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IJCP Group of Publications

Volume 22, Number 11, April 2012

Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor

from the desk of group editor-in-chief 549

What’s New in Medicine KK Aggarwal

Dr KK Aggarwal CMD, Publisher, Group Editor-in-Chief review article

Dr Veena Aggarwal MD, Group Executive Editor

IJCP Editorial Board Obstetrics and Gynaecology Dr Alka Kriplani Dr Thankam Verma, Dr Kamala Selvaraj

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Cardiology Dr Praveen Chandra Dr M Paul Anand, Dr SK Parashar Paediatrics Dr Swati Y Bhave Dr Balraj Singh Yadav Dr Vishesh Kumar Diabetology Dr Vijay Viswanathan Dr CR Anand Moses, Dr Sidhartha Das Dr A Ramachandran, Dr Samith A Shetty Dentistry Dr KMK Masthan Dr Rajesh Chandna

Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan

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Journal of Applied Medicine & Surgery Dr SM Rajendran

Advisory Bodies Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

Role of a Polyherbal Children Health Drink (HiOwna-Jr) in General Health and Cognition of Children: A Preliminary Clinical Safety and Efficacy Study D Palani, MB Manu, Suprabha Hegde

An Efficacy, Safety and Tolerability Study of Ferrous Ascorbate and Folic Acid (Phosfomin-XT) in Iron Deficiency Anemia BB Adsul, Qayum Mukaddam, Prashant Khandeparkar, Manoj Naik

drug review

Anand Gopal Bhatnagar Editorial Anchor

Hetal Parikh, Sameer Raniga, Pankaj Desai, Abhishek Arora

Original article

Gastroenterology Dr Ajay Kumar Dermatology Dr Hasmukh J Shroff

First Trimester Antenatal Ultrasonographic Screening for Aneuploidy - So Far So Good

Review of Antibiotics in the Management of Respiratory Infections: Cefaclor vs Amoxicillin-Clavulanate Pavan Mangla, KK Aggarwal

clinical study 576

Detection of Fetal Malnutrition by CAN Score at Birth and its Comparison with other Methods of Determining Intrauterine Growth Vikram Singhal, Prashant Agal, Nutan Kamath

case report

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

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Printed at Ana Print O Grafix Pvt. Ltd., Greater Noida

Shubha Laxmi Margekar, Venu Gopal Margekar, Ashok Kumar

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Š Copyright 2012 IJCP Publications Ltd. All rights reserved.

The copyright for all the editorial material contained in this journal, in the form of layout, content including images and design, is held by IJCP Publications Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.

The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.

Isolated Duodenal Metastasis of Hepatocellular Carcinoma: A Rare Presentation N Priyathersini, S Rajendiran, RB Sudagar Singh, J Thanka

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Editorial Policies

Solitary Cysticercus Granuloma: A Re-disappearing CT Lesion

Delayed Diagnosis of Fetus Papyraceous with Microcephaly of Surviving Co-Twin Rekha Chaudhary, Suniti Verma, Shaifali Dadhich, Asha Meena, Ram Narayan Sehra

Medilaw 595

Insight on Medicolegal MC Gupta

practice guidelines 596

ACCF/AHA Release Guideline for Early Cardiovascular Risk Assessment photo quiz

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Note: Indian Journal of Clinical Practice does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature in this issue.

Arcuate, Red Plaques with Pustules on the Trunk lighter reading

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Lighter Side of Medicine

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from the desk of group editor-in-chief Dr KK Aggarwal

Padma Shri and Dr BC Roy National Awardee Sr. Physician and Cardiologist, Moolchand Medcity, New Delhi President, Heart Care Foundation of India Group Editor-in-Chief, IJCP Group and eMedinewS Chairman Ethical Committee, Delhi Medical Council Director, IMA AKN Sinha Institute (08-09) Hony. Finance Secretary, IMA (07-08) Chairman, IMA AMS (06-07) President, Delhi Medical Association (05-06) emedinews@gmail.com http://twitter.com/DrKKAggarwal Krishan Kumar Aggarwal (Facebook)

What’s New in Medicine 

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Do not prescribe citalopram at doses that exceed 40 mg/day because of dose-dependent QT-interval prolongation.

For most patients with left ventricular ejection fraction (LVEF) of ≤35% and coronary artery disease (CAD) amenable to coronary artery bypass graft (CABG) surgery, initiate course of optimal medical therapy alone rather than medical therapy plus CABG surgery.

Four types of commonly-used medication (warfarin, insulin, oral antiplatelet agents and oral hypoglycemics) accounted for 67.0% of the adverse drug events in elderly.

In 2012, the US FDA revised its labeling information on statins to only recommend liver function testing prior to initiation of statin therapy and to only repeat such testing for clinical indications.

Routine monitoring of liver function tests in patients receiving statin therapy is not necessary.

Proton pump inhibitors may be associated with an increased risk of Clostridium difficile-associated diarrhea.

Rifapentine is a rifamycin derivative with a long half-life and greater potency against Mycobacterium tuberculosis than rifampin. A 3-month regimen of weekly isoniazid and rifapentine given as directly-observed therapy has been shown to be noninferior to a 9-month self-administered regimen of daily isoniazid in a randomized, open label international trial in predominantly HIV-negative individuals at high-risk for progression from latent tuberculosis infection to active infection.

Exercise may modestly improve obstructive sleep apnea (OSA) even in the absence of significant weight loss.

Intravenous paracetamol is available in a concentration of 10 mg/ml. Ten-fold iatrogenic overdoses have been described in hospitalized young children receiving it. The typical error occurs when the dose in mg is mistakenly given as the volume in mL. A high sodium diet is associated with both a blunting of the proteinuria reduction-induced by the angiotensin-converting enzyme (ACE) inhibitor ramipril and a higher incidence of end-stage renal disease in proteinuric patients with chronic kidney disease enrolled into the REIN and REIN-2 trials A prolonged corrected QT-interval on a resting ECG has limited sensitivity for the detection of long QT-syndrome.

A multicenter study found that a prolonged QTc during exercise recovery provided greater sensitivity.

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review article

First Trimester Antenatal Ultrasonographic Screening for Aneuploidy - So Far So Good Hetal Parikh*, Sameer Raniga**, Pankaj Desai†, Abhishek Arora‡

Abstract Ultrasound has become an integral component of obstetric care, with the vast majority of patients having at least one ultrasound examination during pregnancy. Recent advances in obstetric ultrasonography (USG) have increased its importance in managing pregnancies at risk for aneuploidy and structural abnormality. Antenatal screening of aneuploidy, particularly Down syndrome includes biochemical markers, USG and invasive tests like chorionic villus sampling (CVS) and amniocentesis. In this article, we review and compare these screening modalities with emphasis on USG. In light of current literature, we will discuss first trimester sonographic markers associated with aneuploidy viz. nuchal translucency (NT), fetal nasal bone and ductus venosus flow and their statistical as well as clinical significance in the detection of aneuploidy. We will review the current data and status of first trimester screening for aneuploidy.

Keywords: Aneuploidy, prenatal ultrasound, first trimester, nuchal translucency, fetal nasal bone, ductus venosus flow

T

he use of ultrasound in obstetrics has become ubiquitous. Ultrasound has become an integral component of obstetric care, with the vast majority of patients undergoing at least one ultrasound examination during pregnancy. Recent advances in obstetric ultrasonography have increased its importance in managing pregnancies at risk for aneuploidy and structural abnormality.

Life of an obstetric ultrasonologist was never so difficult and so easy at the same time. Life is easy because of technical developments and types of sophisticated ultrasound units available with 3D and 4D facilities and high-resolution images. With these advancements gross malformations are easy to detect. Life is difficult because of the whole new crop of ultrasound findings with uncertain clinical significance that can be seen with these units. With newer sophisticated sonography units, more and more subtle markers are being picked up, the clinical relevance and importance of these markers is

*Specialist Dept. of Obstetrics and Gynecology, Armed Forces Hospital, Muscat, Oman **Consultant Radiologist Khoula Hospital, Muscat, Oman †Associate Professor Dept. of Obstetric and Gynecology, SSG Hospital and Medical College, Baroda ‡Consultant Radiologist Tata Memorial Hospital, Mumbai Address for correspondence Dr Hetal Parikh 81, Shantinagar, Tarsali Road, Vadodara - 390 009 E-mail: samhet10200@yahoo.com; sameerraniga@yahoo.com

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not still fully understood. The most important decision of advising the invasive tests for the confirmation of the suspected aneuploidy in these patients with soft markers is a challenge.

Antenatal screening of aneuploidy, particularly Down syndrome includes biochemical markers, ultrasonography (USG) and invasive tests like chorionic villus sampling (CVS) and amniocentesis. At present, these invasive procedures are considered as gold standard for the diagnosis of chromosomal anomalies or other genetic diseases. However, these procedures are associated with a finite risk of morbidity and mortality to the fetus. The risk associated with these tests, availability and the cost of analysis precludes the adoption of methods for mass screening of pregnant women. Therefore, diagnostic procedures are only offered on a limited basis to high-risk pregnancies where the benefit outweighs the risk. In low-risk pregnancies, where there is low likelihood of diagnosing a chromosomal abnormality, prenatal diagnosis generally consists of screening procedures by means of ultrasound and maternal serum biochemistry.

The incidence of Down syndrome increases with maternal age. The levels of four maternal serum biochemical markers in the second trimester of pregnancy - alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), estriol and inhibin A - have been found to be associated with Down syndrome.1,2 Second trimester maternal biochemical serum screening for

review article abnormal levels of some or all of these markers is now part of routine obstetrical care in the United States and allows the detection of approximately 60% of cases of Down syndrome, with a false-positive rate of 7%.2,3 Since, there is considerable overlap of maternal serum values for unaffected and chromosomally abnormal fetuses, a positive screening test result needs to be followed by a diagnostic test. Amniocentesis can reliably determine fetal karyotype, but there is a 0.5-1.0% fetal mortality rate associated with this procedure.4 Ultrasound is the imaging modality for the prenatal screening programs aimed at identifying fetal chromosomal abnormalities. Its safety during pregnancy and noninvasiveness are two of its most desirable traits.

We will review the role of USG in the first (up to 13 weeks and 6 days) trimester screening for aneuploidy.

