maternal and Neonatal Risks A new research reported September 28, 2017 in the Journal of Maternal-Fetal and Neonatal Medicine has found that intrapartum fever triggered by bacterial infection may cause neonatal and maternal complications.

Women with intrapartum fever had higher rates of operative vaginal deliveries (34.3% vs. 19.6%) and cesarean sections (20.7% vs. 8.7%).

FDA Improves Access to Reports of Adverse Drug Reactions The US Food and Drug Administration (FDA) has launched a new user-friendly search tool that improves access to data on adverse events associated with drug and biologic products through the FDA’s Adverse Event Reporting System (FAERS) for patients, doctors and others. It enables users to search for and organize data by criteria such as drug/biological product, age of the patient, type of adverse event, year the adverse event occurred or within a specific timeframe.

Addition of Meditation to Healthy Lifestyle and Medical Treatment may Reduce Heart Disease Risk Factors Meditation has the potential to reduce some risk factors for heart disease, but the gold standard for lowering risk remains a heart-healthy lifestyle and following medical recommendations, according to a new scientific statement from the American Heart Association published in the Journal of the American Heart Association.

Diacerin may Aid Glycemic Control in Osteoarthritic Patients with Type 2 Diabetes Diacerein, an immune modulator anti-inflammatory drug, may improve glycemic control in patients with type 2 diabetes, especially those with osteoarthritis. In a study published in October 2017 issue of the journal Diabetes Care, diacerein reduced mean HbA1c levels, with peak of effect at 24th week of treatment and it was also well-tolerated.

2017 Class of Heart Disease and Stroke Survivors Announced for World Heart Day Each year on September 29, World Heart Day encourages people to be heart healthy with the world’s biggest

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AROUND THE GLOBE platform for raising awareness about cardiovascular disease (CVD). In observance of the day this year, the American Heart Association (AHA) the world’s leading voluntary organization dedicated to building healthier lives, free of CVDs and stroke, is honoring 11 women who are sharing their stories to inspire others as part of the 2017 Go Red For Women Class of Real Women, who represent a sisterhood of survivors who actively, urgently and passionately participate in the movement to raise awareness of the issues connecting women and heart diseases and stroke. As the often-surprising faces of heart disease, they are sharing their powerful stories to inspire others through the changes they’ve made to improve their own health… (AHA, September 27, 2017).

Early Mobilization Post-sports Injury Shortens Recovery Period in Athletes

Coffee may not Relieve Symptoms of Parkinson’s Disease

In an in vitro study reported August 30, 2017 in the journal Science Advances, the combination of ceftazidime with avibactam markedly killed rapidly growing, intracellular and semidormant Mycobacterium tuberculosis, though neither ceftazidime nor avibactam alone killed the bacteria. Most clinical strains from MDR/XDR (multidrug-resistant and extensively drugresistant)-TB patients were susceptible to ceftazidime + avibactam combination.

A study published in the September 27, 2017, online issue of the journal Neurology has said that caffeine may not relieve movement symptoms for people with Parkinson’s disease. No improvement in movement symptoms or quality of life was observed for people who had taken the 200 g caffeine capsules, equivalent of three cups of coffee daily, compared to those who took the placebo capsules.

Cancer Patients Less Likely to Receive Treatments for Heart Attack Patients with heart attack were less likely to receive recommended drugs (antiplatelet agents, statins) and percutaneous coronary intervention (PCI), and more likely to die in hospital if they had cancer than if they did not, suggests a new study published September 20, 2017 in the European Heart Journal: Acute Cardiovascular Care. Complications and in-hospital mortality were also higher in patients with cancer.

FDA Approves First Continuous Glucose Monitoring System for Adults not Requiring Blood Sample Calibration The US Food and Drug Administration (FDA) has approved the FreeStyle Libre Flash Glucose Monitoring System, the first continuous glucose monitoring system that can be used by adult patients to make diabetes treatment decisions without calibration using a blood sample from the fingertip (often referred to as a “fingerstick”). It is intended for use in people 18 years of age and older with diabetes; after a 12-hour start-up period, it can be worn for up to 10 days.

Starting rehabilitation 2 days after severe muscle injury rather than waiting for 9 days shortened the interval from injury to pain-free recovery and return to sports by 3 weeks without any significant increase in the risk of reinjury. These findings from a study are published online September 28, 2017 in the New England Journal of Medicine.