The most common reason for prenatal diagnosis of chromosome abnormalities is to look for evidence of trisomies, Turner syndrome and triploidy. Trisomy 13, 18, and 21 are the most common, with trisomy 21 comprising about half of all the trisomies identified.

In the first trimester, a common feature of many chromosomal defects is increased nuchal translucency (NT) thickness. In later pregnancy, each chromosomal defect has its own syndromal pattern of abnormalities.

We also review and compare these screening modalities with emphasis on USG. In light of current literature, we will discuss first trimester sonographic markers associated with aneuploidy and its statistical as well as clinical significance in the detection of aneuploidy.

FIRST TRIMESTER SCREENING FOR ANEUPLOIDY Prenatal screening for aneuploidies and especially Down syndrome has expanded substantially over the past 20 years. Initially, only women at risk were offered the option of invasive prenatal diagnosis. However, with the advent of second trimester multiple marker serum screening test or abnormal second trimester sonographic markers or soft signs, prenatal invasive tests are offered to general obstetric population identified to have one of these markers positive.

The most efficient multiple marker screening test in second trimester is known as the ‘quad’ screen, a biochemical marker panel comprised of AFP, hCG, unconjugated estriol and inhibin-A.5 This combination approach is far from perfect and has sensitivity of 67-76% for Down syndrome with a 5% false-positive rate.6 This common method of screening has several limitations, the earliest it can reliably be performed is 15 weeks and hence limiting the choice of definitive diagnosis of aneuploidy to amniocentesis. Over 25%

of Down syndrome cases cannot be detected with this screening approach and with the false-positive rate of 5% and the pregnancy loss rate of one in 200 associated with amniocentesis, about one normal fetus is lost for every three fetuses with Down syndrome detected.7 It is easy to understand that the current approach of second trimester screening is far from perfect and hence a great deal of interest has been directed toward shifting prenatal screening for aneuploidies to the first trimester using sonographic measurement of the fetal NT alone and in combination with other sonographic and biochemical markers.

FETAL NUCHAL TRANSLUCENCY In 1992, Nicolaides et al introduced the term ‘nuchal translucency’, which was defined as the thickness of the translucent space between the skin and the soft tissue overlying the fetus cervical spine, measured in millimeters and tenths of a millimeter via ultrasound.8 NT ultrasound has pushed prenatal screening for Down syndrome into the first trimester. NT refers to the normal subcutaneous fluid-filled space between the back of the fetal neck and the overlying skin.

It can be measured accurately and reproducibly on ultrasound between 10 and 14 weeks of gestation (Fig. 1). It is seen that thickening of NT is associated with increased risk for Down syndrome, other aneuploidies, major structural malformations and adverse pregnancy outcomes (Fig. 2). The association increases with increase in nuchal thickness. The etiology for this nuchal fluid accumulation has still not been defined and various theories offer an explanation.

The most cited are: Deficient and transitory lymphatic drainage of the cervical region due to disorders in the lymphatic connections,9,10 excessive perfusion of the protective mechanism of the central nervous system as a result of the rapid growth of the initial placenta which consequently increases the circulatory volume11 and cardiac alterations - mainly the narrowing of the aortic isthmus and consequently increasing the vascular flow of the fetal cervical region12-14 or cardiac failure with abnormal ductus venosus tracing.15 Some publications consider NT 2.5 mm10,16,17 as positive screening values, whereas the great majority uses a fixed value of NT 3 mm.18-21 However, recent literature suggests that it is inappropriate to choose a single millimeter cut-off to define a specific NT measurement as abnormal.22 They recommended the use of 95th percentile value for the specified gestational age or multiples of the median as the cut-off upper limit for the diagnosing thickened NT. The natural increase of NT

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review article

Figure 1. Shows the correct technique for measuring NT in first trimester.

Figure 2. Shows thickening of NT.

measurement by 17% per week should be considered when calculating cut-offs for the use with an increased NT.23 Unfortunately, detailed information on such cutoffs is not available in the literature.

An abnormal NT measurement is 13 times more likely to be present in cases of Down syndrome. Because Down syndrome pregnancies are more likely to result in fetal demise in first trimester as many as 40% the figure mentioned above may be overestimated.

They also mentioned the shortcoming of current literature on NT- in form of consideration of first trimester loss of Down fetuses, karyotypic confirmation of all suspected cases, lack of information on the success rate at obtaining an NT measurement and lack of control group for comparison between first trimester screening and the current standard of care of second trimester multiple marker screening.7

Dr Ellen Mozurkewich and coauthors of the University of Michigan, Ann Arbor analyzed 27 studies at the annual meeting of Society for Maternal-Fetal medicine, which included 1,63,450 high-risk subjects and reported that NT measurements identified 78% of fetuses affected by trisomy 21, 82% of those with trisomy 18, 90% of those with trisomy 13 and 96% of those with monosomy X. The negative predictive value for all four conditions was 99%. The false-positive rate for each of the conditions was <5%. They concluded that NT is a sensitive marker for identifying aneuploidy in highrisk population.24 Few studies have evaluated the NT thickness and prevalence of aneuploidy and suggested that the association between the two becomes stronger with increasing thickness of NT.18,25 Pandya et al found prevalence of aneuploidy 7% at 3 mm NT and 70-78% at 8 and 9 mm thickness, respectively.25 NT shows spontaneous regression by 20 weeks.

The current literature suggests that NT ultrasound screening has tremendous potential as powerful prenatal screening for aneuploidy. Results of studies in the general obstetric population in a routine clinical setting have been mixed, with a range of detection rates for Down syndrome between 29 and 100%. Brigatti et al reviewed 30 published studies on the performance of NT-based screening for Down syndrome in the general population between 1966 and April 2003.7 They used data from all 30 studies, a total 3,16,311 patients and concluded an overall sensitivity for Down syndrome of 77% with a 6% false-positive rate.

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NT measurement can also detect other aneuploidies and the detection rate for trisomy 18 was 81% and Turner syndrome was 80% and 63% for triploidy.22 Approximately 80% of the affected fetuses with these aneuploidies result in spontaneous abortion.26 NT-based screening may preferentially identify those pregnancies with the highest likelihood of intrauterine death.27 Hence, the role of first trimester screening is debatable.

NT Measurement with Maternal Serum Markers in First Trimester: Combined and Integrated Approach First trimester maternal serum markers include free b-component of hCG (FβhCG) and PAPP-A. The combination of increased level of FβhCG and reduced level of PAPP-A with maternal age demonstrate a detection rate of approximately 60% with a 5% falsepositive rate.28 Brigatti et al reviewed the combined approach by maternal serum markers and NT-based screening.7

review article As mentioned in their paper, the first trimester serum markers seem to be independent of NT. They reviewed seven published studies of the combined method of screening and found the overall sensitivity for Down syndrome of 82% for a 5% false-positive rate.

Using the NT measurement and serum markers from the first trimester in combination with maternal serum analytes from the second trimester will provide one single Down syndrome risk assessment and is found to be superior to either approach separately in each trimester alone. This two-step approach, commonly known as the â&#x20AC;&#x2DC;integrated test,â&#x20AC;&#x2122; involves the combination of NT ultrasound and maternal serum PAPP-A in the first trimester followed by maternal serum AFP, hCG, unconjugated estriol and inhibin-A in the second trimester, with a single result proved in the second trimester. This integrated test has a higher sensitivity with less false-positive rates. First trimester screening does not eliminate the need for second trimester ultrasound for the detection of gross structural fetal anomalies.

NT ultrasound is extremely operator-dependent. Quality control is the most important factor to standardize the practice of NT ultrasound. Criteria to maximize good quality of NT ultrasound includes: Gestation should be limited between 10 and 14 weeks (Crown Rump Length [CRL] 36-80 mm), fetus should be examined in a mid-sagittal plane, fetal neck should be in a neutral position, fetal images should occupy at least 75% of the viewable screen, fetal movement should be awaited to distinguish between amnion and overlying fetal skin, calipers should be placed perpendicular to the fetal body axis, at least three NT measurements should be obtained, with the mean value and at least 20 minutes may need to be dedicated to the NT measurement before abandoning the effort as failed.7

First Trimester Fetal Nasal Bone Ossification of the nasal bones first appears at a CRL of 42mm, and nasal bone increases linearly with gestation. Fetuses with Down syndrome have a flat face with small nasal bone. In a study that evaluated the association between nasal bone hypoplasia and Down syndrome at 11-14 weeks gestation, nasal ossification was absent in 73% of Down syndrome fetuses versus 0.5% of chromosomally normal fetuses.29 Few other studies concluded a similar association between absence of fetal nasal bone at 11-14 weeks sonography and its association with Down syndrome.30-32 The authors of the above study believed that the absence of fetal nasal bone to be independent of NT size and the two ultrasound screening methods could be combined into

one modality, with a predicted sensitivity of 85% for a 1% false-positive rate. The adequate imaging of the fetal nose can be obtained in a midsagittal plane of the fetus, in perfect profile and with slight neck flexion; the fetal spine should be facing downward and two echogenic lines at the fetal nose bone profile the superficial one of the nasal skin and the deeper echogenic line representing the nasal bone.7

First Trimester Fetal Ductus Venosus Flow First trimester ductus venosus (DV) flow studies33-37 have been identified as useful for aneuploidy screening.

Forward biphasic pulsatile flow is normal, whereas reversed flow at the time of atrial contraction has been associated with aneuploidy and cardiac defects.

Abnormality in the ductus flow represents the presence of complex cardiac anomalies, which may or may not be detected early in the antenatal period. DV flow velocimetry following an NT ultrasound evaluation is useful for modifying the risk for aneuploidy; it increases the detection rate and reduces the falsepositive rate. Accurate measurement of DV flow is very important and technically challenging as the DV is as small as 2 mm at 10-14 weeks. Quality control and technical competence with experienced sonographer is required. It is desirable to use the smallest possible Doppler sample volume, keep the sample midway between the umbilical venous sinus and the inferior vena cava.7 Mavrides et al showed a clear association between abnormal flow in the DV and fetal aneuploidy. They concluded that the use of DV velocimetry in combination with NT is better than either test alone, since it increases the sensitivity in the detection of Down syndrome to 94% and decreases the likelihood ratio of a negative test to 0.08.38 Borrell et al concluded in their study that there is a high proportion of fetuses with trisomies 21, 18 and 13 (around 75%) in which the DV PIV (Pulsatility index for veins) is increased (above the 95th percentile) at 10-14 weeks and this proportion is similar to that observed for increased NT measurement.39

Other Sonographic Signs in First Trimester Other sonographic signs in the first trimester that suggest the presence of aneuploidy includes sacembryo disproportion: Too small gestational sac, too large gestational sac, amnion too close to embryo, large, small or irregular yolk sac, shapeless embryo.40-42 However, these signs are not of clinical significance, as most of these embryos will end up in spontaneous abortion. Trisomy is one of the commonest aneuploidy in these fetuses.41

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review article CURRENT STATUS OF SCREENING ULTRASOUND IN FIRST TRIMESTER Ultrasound is an excellent tool, but it is far from perfect.

If patients are falsely reassured by an ultrasound examination, they may decide to forego definitive testing when that is indeed what they desire. Equally worrisome is the patient who is counseled that a particular finding has more significance than it does, and she decides to have an invasive test that is not indicated and not really desired. In the current intense medicolegal environment, often medical recommendations are made more to protect the providers from possible litigation than they are based on true medical opinion. Clearly, an invasive test is unlikely to miss the diagnosis.7 It is a time for introspection. What is the current status of USG and sonographically detected markers in our country? First of all, no definite large-scale prospective or retrospective study is being done in our country to have our own norms and hence we will have to rely on the international statistics and literature available. Most of our patients fall in the category of low risk if we consider age 35 or above as the high-risk patients. The significance of these markers in the low-risk population has to be established.

For most of the patients with sonographically detected markers for congenital anomalies, the definitive invasive tests are not being done at most of the centers except for few highly specialized centers. We need to correlate our findings with biochemical markers and autopsy study. This is not done routinely because of socioeconomic constraints. The rate of abortion in the fetus with aneuploidy is relatively high and hence many of the fetuses are lost even before their first ultrasound screening. Being an operator-dependent modality, quality control and training in USG with registration and if possible grading of sonographers should be done in a specialized field like this to ensure high detection rate and standardization of practice. Last but not the least, expertise must match the technical advancement and the unavailability of high end USG units at most of the community and government healthcare set-up is an important limiting factor.

personalized risk assessment and has allowed many women a reasonable alternative to invasive test. The best estimate of risk seems to be achieved through the combined use of ultrasound, maternal serum screening and maternal age. As with many screening tests, it occasionally misses the diagnosis; this shortcoming must be well-understood. In the right hands and with appropriate counseling, ultrasound is an excellent tool. Despite its limitations, it provides information that is unmatched to other screening tests, especially when we are dealing with important issues like aneuploidy. After all, it is a teamwork that matters.

Since an entire generation of geneticians, obstetricians and perinatologists are working hard to provide a eugenic society, the onus is on the ultrasonologist and imaging specialists to assistant their clinical colleague in this task.

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Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Royston P, Chard T, et al. Maternal serum screening for Down’s syndrome in early pregnancy. BMJ 1988;297(6653):883-7.

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Palomaki GE, Knight GJ, McCarthy J, Haddow JE, Eckfeldt JH. Maternal serum screening for fetal Down syndrome in the United States: a 1992 survey. Am J Obstet Gynecol 1993;169(6):1558-62.

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Randomised trial to assess safety and fetal outcome of early and midtrimester amniocentesis. The Canadian Early and Mid-trimester Amniocentesis Trial (CEMAT) Group. Lancet 1998;351(9098):242-7.

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Wald NJ, Densem JW, George L, Muttukrishna S, Knight PG. Prenatal screening for Down’s syndrome using inhibin-A as a serum marker. Prenat Diagn 1996;16(2): 143-53.

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Philippe Jeanty. Lecture series on congenital anomalies.

CONCLUSION The application of prenatal ultrasound in aneuploidy risk assessment is a very valuable tool and based on the exponential increase in the number of research studies being published and technical advancement in the ultrasound units, the value is only going to increase further. Ultrasound allows patients to obtain more

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10. Greco P, Loverro G, Vimercati A, Marzullo A, Caruso G, Selvaggi L. Pathological significance of first-trimester fetal nuchal oedema. Prenat Diagn 1996;16(6):503-9.

11. von Kaisenberg CS, Nicolaides KH, Brand-Saberi B. Lymphatic vessel hypoplasia in fetuses with Turner syndrome. Hum Reprod 1999;14(3):823-6.

review article 12. Moscoso G. Fetal nuchal translucency: a need to understand the physiological basis. Ultrasound Obstet Gynecol 1995;5(1):6-8.

27. Pandya PP, Snijders RJ, Psara N, Hilbert L, Nicolaides KH. The prevalence of non-viable pregnancy at 10-13 weeks of gestation. Ultrasound Obstet Gynecol 1996;7(3):170-3.

13. Hyett J, Moscoso G, Nicolaides K. Increased nuchal translucency in trisomy 21 fetuses: relationship to narrowing of the aortic isthmus. Hum Reprod 1995;10(11):3049-51

28. Cicero S, Curcio P, Papageorghiou A, Sonek J, Nicolaides K. Absence of nasal bone in fetuses with trisomy 21 at 11-14 weeks of gestation: an observational study. Lancet 2001;358(9294):1665-7.

14. Pandya PP, Johnson SP, Malligianis P, Nicolaides KH. First trimester fetal nuchal translucency and screening for chromosomal abnormalities. In: Ultrasound and Early pregnancy. Jurkovic, Jauniaux (Eds.), Parthenon Publishing, London and New York 1996:p.81-94.

15. Assessment of risks. In: Ultrasound Markers for Fetal Chromosomal Defects. Sniijders RJ, Nicolaides KH (Eds.), 1996:p.63-120.

16. Pandya PP, Goldberg H, Walton B, Riddle A, Shelley S, Snijders RJ, et al. The implementation of first-trimester scanning at 10-13 weeks’ gestation and the measurement of fetal nuchal translucency thickness in two maternity units. Ultrasound Obstet Gynecol 1995;5(1):20-5.

17. Hafner E, Schuchter K, Liebhart E, Philipp K. Results of routine fetal nuchal translucency measurement at weeks 10-13 in 4233 unselected pregnant women. Prenat Diagn 1998;18(1):29-34.

18. Nicolaides KH, Brizot ML, Snijders RJ. Fetal nuchal translucency: ultrasound screening for fetal trisomy in the first trimester of pregnancy. Br J Obstet Gynaecol 1994;101(9):782-6.

19. Bewley S, Roberts LJ, Mackinson AM, Rodeck CH. First trimester fetal nuchal translucency: problems with screening the general population. 2. Br J Obstet Gynaecol 1995;102(5):386-8.

20. Cha’ban FK, Van Splunder P, Los FJ, Wladimiroff JW. Fetal outcome in nuchal translucency with emphasis on normal fetal karyotype. Prenat Diagn 1996;16(6):537-41.

21. Reynders CS, Pauker SP, Benacerraf BR. First trimester isolated fetal nuchal lucency: significance and outcome. J Ultrasound Med 1997;16(2):101-5.

22. Snijders RJ, Noble P, Sebire N, Souka A, Nicolaides KH. UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal-translucency thickness at 10-14 weeks of gestation. Fetal Medicine Foundation First Trimester Screening Group. Lancet 1998;352(9125):343-6.

23. Scott F, Boogert A, Sinosich M, Anderson J. Establishment and application of a normal range for nuchal translucency across the first trimester. Prenat Diagn 1996;16(7):629-34.

24. Nancy Walsh. Nuchal translucency helps identify aneuploidy in high-risk patients. (Brief Article): An article from: Family Practice News, 2005.

25. Pandya PP, Brizot ML, Kuhn P, Snijders RJ, Nicolaides KH. First-trimester fetal nuchal translucency thickness and risk for trisomies. Obstet Gynecol 1994;84(3):420-3.

26. Benn PA. Advances in prenatal screening for Down syndrome: II first trimester testing, integrated testing, and future directions. Clin Chim Acta 2002;324(1-2):1-11.

29. Wald NJ, Hackshaw AK. Combining ultrasound and biochemistry in first-trimester screening for Down’s syndrome. Prenat Diagn 1997;17(9):821-9.

30. Otaño L, Aiello H, Igarzábal L, Matayoshi T, Gadow EC. Association between first trimester absence of fetal nasal bone on ultrasound and Down syndrome. Prenat Diagn 2002;22(10):930-2.

31. Viora E, Masturzo B, Errante G, Sciarrone A, Bastonero S, Campogrande M. Ultrasound evaluation of fetal nasal bone at 11 to 14 weeks in a consecutive series of 1906 fetuses. Prenat Diagn 2003;23(10):784-7.

32. Cicero S, Rembouskos G, Vandecruys H, Hogg M, Nicolaides KH. Likelihood ratio for trisomy 21 in fetuses with absent nasal bone at the 11-14-week scan. Ultrasound Obstet Gynecol 2004;23(3):218-23.

33. Favre R, Cherif Y, Kohler M, Kohler A, Hunsinger MC, Bouffet N, et al. The role of fetal nuchal translucency and ductus venosus Doppler at 11-14 weeks of gestation in the detection of major congenital heart defects. Ultrasound Obstet Gynecol 2003;21(3):239-43.

34. Murta CG, Moron AF, Avila MA, Weiner CP. Application of ductus venosus Doppler velocimetry for the detection of fetal aneuploidy in the first trimester of pregnancy.

Fetal Diagn Ther 2002;17(5):308-14.

35. Bilardo CM, Müller MA, Zikulnig L, Schipper M, Hecher K. Ductus venosus studies in fetuses at high risk for chromosomal or heart abnormalities: relationship with nuchal translucency measurement and fetal outcome. Ultrasound Obstet Gynecol 2001;17(4):288-94.

36. Matias A, Montenegro N. Ductus venosus blood flow in chromosomally abnormal fetuses at 11 to 14 weeks of gestation. Semin Perinatol 2001;25(1):32-7.

37. Zoppi MA, Putzolu M, Ibba RM, Floris M, Monni G. First-trimester ductus venosus velocimetry in relation to nuchal translucency thickness and fetal karyotype. Fetal Diagn Ther 2002;17(1):52-7.

38. Mavrides E, Sairam S, Hollis B, Thilaganathan B. Screening for aneuploidy in the first trimester by assessment of blood flow in the ductus venosus.

BJOG 2002;109(9):1015-9.