Experimental Study Shows Potential Anti-TB Effect of Ceftazidime + Avibactam in Highly Drug-resistant TB

USPSTF Draft Recommendations for Falls and Fracture Prevention In a draft recommendation, the US Preventive Services Task Force (USPSTF) recommends exercise to prevent falls in community-dwelling adults age 65 years or older who are at increased risk for falls. And, clinicians should selectively offer multifactorial interventions to prevent falls in this population group. However, the Task Force has recommended against vitamin D supplementation to prevent falls in community-dwelling adults age 65 years or older. The draft recommendations are posted on its website for public comment up to October 23, 2017.

Umbilical Cord Stem Cells Show Promise as Treatment for Heart Failure As per a study published September 26, 2017 in the journal Circulation Research, a heart failure treatment using umbilical cord-derived stem cells may lead to notable improvements in heart muscle function and quality-of-life. Compared to the placebo treatment, the stem cell therapy was safe and showed sustained and significant improvement in pumping capacity of the heart leading to better quality-of-life.

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LIGHTER READING

ON TRIAL

LONG LIFE

After a trial had been going on for 3 days, Finley, the man accused of committing the crimes, stood up and approached the judge’s bench. “Your Honor, I would like to change my plea from ‘innocent’ to ‘guilty’ of the charges.”

I recently picked a new primary care physician.

After two visits and exhaustive lab tests, he said I was doing “fairly well” for my age. A little concerned about that comment, I couldn’t resist asking him, “Do you think I’ll live to be 90?”

The judge angrily banged his fist on the desk.

“If you’re guilty, why didn’t you say so in the first place and save this court a lot of time and inconvenience?” he demanded.

He asked, do you smoke tobacco or drink beer/ wine?” “Oh no,” I replied. “I’m not doing either.”

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THAT ONE DOES WORK Customer: My keyboard is not working anymore.

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Then he asked, “Do you eat rib-eye steaks and barbecued ribs?” I said, “No, my other Doctor said that all red meat is very unhealthy!”

“Do you spend a lot of time in the sun, like playing golf, sailing, hiking, or bicycling?”

No, I don’t,” I said.

He asked, “Do you gamble, or drive fast cars?”

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Customer: No. I can’t get behind the computer.

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Dr. Good and Dr. Bad SITUATION: A healthy male with increased WHtR wanted to

know his odds of developing diabetes.

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THESE ARE NOT RELATED

YES, YOU ARE AT RISK OF DEVELOPING DIABETES

Customer: Yes, there’s another one here. Ah...that one does work.

ABSENT-MINDED PROFESSOR One of the world’s greatest scientists was also recognized as the original absent-minded professor. One day, on board a train, he was unable to find his ticket. The conductor said, “Take it easy. You’ll find it.”

When the conductor returned, the professor still couldn’t find the ticket. The conductor, recognizing the famous scientist, said, “I’m sure you bought a ticket. Forget about it.”

“You’re very kind,” the professor said, “but I must find it, otherwise I won’t know where to get off.”

© IJCP Academy

HUMOR

Lighter Side of Medicine

LESSON:

In an evaluation of 2,900 nondiabetic participants (mean age 44.3 years), in a screening program, during the follow-up, 3.5% new cases of diabetes were diagnosed. The cut-off WHtR value for diabetes development was 0.51. WHtR had the highest AUROC value for diabetes development among three adiposity indices (0.716, 95% CI 0.669-0.763; 0.702, 95% CI 0.655-0.750 for WC; 0.700, 95% CI 0.651-0.750 for BMI). After adjusting for confounding variables, the ORs of WHtR and WC for diabetes development were 1.95 (95% CI 1.14-3.34) and 1.96 (95% CI 1.10-3.49), respectively. Increased baseline WHtR and WC were associated with the development of diabetes after 4 years. WHtR appeared to be a useful tool to identify individuals at high risk for diabetes.

Endocrinol Metab (Seoul). 2016 Jan 6. [Epub ahead of print]

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Information for Authors Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767).

Indian Journal of Clinical Practice strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so.

The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript.

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name of the corresponding authors, acknowledgment of financial support and abbreviations used.

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A subtitle can be added if necessary.

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Methods – These should be described in sufficient detail to permit evaluation and duplication of the work by others.

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This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.

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Examples of common forms of references are: Articles Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes.

Q. J. Expt. Physiol. 1955;40:89-111.

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Books

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Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.

Indian 1.____________Foreign 1.________________

Articles in Books

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Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.

3.____________ 3.________________

4.____________ 4.________________

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