39. Borrell A, Martinez JM, Serés A, Borobio V, Cararach V, Fortuny A. Ductus venosus assessment at the time of nuchal translucency measurement in the detection of fetal aneuploidy. Prenat Diagn 2003;23(11):921-6.

40. Levi CS, Lyons EA, Lindsay DJ. Ultrasound in the first trimester of pregnancy. Radiol Clin North Am 1990;28(1):19-38.

41. Levi CS, Lyons EA, Lindsay DJ. Early diagnosis of nonviable pregnancy with endovaginal US. Radiology 1988;167(2):383-5.

42. Lyons EA, Levi CS. Ultrasound in the first trimester of pregnancy. Radiol Clin North Am 1982;20(2):259-70.

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Original Study

Role of a Polyherbal Children Health Drink (HiOwna-Jr) in General Health and Cognition of Children: A Preliminary Clinical Safety and Efficacy Study D Palani*, MB Manu**, Suprabha Hegdeâ&#x20AC;

Abstract Background: Many children worldwide suffer from nutritional deficiencies, which adversely affect their physical and mental development and increase susceptibility to infections. Meeting the nutritional demands required for development is crucial for optimal health of children, which directly influences physical and mental health later in life. Aim: To evaluate the clinical efficacy and safety of a polyherbal formulation in maintaining general growth, health and cognition in children.

Material and Methods: An open clinical trial was conducted in children after approval from the ethical committee. Fifty children, both male and female, aged between 2-10 years and whose parent or guardian had given the consent to participate in the clinical study were included in the trial. Subsequently, all children underwent a simple physical and systemic examination.

They were advised to consume the respective formulations as defined by the protocol as follows: The subjects in the age group 2-6 years were instructed to take 12.5 g; those in 7-10 years age group were instructed to take 25 g of the health drink along with milk orally twice-daily for the period of two months. All the enrolled children were monitored at monthly intervals for two months, for the effect of health drink as well as any reported or observed adverse effects. At each visit, the subjects were evaluated for general health and growth. In addition, cognition was evaluated in children aged between 5-10 years.

Results: Height, weight and BMI and general health improved with the use of HiOwna-Jr as determined by reduction of the frequency of respiratory illness and improving appetite in children between 2-10 years of age. Cognition parameters like attention, memory and concentration in children aged 5-10 years also showed beneficial results. All the children liked the formulation and completed the study. Overall compliance to the study was good. No adverse effects were either reported or observed. Conclusion: Therefore, it can be concluded that HiOwna-Jr given in addition to regular balanced diet helps to maintain adequate natural linear growth, enhances immunity and favorably modifies cognition in children.

Keywords: HiOwna-Jr, growth, cognition

M

icronutrient deficiencies compromise the health and development of many children worldwide.

They can negatively affect their physical and mental development and increase susceptibility to infections.1-3 Micronutrient interventions might benefit the health and development of children and multiple micronutrients might be more effective than single micronutrients. Food fortification is a practical way to provide extra micronutrients to children. Recent estimates indicate that 20% of young children are underweight, 32% are stunted and 10% are wasted, which increases mortality and morbidity and also hinders them from meeting their full potential.4,5 *Medical Advisor **Chief Medical Officer â&#x20AC; Ayurvedic Expert Research and Development, The Himalaya Drug Company, Makali, Bangalore Address for correspondence Dr D Palani MBBS, MD (Pharmacology) Medical Advisor, Research and Development The Himalaya Drug Company, Makali, Bangalore - 562 123 E-mail: dr.palani@himalayahealthcare.com

Intercurrent illness plays a significant role when growth and weight gain are marginal in the baseline state. Specifically, intercurrent infection may cause poor intake because of lethargy and vomiting, or may produce a hypermetabolic state because of fever.

The immunocompromised are more prone to gastrointestinal (GI) infections, and it is important to consider opportunistic infections such as gram-negative, staphylococcal, fungal and parasitic infestations.

Patients who have disabilities may convalesce more slowly due to their hypostatic state and inability to rid themselves of respiratory secretions. Urinary tract infections (UTIs) are more common because of a neurogenic bladder associated with central nervous system (CNS) and spinal conditions, or because of congenital urologic anomalies. Other intercurrent conditions include inflammatory conditions such as collagen vascular disease, inflammatory bowel disease and malignancy.6 Undernutrition, growth failure, overweight, micronutrient deficiencies and osteopenia are nutritional

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Original Study comorbidities that affect the neurologically impaired child. Studies have reviewed the epidemiology, pathogenesis, assessment and treatment of these disorders in neurologically impaired children.7,8 All children and adolescents have caloric requirements necessary for metabolism, growth, activity, fecal losses and specific dynamic action of protein. The basic building blocks that provide these calories are protein, including essential amino acids (approximately 4 cal/g); fat, including essential fatty acids (approximately 9 cal/g); and carbohydrate (approximately 4 cal/g).

In addition, it is important to consider water, trace element and vitamin needs. To attain normal growth, it is necessary to meet both height and weight needs.

All nutrients must be ingested, retained, processed, absorbed, metabolized and excreted; the net result of which should produce nutritional sufficiency. Ingestion and retention are dependent upon proper mechanics.

As children and adolescents are all works in progress, there are changes over time in metabolic, activity and growth needs in all of them, disabled or not. It is impossible to establish a single simple formula or equation to calculate all dietary needs.6 Children with neurological disabilities usually have progressive weight deficits due to fat loss, although muscle and visceral proteins are maintained. Some children demonstrate a lack of weight gain in the presence of linear growth, leading to a decreased body mass index (BMI). Others have progressive muscle atrophy unresponsive to nutritional intervention because of their underlying disorder. Although neurologically impaired children are usually shorter and weigh less than unaffected children, a small proportion (8-14%) may be overweight based on weight-forheight or triceps skin fold thickness criteria.9,10 Globally, the overall quality of the diet of school-age children and adolescents may be inadequate in large parts of the population. Families with a low socioeconomic status often cannot afford healthy diets;11 they have less access to micronutrient-rich foods like fruits, vegetables, meat, fish and dairy.12 Also, school-age children may have more independent eating pattern;13 this can include more out-of-home food consumption without supervision, which is likely to result in increased intake of foods of low nutritional value, such as soft drinks and salty snacks in place of micronutrient-rich foods.14 School-age children and adolescents are in a stage of considerable physical and mental development. The brain continues to mature until young adulthood, and cognitive functions, in particular the higher-

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order cognitive functions (reasoning, planning, abstract thinking, etc.), develop and become more structured during this period.15 Hence, it is crucial to meet the nutritional demands for optimal health, which can influence health and productivity later in life. Undernutrition is also related to an increased risk of morbidity.16 Vitamin A and zinc deficiency are associated with impaired immune function and higher susceptibility to infection and diarrhea.17 Deficiency of micronutrients like iodine may affect mental development,18 leading to structural and functional impairment of the CNS.19 Undernourished or anemic children are less active and less likely to explore and interact with their environment, which can lead to suboptimal development.20 Interventions with (multiple) micronutrients have led to beneficial effects on linear growth,21 health22 and cognitive development23 in school children.

Wide range of contemporary and stylish health drinks are available for children as they are always active and playing during this age and the pressure is on the home maker to keep the energy level of the kids.

These are available in various flavors in order to meet the changing consumer preferences and good enough to attract children.

HiOwna-Jr is an innovative natural polyherbal formulation designed to promote general health and wellbeing of children, to support the optimum natural linear growth and development of children between 2-10 years of age, to additionally enhance immunity and to help maintain adequate natural cognitive function.

Aim To evaluate the clinical efficacy and safety of a polyherbal formulation in maintaining health, growth and cognition in children.

Material and Methods This was an open clinical trial conducted in children of known families. Local ethical committee approval was obtained before initiation of the study. Those who opted for treatment were informed of voluntary nature of trial and written consent was obtained from the parent or guardian. They were free from withdrawal of the study.

Inclusion Criteria Fifty children including both male and female, aged between 2-10 years and whose parent or guardian had given the consent to participate in the clinical study was

Original Study included in the trial. Children suffering from any cardiac, hepatic or renal failure or regularly on any treatment or concurrently taking medicines for any illness, any congenital anomaly like cleft lip, etc., which hampers food intake were excluded from the study. Those with a strong history of food or drug allergy of any kind and subjects parent not willing to provide informed consent or abide by the requirements of the study.

Informed Consent Process All parents who were willing their children to participate in the study were given detailed description about the investigational product, nature and duration of the study. Also, subject’s responsibilities after entering, the study were explained. Subjects were prescreened by the investigators for the inclusion criteria. Only subjects who met the requirements of this section, signed an informed consent form (by the parent/guardian), subjects or parents and guardian who were willing to follow instructions given by the investigator and have an updated medical history on file with the investigator were entered in the study.

A written informed consent by the parent or guardian using an ‘informed consent form’ was obtained from each study subject. The parent or guardian of each study subject was informed about the study verbally as well as using a patient information sheet, in an easy-tounderstand language.

2: Able to recollect 4-7 of the objects 3: Able to recollect >7 of the object At each follow-up visit, information about intercurrent illness, therapeutic interventions and concomitant medication/s were recorded. All the adverse events reported or observed by patients were also recorded with information about severity, date of onset, duration and action taken regarding the study drug.

The demographic data is presented in Table 1.

Relation of adverse events to study medication was predefined as ‘Unrelated’ (a reaction that does not follow a reasonable temporal sequence from the administration of the drug), ‘Possible’ (follows a known response pattern to the suspected drug, but could have been produced by the subject’s clinical state or other modes of therapy administered to the subject), and ‘Probable’ (follows a known response pattern to the suspected drug that could not be reasonably explained by the known characteristics of the subject’s clinical state).

Blood investigations were not performed for any subjects during the study procedure. 



Primary endpoints: Improvement in general health, growth and cognition.

Secondary endpoints: Short-term safety as assessed by incidence of adverse events, and compliance to the drug therapy.

Study Procedure

Statistical Analysis

At entry, a detailed medical history was obtained from all the enrolled subjects. All children then underwent a simple physical and systemic examination. All children were advised to consume the respective formulations as defined by the protocol as follows: The subjects in the age group 2-6 years were instructed to take 12.5 g; those in the 7-10 years age group were asked to take 25 g of the health drink along with milk orally twicedaily for the period of two months.

All values are expressed as compared to ‘At entry’ as mean ± SD. Statistical analysis was performed using repeated measures of ANOVA followed by Tukey’s multiple comparison test for parameters like height, weight and BMI. Functional parameters like appetite, frequency of respiratory tract infection (RTI) and cognitive attention, memory and concentration was evaluated by repeated measures of ANOVA using Friedman test followed by Dunnett’s multiple comparison test.

Subjects were assessed at entry and at monthly intervals for the period for two months. At each visit the subjects were evaluated for general health and growth.

Cognition (attention, memory and concentration) was also evaluated in children aged between 5-10 years. Ten commonly seen objects were kept and the children were asked to observe these objects and recollect and tell the name of the object. They were scored from 0 to 3: 0: Nil 1: Able to recollect 1-3 of the objects

The minimum level of significance was fixed at p < 0.05. Statistical analysis was performed using Graphpad Prism Software Version 4.00 for Windows, San Diego, California, USA. Table 1. Demographic Characteristics on Entry Number of subjects Age (years) Sex (M:F)

40 5.75 ± 2.62 (Min: 2 years; Max: 10 years) 24:16

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Original Study Results The effect of HiOwna-Jr on parameters of height, weight and BMI are shown in Table 2. The mean height (cms), which was 110.6 ± 18.1 at entry, improved to 111.3 ± 18.3 by the first month (p < 0.001) and it further improved to 112.4 ± 18.5 at 2 months (p < 0.001). Mean weight (kgs), which was 18.70 ± 5.23 at entry improved to 19.12 ± 5.23 at the first month and further improved to 19.27 ± 5.23 at 2 months after HiOwna-Jr administration. Similarly, BMI (kg/m2) also improved from 15.19 ± 1.85 at entry to 15.36 ± 1.96 at the first month (p < 0.001) and further to 15.19 ± 1.97 at 2 months (p < 0.001) following HiOwna-Jr administration.

The effects on general health functional parameters like appetite, frequency of RTI are shown in Table 3.

The appetite score, which was 1.53 ± 0.51 at entry, improved to 2.53 ± 0.51 at the first month (p < 0.001 as compared to at entry value), which further improved to 2.88 ± 0.33 at 2 months (p < 0.001) with HiOwna-Jr administration. Frequency of RTI which was 1.58 ± 1.01 at entry improved to 0.83 ± 0.75 at first month (p < 0.001 as compared to at entry values), which further improved to 0.33 ± 0.47 with continued HiOwna-Jr administration at 2 months (p < 0.001).

The effect of HiOwna-Jr on cognitive parameters like attention, memory and concentration in children of age group 5-10 years are shown in Table 4.

Attention score at entry was 1.52 ± 0.51. It improved to 2.40 ± 0.58 (p < 0.001 as compared to at entry values) at the first month, which further improved to 2.92 ± 0.28 at the end of second month (p < 0.001) with HiOwna-Jr administration. Similarly, memory score, which was 1.60 ± 0.50 at entry improved to 2.40 ± 0.58 at first month (p < 0.001) and further improved to 2.96 ± 0.20 at 2 months (p < 0.001) after HiOwna-Jr administration. Concentration also improved from 1.56 ± 0.51 to 2.60 ± 0.50 at first month (p < 0.001 as compared to at entry value) and further improved to 2.84 ± 0.37 at the second month (p < 0.001) following administration of HiOwna-Jr. For all the parameters, the results indicate marked improvement in most subjects on HiOwna-Jr treatment for a period of two months. No clinically significant adverse reactions were either reported or observed, during the entire study period and overall compliance to the treatment was excellent.

Discussion Low energy and protein intakes are the primary cause for poor growth and undernutrition due to protein energy deficiency and are associated

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Table 2. Effect of HiOwna-Jr on Height, Weight and BMI (n = 40) Parameter

At entry

1st month

2nd month

Height (cms)

110.6 ± 18.1

111.3 ± 18.3 ap < 0.001

112.4 ± 18.5 a,bp < 0.001

Weight (kgs)

18.70 ± 5.23

19.12 ± 5.23 ap < 0.001

19.27 ± 5.23 a,bp < 0.001

BMI (kg/m2)

15.19 ± 1.85

15.36 ± 1.96 ap < 0.001

15.19 ± 1.97 a,bp < 0.001

aAs

compared to at entry values; bAs compared to 1st month values.

Table 3. Effect of HiOwna-Jr on Functional Parameters (n = 40) Parameter

At entry

1st month

2nd month

Appetite

1.53 ± 0.51

2.53 ± 0.51 ap < 0.001

2.88 ± 0.33 ap < 0.001

Frequency of RTI

1.58 ± 1.01

0.83 ± 0.75 ap < 0.001

0.33 ± 0.47 ap < 0.001 bp < 0.05

aAs

compared to at entry values; bAs compared to 1st month values.

Table 4. Effect of HiOwna-Jr on Cognitive Functional Parameters in Children Aged between 5-10 Years Age Group (n = 25) Parameter

At entry

1st month

2nd month

Attention

1.52 ± 0.51

2.40 ± 0.58 ap < 0.001

2.92 ± 0.28 ap < 0.001

Memory

1.60 ± 0.50

2.40 ± 0.58 ap < 0.001

2.96 ± 0.20 ap < 0.001

Concentration 1.56 ± 0.51

2.60 ± 0.50 ap < 0.001

2.84 ± 0.37 ap < 0.001

aSignificance

as compared to at entry values.

with increased susceptibility to infectious diseases.

Food fortification is a practical way to combine the benefits of energy repletion, adequate supply of fat and protein, micronutrients to optimize the growth and development of children. Mental development of children can be affected by malnutrition directly through insufficient supply of essential micronutrients, leading to structural and functional impairment of the CNS. Micronutrient deficiencies can also have an indirect effect on mental and motor development.

Undernourished or anemic children are less active and less likely to explore and interact with their environment, which can lead to suboptimal development. Interventions with (multiple) micronutrients have led to beneficial effects on linear growth, health and cognitive development in school children.

Original Study HiOwna-Jr contains principal herbal ingredients like Nartaka (Eleusine coracana), Maricha (Piper nigrum), Amalaki (Emblica officinalis), Mandukaparni (Centella asiatica) and other nutrients like sucrose, peeyusha (colostrum) skimmed milk powder, corn solids (maltodextrin), pea protein powder, whey protein concentrate, minerals (calcium, phosphorous, iron, magnesium, zinc, chromium, selenium, molybdenum, iodine), vitamins (vitamin A, vitamin C, vitamin D, vitamin E, vitamin K, vitamin B1, vitamin B2, vitamin B6, vitamin B12, niacin, biotin, folic acid and pantothenic acid). These ingredients provide balanced nutrition and help in promoting overall health of children by their nutritive, energy boosting, digestive, memory enhancing and immunomodulatory properties.

Proteins, carbohydrates and fats provide energy, promote growth and development and regulate body functions. Vitamins and minerals have a beneficial effect on linear growth, health and cognitive development in school children. The beneficial effects of the health drink are discussed as follows:

Nutritive and Health-promoting E. coracana is known for its nutritive and strength enhancing properties.24,25 It is rich in protein, iron, calcium, phosphorus, fiber and vitamins. The calcium content is higher than all cereals. Ragi contains the best quality protein including essential amino acids, vitamin A, vitamin B and phosphorus. Thus, it is a good source of diet for growing children. Ragi provides highest level of calcium, antioxidants, phytochemicals, which makes it easily and slowly digestible. Malting of finger millet improves its digestibility, sensory and nutritional quality as well as pronounced effect in the lowering the antinutrients.26 Bovine colostrum is an excellent source of nutrition which helps in promoting body growth.27 Proteins, carbohydrates and fat are required for growth, maintenance and highly specialized functions of the body as well as energy sources.28 Vitamins and minerals are known for their health promoting functions in the body.29

Enhancement of Nutrient Absorption and Gastroprotective Effects P. nigrum, which is a rich source of piperine increased the secretion of bile in experimental studies.30 This suggests that it aids the digestion and absorption of dietary fats. It has been found to protect against the gastric damage caused by gastric irritant agents, which might be related to the inhibition of gastric motor activity and the stimulation of prostaglandin synthesis.31 Dietary piperine, by favorably stimulating

the pancreatic digestive enzymes enhances the digestive capacity and significantly reduces the GI food transit time, increases bioavailability of many phytochemicals by its inhibitory influence on enzymatic drug biotransforming reactions in the liver. This property is also partly attributed to increased absorption due to its effect on the ultrastructure of intestinal brush border.32

Immunomodulatory Activity An experimental study showed that the presence of E. officinalis or Amla was effective against the cytotoxic effects of chromium (Cr)-induced oxidative damage of murine macrophages and enhanced cell survival, decreased free radical production and led to higher antioxidant levels similar to that of control cells. Further, Cr treatment decreased phagocytosis and γ-interferon (γ-IFN), while E. officinalis inhibited Cr-induced immunosuppression and significantly restored both phagocytosis and γ-IFN production by macrophages.33 These findings indicate its cytoprotective and immunomodulatory properties. In another in vitro study, E. officinalis relieved the immunosuppressive effects of Cr on lymphocyte proliferation and even restored the IL-2 and γ-IFN production considerably.34 An experimental study conducted on mice demonstrated that the aqueous extract of E. officinalis was very effective in reducing cyclophosphamide-induced suppression of humoral immunity.35 Bovine colostrum had the ability to increase IgA indicating its potential to enhance human special immune response.36

Promoting Mental Health A double-blind clinical trial on C. asiatica observed a significant increase in the general mental ability of mentally retarded children after three months and six months of administration. Significant improvement was found in the overall general adjustment, attention and concentration after six months.37 Another study concluded that C. asiatica leaf extract had a neuronal dendritic growth stimulating property; hence, the extract could be used to enhance neuronal dendrites in stress and neurodegenerative and memory disorders.38 These studies indicate that C. asiatica improves memory and learning ability. Micronutrients such as vitamins and minerals when delivered through either supplements or fortified foods were found to have a positive effect on reasoning ability and academic performance in school children.39 Conclusion This clinical study clearly demonstrates that HiOwna-Jr, an polyherbal natural health drink supplement, when

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Original Study given in addition to regular diet showed a trend towards improvement in the growth as determined by height, weight and BMI including general health as determined by reduction of the frequency of RTI and improving appetite in children aged 2-10 years. The improvement in the growth corresponded to the normal natural growth in the children, which implies that HiOwna-Jr helps in the natural normal linear growth of children.

Cognition parameters like attention, memory and concentration evaluated in school-going children aged 5-10 years also showed beneficial results. All the children liked the taste and flavor and there were no dropouts. Overall compliance to the study was good.

No adverse effects were either reported or observed during the clinical study. It is safe without any adverse effects for short-term and long-term use. Therefore, it can be concluded that HiOwna-Jr given in addition to regular balanced diet helps to maintain adequate natural linear growth, enhances immunity and favorably modifies cognition in children.

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Original article

An Efficacy, Safety and Tolerability Study of Ferrous Ascorbate and Folic Acid (Phosfomin-XT) in Iron Deficiency Anemia BB Adsul*, Qayum Mukaddam**, Prashant Khandeparkar**, Manoj Naik**

Abstract Aim: This study was aimed to assess efficacy, safety and tolerability of combination of ferrous ascorbate and folic acid (Phosfomin-XT) in patients with iron deficiency anemia (IDA). Settings and design: A total of 56 patients, who were between 18-55 years of age, with hemoglobin (Hb) 6-9 g/dl and serum ferritin <15 mg/l also complying with the inclusion and exclusion criteria in the protocol were enrolled in the study after obtaining necessary approvals and informed consent. All were dispensed with Phosfomin-XT fixed-dose combination (FDC) of ferrous ascorbate (equivalent to elemental iron 100 mg) + folic acid 1.5 mg tablet once-daily after food for eight weeks. Patients were assessed at baseline and Weeks 2, 4, 6 and 8 for change in Hb level, clinical evaluation and target Hb achievement. Results: Baseline mean Hb was 08.39 ± 0.75 g/dl, which significantly increased to 9.76 ± 0.70 g/dl (16.3%) at Week 2 and further increased to 10.70 ± 0.70 g/dl (27.53%) at Week 4. At Week 6, it increased to 11.55 ± 0.67 g/dl (37.7%) and at Week 8, it increased to 12.53 ± 1.09 g/dl. Conclusions: The present study concludes that Phosfomin-XT (ferrous ascorbate, equivalent to elemental iron 100 mg + folic acid 1.5 mg) tablet should be preferred as first choice of oral iron salts to treat IDA due to positive effect on Hb value and superior tolerability.

Keywords: Iron deficiency anemia, ferrous ascorbate, folic acid

I

ron deficiency is the most common single cause of anemia worldwide, accounting for about half of all anemia cases. Estimates of iron deficiency worldwide range very widely, but the number almost certainly exceeds one billion globally.1 The principal cause of iron deficiency anemia (IDA) in developing countries is blood lost during menstruation in premenopausal women and not compensated by intake from food and supplements.

India continues to be one of the countries with very high prevalence. The National Family Health Survey (NFHS-3) reveals the prevalence of anemia to be 70-80% in children, 70% in pregnant women and 24% in adult men. Prevalence of anemia in India is high because of low dietary intake, poor availability of iron and chronic blood loss due to hookworm infestation and malaria.2-4 IDA is one result of an advanced stage iron deficiency, which is even more *Associate Professor Dept. of Community Medicine, LTMMC and LTMG Hospital, Sion, Mumbai **Medical Services Division, Abbott Healthcare Pvt. Ltd., Mumbai Address for correspondence Dr BB Adsul Associate Professor Dept. of Community Medicine, LTMMC and LTMG Hospital Sion, Mumbai - 400 022

common. Iron deficiency ranges from iron depletion, which yields little physiological damage, to IDA, which can affect the function of numerous organ systems.

Iron depletion causes the amount of stored iron to be reduced, but has no effect on the functional iron.

However, a person with no stored iron has no reserves to use if the body enters a state in which it requires more iron than is being absorbed from the diet.

Folic acid, after absorption from the gastrointestinal tract, is converted to tetrahydrofolic acid by the liver, which is a cofactor in the biosynthesis of purines and thymidylates of nucleic acids. An exogenous source of folic acid is necessary for the maintenance of normal erythropoiesis.

A study suggests that there is 2-fold relation in IDA and folic acid deficiency, where it is likely that in both IDA and megaloblastic anemia, iron deficiency plays an important part in converting subclinical folic acid deficiency by producing additional stress of folate metabolism.3 Aim To establish the efficacy, safety and tolerability of the combination of ferrous ascorbate and folic acid in treatment of IDA.

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Original article

Design This was an open prospective noncomparative post marketing clinical trial conducted at the OPD of LTMMC and LTMG Hospital, Sion, Mumbai. The study was conducted in keeping with the principles described in the Declaration of Helsinki and Indian Good Clinical Practices (GCP) guidelines. The clinical trial protocol was approved by the Institutional Ethics Committee.

Inclusion Criteria A total of 56 patients of both genders, who were between 18-55 years of age, visiting the OPD were enrolled in the study after obtaining written informed consent from each. The inclusion criteria were: Patient not on any iron supplement for three months prior to enrolment to the study and presence of IDA: Low hemoglobin (Hb 6-9 g/dl) + low serum ferritin (<15 µg/l) showing no occult blood in stool.

Exclusion Criteria Patients who were pregnant (confirmed with dipstick method), planning to conceive within next three months including patients who were receiving treatment to facilitate conception, lactating women, were excluded from the study. Also, patients suspected of hypersensitivity to iron or any of the components or ferrous ascorbate were also excluded from the study.

Procedures All the patients enrolled in the study were dispensed with fixed-dose combination (FDC) of ferrous ascorbate (equivalent to elemental iron 100 mg) + folic acid 1.5 mg (Phosfomin-XT) once-daily after food for eight weeks. Patients were assessed at baseline and Weeks 2, 4, 6 and 8 (end of the study) for change in mean Hb level from baseline to each visit. Evaluation of clinical signs and symptoms of anemia were also assessed at each visit.

Percentage of patients achieving target Hb level of ≥12 g/dl were assessed at the end of the study. Global assessment of efficacy by patient and investigator was assessed at the end of the study on a 4-point rating scale. Safety was assessed by percentage incidence of gastrointestinal side effects during eight weeks of treatment with study drug and other adverse events of treatment. Global assessment of tolerability was also assessed at end of the study.

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Results Fifty patients were included for final efficacy analysis, six patients were lost to follow-up. Demographic data had mean age of 32.18 ± 10.4 (years), mean weight of 48.15 ± 8.44 (kg) and mean height of 152.28 ± 6.44 (cm) showing normality of the cases (Table 1). Baseline mean pulse rate was 84.64 ± 5.80, mean 98.33 ± 0.41, mean respiratory rate was 19.04 ± 7.68, mean systolic blood pressure was 117.5 ± 7.73 and mean diastolic blood pressure was 73.00 ± 6.42, which also indicates the normality. Baseline mean Hb was 08.39 ± 0.75 g/dl, which significantly increased to 9.76 ± 0.70 g/dl (16.3%) at Week 2 and further increased to 10.70 ± 0.70 g/dl (27.53%) at Week 4.

At Week 6, it increased to 11.55 ± 0.67 g/dl(37.7%) and at Week 8, it increased to 12.53 ± 1.09 g/dl. At all visits the surge was significant (p < 0.05) (Fig. 1). Percentage of patients achieving target Hb level of ≥12 mg/dl was significant (p < 0.05) at Week 6 (44.00%) and at Week 8 (76.00%) (Fig. 2 and Table 2).

Baseline percentage of patients having moderate-tosevere fatigue was 74.00%, which significantly reduced to 24.00% after two weeks and 2.00% after six weeks.

None of the patients had fatigue at the end of the study Table 1. Demographic Data (n = 56) Criteria

No.

Patients enrolled

56

Patients dropout

06

Cases analyzed for efficacy

50

Parameter

Mean

SD

Range

Age (years)

32.18

10.04

19-53

Weight (kg)

48.15

8.44

32-77

Height (cm)

152.28

6.44

135-169

Mean hemoglobin level

Methods

20 18 16 14 12 10 8 6 4 2 0

Changes in mean hemoglobin level after the treatment

8.39

Baseline

9.76

10.70

2 4 Duration in weeks

Figure 1. Mean hemoglobin changes.

11.55

6

12.53

8

Original article (p < 0.05). Moderate-to-severe pallor was observed in 88.00% patients at baseline, which reduced to 26% at Week 2 and 10.00% at Week 4. In none of the patients moderate-to-severe pallor was observed at Week 6 and Week 8 (p < 0.05). Breathlessness due to anemia was observed in 4.00% cases at baseline which significantly reduced to 2% at Week 2 and 0.00% at Weeks 4, 6 and 8 (p < 0.05) (Table 3).

Changes in proportion of cases with achieved targets of ≥12 hemoglobin level

Proportion of cases

100 90 80 70 60 50 40 30 20 10 0

≥12 ≤12

Global Assessment Baseline

2 4 6 Duration in weeks

Global assessment for efficacy by patients and investigator towards the therapy showed that 98.00% patients observed good-to-excellent efficacy (Fig. 3).

Global assessment for tolerability by investigator and patient showed that 99.00% patients tolerated the medication well (Fig. 4).

8

Figure 2. Percentage of patients achieving target hemoglobin.

Table 2. Changes in Mean Hemoglobin Level after the Treatment Duration in weeks

Mean Hb (g/dl) (X ± SD)

Adverse Events Only four out of 56 patients had adverse events, which were mild in intensity and did not persist beyond two weeks. Adverse events included nausea (1 patient), constipation (2 patients), vomiting (1 patient) (Table 4).

Hb levels (g/dl) from baseline

Baseline

08.39 ± 0.75

2

*09.76 ± 0.70

1.36

4

*10.70 ± 0.70

2.31

6

*11.55 ± 0.67

3.16

8

*12.53 ± 1.09

4.14

Discussion Iron deficiency anemia is the commonest occurring anemia in Indian population. Estimates suggest that over one-third of the world’s population suffers from

By student ‘t’ test, *p < 0.05 significant.

Table 3. Efficacy Parameters (Signs and Symptoms) Parameters Fatigue

Pallor

Breathlessness

Duration

None

Mild

Moderate

Severe

No

%

No

%

No

%

No

%

Baseline

11

022.0

02

04.0

26

52.0

11

22.0

2 weeks

12

024.0

26

52.0

*11

22.0

*01

02.0

4 weeks

32

064.0

15

30.0

*03

06.0

-

-

6 weeks

46

092.0

03

06.0

*01

02.0

-

-

8 weeks

*50

100.0

-

-

-

-

-

-

Baseline

-

-

06

12.0

34

68.0

10

20.0

2 weeks

05

010.0

32

64.0

*12

24.0

*01

02.0

4 weeks

32

064.0

13

26.0

*05

10.0

-

-

6 weeks

*45

090.0

05

10.0

-

-

-

-

8 weeks

*50

100.0

-

-

-

-

-

-

Baseline

48

096.0

02

04.0

-

-

-

-

2 weeks

49

098.0

01

02.0

-

-

-

-

4 weeks

50

100.0

-

-

-

-

-

-

6 weeks

50

100.0

-

-

-

-

-

-

8 weeks

50

100.0

-

-

-

-

-

-

*By Chi-square test, p < 0.05 significant.

Indian Journal of Clinical Practice, Vol. 22, No. 11, April 2012

567

Original article 2.0%

48.0%

Excellent Good Fair Poor

50.0%

Figure 3. Overall global assessment of efficacy at the end of study by investigator.

2.0%

30-60 mg is used as prophylaxis for IDA in pregnancy, and also for treatment of IDA in children. Folic acid being a very essential vitamin in process of erythropoiesis has significant role in keeping the cell morphology intact. It is observed that low serum folate levels are associated with the iron deficiency and thus are related to the vicious cycle of deficiencies of iron and folate.5 Combination of ferrous ascorbate and folic acid covers both the aspects of IDA, where ferrous ascorbate covers fastest rise in iron levels and folic acid covers serum folate levels. There are no published studies on efficacy of FDC of ferrous ascorbate and folic acid in the treatment of IDA. In the present study, a significant improvement was seen in Hb levels, signs and symptoms of IDA like fatigue, pallor, breathlessness with FDC of ferrous ascorbate and folic acid. This FDC of ferrous ascorbate and folic acid also showed excellent gastrointestinal tolerability.

Conclusion

44.0%

Excellent Good Fair Poor

54.0%

Figure 4. Overall global assessment of tolerability at the end of study by investigator.

Table 4. Adverse Events

This study was an effort to assess the efficacy and tolerability of the FDC of ferrous ascorbate and folic acid and seems to show very promising outcomes although further studies on bigger sample size can be more conclusive.

Phosfomin-XT (ferrous ascorbate, equivalent to elemental iron 100 mg + folic acid 1.5 mg) tablet should be preferred as first choice of oral iron salts to treat IDA due to its effect on improvement in Hb levels and excellent gastrointestinal tolerability.

Acknowledgment

Events

No of cases (n = 56)

Percentage (%)

Nausea

01

01.8

Constipation

02

03.6

References

Vomiting

01

01.8

1.

Total

04

06.0

Brady PG. Iron deficiency anemia: a call for progressive diagnostic evaluation. South Med J 2007;100(10):966-7.

2.

Government of India National Family Health Survey-3 (2005-2006). Vol. 11, Chapter-8, Maternal Health International Institute for Population Sciences 2007:p191-22.

3.

Chanarin I, Rothman D, Berry V. Iron deficiency and its relation to folic-acid status in pregnancy: results of a clinical trial. Br Med J 1965;1(5433):480-5.

4.

Johnson G, Jacobs P. Bioavailability and the mechanisms of intestinal absorption of iron from ferrous ascorbate and ferric polymaltose in experimental animals.

Exp Hematol 2009;18(10):1064-9.

5.

Morris MS, Jacques PF, Rosenberg IH, Selhub J. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr 2007;85(1):193-200.

anemia, mostly IDA. For nearly four decades, studies on iron preparations have been benchmarked against ferrous ascorbate. Properties of ferrous ascorbate are thus considered the gold standard in iron therapy.

Ferrous ascorbate is a synthetic molecule of ascorbic acid and iron. Ascorbic acid enhances absorption of iron. Ascorbic acid reduces ferric iron to ferrous iron, which remains soluble even at neutral pH. Ferrous form is absorbed thrice as much as ferric form of iron, the discrepancy becomes even more, when treated with higher dosage of ferric salts.4 Elemental iron 100 mg is used for the treatment of IDA in pregnancy and

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This study was supported by Abbott Healthcare Pvt. Ltd.

drug review

Review of Antibiotics in the Management of Respiratory Infections: Cefaclor vs AmoxicillinClavulanate Pavan Mangla*, KK Aggarwal**

Abstract Cefaclor, a broad-spectrum semi-synthetic second generation oral cephalosporin with documented activity against many grampositive and gram-negative pathogens, as well as some anaerobes has established a record of efficacy in the management of respiratory tract infections (RTIs). Despite over three decades of widespread use, it remains clinically effective in patients with RTIs, making it competitive with amoxicillin-clavulanate and with macrolides, and fluoroquinolones, including many newer agents used for RTIs. Factors contributing to the efficacy and tolerability of cefaclor include its molecular stability, activity against the most prevalent gram-positive and gram-negative respiratory tract pathogens, rapid absorption, >90% bioavailability and good penetration into respiratory mucosa. When compared to amoxicillin-clavulanate, it is much better tolerated with less gastrointestinal adverse events thus ensuring better patient compliance.

Keywords: Respiratory tract infections, cefaclor, second generation cephalosporin, amoxicillin-clavulanate

R

espiratory tract infections (RTIs) are among the most common causes of morbidity in the community worldwide.1 Streptococcus pneumoniae is the most common bacterial cause of upper and lower respiratory tract community infections, particularly pneumonia.2 Additionally, it is one of the most frequent causative agents in meningitis and bacteremia, as well as the main cause of upper respiratory noninvasive infections, such as otitis media and sinusitis.3-5 Though infections caused by S. pneumoniae can occur in all age groups, they are more prevalent in children and the elderly.2,6,7 Furthermore, other bacterial pathogens are often implicated in RTIs. Haemophilus influenzae is recognized as a frequent cause of acute sinusitis in children and adults as well as pneumonia in developing countries like India; these respiratory infections are caused most commonly by non-type b strains. Finally, although a less frequent cause of RTIs, Moraxella catarrhalis may be associated with diverse disease conditions, such as laryngitis in adults.8 It has also been associated with acute exacerbations of chronic obstructive pulmonary disease (COPD), pneumonia in the elderly and hospital respiratory infections.8 Since, nearly all community-acquired

and healthcare-associated respiratory infections are treated empirically, there is need for a broad-spectrum antibiotic which is effective against the common respiratory tract pathogens.

*Chest Physician Moolchand Medcity, New Delhi **Senior Physician and Cardiologist Moolchand Medcity, New Delhi

Cefaclor, which was introduced in 1979, has established a record of efficacy in the management of RTIs. Factors contributing to the efficacy and tolerability of cefaclor

Cefaclor in RTI Cefaclor, a broad-spectrum semi-synthetic secondgeneration oral cephalosporin with documented activity against many gram-positive and gram-negative pathogens, as well as some anaerobes, is a good therapeutic option since resistance of all three common respiratory tract pathogens to cefaclor is very low.

In a study undertaken to determine the antimicrobial activity of cefaclor against common respiratory tract pathogens isolated, it was demonstrated that of the 163 S. pneumoniae, 87 M. catarrhalis and 216 H. influenzae isolates >95% isolates were susceptible to cefaclor. The MIC90 of cefaclor against these pathogens was <2 Âľg, which indicates that cefaclor would be effective in >90% of cases infected with these bacteria.9 Moreover, since it lacks antitubercular activity, unlike fluoroquinolones, it is particularly useful when diagnosis is in doubt especially in a country like India, where tuberculosis is rampant.

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Drug Review

Antimicrobial Spectrum Cefaclor has demonstrated bactericidal action against many gram-positive aerobes, gram-negative aerobes and some anaerobic bacteria, including Staphylococcus aureus, S. pneumoniae, S. pyogenes and H. influenzae (including ampicillin-resistant strains).11 In a comparative study undertaken to evaluate the in vitro activity of cefaclor and other oral cephalosporins against a large number of freshly isolated clinical strains of gram-negative and gram-positive bacteria, it was demonstrated that cefaclor has a superior action against S. pneumoniae.12 Cefaclor was also the most active antibiotic against strains of H. influenzae, and was shown to be more active than cephalexin and cephradine against non-b-lactamase producing strains of Klebsiella species.12 Cefaclor also has demonstrated efficacy against b-lactamaseproducing H. influenzae-resistant to ampicillin.13 Cefaclor was also highly active against both b-lactamasepositive and -negative strains of H. influenzae at the recommended inoculum size and when compared to cephradine and cephalexin, cefaclor has been shown to be less resistant to staphylococcal penicillinase.14 In another study, the in vitro activity of cefaclor was compared with that of cephalexin and cephradine, and it was found that cefaclor was the most active of the oral agents against H. influenzae (especially non-b-lactamase producing strains). Similar results were observed in another study where cefaclor was shown to be at least three times as active as cephradine at 2 Îźg/ml and at least one and a half times as active as cephalexin at this concentration against both penicillinase-producing and nonpenicillinase-producing strains of S. aureus.

Cefaclor, cephradine and cephalexin inhibited 32, 9 and 17% of penicillinase- and 80, 25 and 50% of nonpenicillinase-producing strains of S. aureus (Fig. 1). At 2 Îźg/ml, cefaclor inhibited all b-lactamasepositive and -negative strains of H. influenzae at the generally recommended inoculum of 104 CFU/ml, in contrast to cephalexin and cephradine, which required

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Indian Journal of Clinical Practice, Vol. 22, No. 11, April 2012

100 Cefaclor (80%)

90 80 Percentage (%)

include its molecular stability, activity against the most prevalent gram-positive and gram-negative respiratory tract pathogens, rapid absorption, >90% bioavailability and good penetration into respiratory mucosa. Despite over three decades of widespread use, it remains clinically effective in patients with RTIs, making it competitive with amoxicillin-clavulanate and with macrolides and fluoroquinolones, including many newer agents used for RTIs.10

70 Cephalexin (50%)

60 50 40 30 20 10 0

Cefaclor (32%) Cephalexin (17%) Cephradine (9%) Penicillinaseproducing strains

Cephradine (25%)

Nonpenicillinaseproducing strains

Figure 1. Susceptibility of penicillinase-producing and nonpenicillinase-producing strains of S. aureus at 2 mg/ml of antibiotic concentration.

substantially greater concentrations to achieve the same order of activity and which were also considerably affected by Haemophilus b-lactamase.14 Clinical efficacy of cefaclor in Pneumonia Despite the ongoing development of more-potent antibacterial agents and improvements in diagnostic and investigational techniques, pneumonia remains an important disease. Over the last several decades, the microbiology of community-acquired pneumonia (CAP) appears to have changed. Earlier studies reported S. pneumoniae to be by far the most prevalent pathogen.

Recent studies, however, have shown that other pathogens have become increasingly more significant.

These include H. influenzae, M. catarrhalis, S. aureus and Haemophilus parainfluenzae.

In a multicenter, randomized, double-blind trial, the efficacy and safety of cefaclor was compared with those of cefdinir in the treatment of CAP.15 Patients received either 10 days of treatment cefaclor (n = 343) at 500 mg thrice-daily or 10 days of treatment with cefdinir (n = 347) at 300 mg twice-daily. Microbiological assessments were performed on sputum specimens obtained at admission and at the two post therapy visits, if available. Respiratory tract pathogens were isolated from 538 (78%) of 690 patient admission sputum specimens, with the predominant pathogens being H. parainfluenzae, H. influenzae, S. pneumoniae and S. aureus. The microbiological eradication rates at the test-of-cure visit were 93% (245 of 264 pathogens) and 92% (238 of 260 pathogens) for the evaluable patients treated with cefaclor and cefdinir, respectively.

Drug Review Diarrhea incidence during therapy was higher for patients treated with cefdinir (13.7%) than for patients treated with cefaclor (5.3%). These results indicate that cefaclor is as effective as cefdinir in the treatment of pneumonia but it has a better tolerability profile.

Cefaclor has also been shown to an effective oral antibiotic for switching over from a parenteral antibiotic in management of CAP. A study was conducted to compare the therapeutic outcome and analyze costbenefit of a ‘conventional’ (7-day course of IV antibiotic therapy) versus an abbreviated (2-day IV antibiotic course followed by ‘switch’ to oral antibiotics) therapy for in-patients with CAP.16 The investigators used a multicenter prospective, randomized, parallel group with a 28-day follow-up, at the Universitybased teaching hospitals. Ninety-five patients were randomized to receive either a ‘conventional’ course of IV antibiotic therapy with cefamandole 1 g IV every 6-hour for seven days (n = 37), or an abbreviated course of IV therapy with cefamandole (1 g IV every 6-hour for 2 days) followed by oral therapy with cefaclor (500 mg every 8-hour for 5 days). No difference was found in the clinical courses, cure rates, survival or the resolution of the chest radiograph abnormalities among the two groups. The mean duration of therapy (6.88 days for the conventional group compared to 7-30 days for the early oral therapy group) and the frequencies of overall symptomatic improvement (97% vs 95%, respectively) were similar in both groups.

Patients who received early oral therapy had shorter hospital stays (7.3 vs 9.71 days, p = 0.01), and a lower total cost of care ($2953 vs $5002, p < 0.05). It was concluded that early transition to an oral antibiotic after an abbreviated course of IV therapy in CAP is substantially less expensive and has comparable efficacy to conventional IV therapy.

Cefaclor versus Amoxicillin-Clavulanate In the Indian scenario, for empiric treatment of RTIs, usually second-generation cephalosporins like cefaclor and amoxicillin plus a b-lactamase inhibitor are prescribed. A comparison of the efficacy and safety of cefaclor and amoxicillin-clavulanate in the management of common RTIs is given below.

Acute Pharyngotonsillitis Acute pharyngotonsillitis (APT) is one of the most common inflammatory processes of adults and children in an outpatient setting. Increasing failure rates, hypersensitivity to penicillin, the required

multiple daily doses and common side effects lead to poor patient compliance and thus inadequate treatment duration, providing therefore ground for considering alternative antimicrobial agents.

A multicenter, randomized, single-blind study was undertaken in order to compare the efficacy and safety of cefaclor (375 mg b.i.d.) and amoxicillin-clavulanate (625 mg b.i.d.) in 10 days treatment regimen of ambulatory patients with APT.17 A total of 200 patients (age range between 12-65 years) with symptoms of APT and positive antigen strep test were enrolled into the study. Clinical and bacteriological responses were assessed after the end of treatment (14-18th day) and at the follow-up visit (38-45th day). All Group A b-hemolytic streptococci (GABHS) strains, isolated from throat cultures, were tested for in vitro sensitivity to the antibiotics used in the study and no strain was found resistant to both antibiotics.

It was demonstrated that both antibiotics had almost 99% effectiveness at the post therapy visit. On the follow-up visit, an increased tendency of relapses was observed in the amoxicillin-clavulanate-treated group, compared to cefaclor-treated group (8.33% vs 3.29%). Relative-risk of relapse in patients treated with amoxicillin-clavulanate was 2.6 greater compared to cefaclor. There were significantly higher rates of gastrointestinal adverse events in group treated with amoxicillin-clavulanate (29/97 patients; 29.89%) compared to cefaclor (16/95 patients; 16.84%) (p < 0.03). Frequency of other adverse events did not differ significantly between the groups (Table 1).17 It was concluded that cefaclor and amoxicillinclavulanate provide a clinically and bacteriologically effective treatment for patients with pharyngotonsillitis caused by GABHS, but cefaclor treatment is significantly safer in regard to gastrointestinal side effects and relative risk of relapse in patients treated with amoxicillin-clavulanate was 2.6 greater compared to cefaclor.17 Another study was undertaken to compare the efficacy and safety of a new regimen of cefaclor (25 mg/kg b.i.d.) with amoxicillin-clavulanate for the treatment of pediatric patients with APT.18 A total of 673 children Table 1. Comparison of Cefaclor and AmoxicillinClavulanate in Treatment of APT Parameter

Cefaclor

Amoxicillin-clavulanate

Relapse rate

3.29%

8.33%

Adverse effects

16.8%

29.89%

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Drug Review (age range, 2-12 years) with signs and symptoms of APT were enrolled; 245 of these children who had a positive throat culture for GABHS entered the study and were randomly assigned to receive cefaclor 25 mg/kg b.i.d. or amoxicillin-clavulanate 15 mg/kg t.i.d.16 A 10-day antibiotic course was prescribed for each patient. Clinical and bacteriologic responses were assessed at the end of treatment (Day 10) and at the follow-up visit (Day 30). All GABHS strains isolated from throat cultures were tested for in vitro sensitivity to the antibiotics used in the study. No GABHS strain was resistant to cefaclor or to amoxicillin-clavulanate.

It was shown that cure rates for cefaclor given b.i.d. and amoxicillin-clavulanate given t.i.d. were 91.9% and 90.5%, respectively.18

Acute Otitis Media Acute otitis media (AOM) is the most frequent RTI of infancy and childhood. S. pneumoniae, H. influenzae and M. catarrhalis are the most common etiopathogens.19 Antibiotic resistance is increasing among the pathogens that commonly cause AOM.20 The efficacy and safety of cefaclor was compared with amoxicillin-clavulanate in 167 children with AOM. In this multicentric prospective trial, both cefaclor and amoxicillin-clavulanate caused a significant improvement in all the signs and symptoms after a 10-day treatment period. However, it was seen that the reduction in most of the symptoms was significantly more in cefaclor arm as compared to amoxicillinclavulanate arm.19 The clinical success (clinical cure + improvement) at the end of therapy was significantly more in cefaclor arm: 98% with cefaclor versus 85% with amoxicillin-clavulanate (p < 0.05). Bacteriological eradication was seen in 95% of patients in cefaclor group and 78% of patients in amoxicillin-clavulanate group (Table 2).19

Table 2. Comparison of Cefaclor and AmoxicillinClavulanate in Children with AOM Parameter

Cefaclor

Amoxicillinclavulanate

Clinical success (clinical cure + improvement)

98%

85%

Bacteriological eradication

95%

78%

Based on their observations, the investigators came to the conclusion that cefaclor is a well-tolerated and effective antibiotic option for AOM in children and it is superior to the combination of amoxicillinclavulanate in efficacy and tolerability in AOM. Its expanded-spectrum of activity, ability to achieve adequate concentrations in tissues, suitability for twicedaily dosing and proven tolerability make it a good alternative to agents traditionally used in AOM.19

Acute Exacerbations of Chronic Bronchitis Cefaclor and amoxicillin-clavulanate are active against H. influenzae, S. pneumoniae, M. catarrhalis and S. aureus, the pathogens commonly associated with acute exacerbations of chronic bronchitis (AECB).

A randomized, parallel-group, single-blind, multicenter study was conducted to compare the efficacy and safety of 7-day treatment regimens of cefaclor AF (750 mg b.i.d. [n = 73]) and amoxicillin-clavulanate (875/125 mg b.i.d. [n = 72]) in AECB.21 There were no statistically significant differences between the groups for improvement in clinical response measured by pulmonary peak expiratory flow (PPEF), or for common symptoms associated with AECB. However, nausea and vomiting, and abdominal pain, the most frequently occurring adverse events in the amoxicillin-clavulanate group, were not reported in the cefaclor group.

Take Home Messages 

Cefaclor is an orally administered second generation cephalosporin that is effective against the common causative bacteria in respiratory tract infections.



Has proven bacterial and clinical cure rates.



Well-tolerated with less gastrointestinal adverse events compared to amoxicillin-clavulanate.



Promotes compliance with twice-daily dosing and excellent tissue penetration.



Superior to amoxicillin-clavulanate in terms of patient compliance and higher efficacy rates.



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Cefaclor does not exhibit resistance to most common pathogens responsible for respiratory infections like S. pneumoniae, H. influenzae and M. cattarrhalis.

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Drug Review References 1.

Kiffer CR, Pignatari AC. Pharmacodynamic evaluation of commonly prescribed oral antibiotics against respiratory bacterial pathogens. BMC Infect Dis 2011;11:286.

2.

Lim WS, Macfarlane JT, Boswell TCJ, Harrison TG, Rose D, Leinonen M, et al. Study of community acquired pneumonia aetiology (SCAPA) in adults admitted to hospital: implications for management guidelines.

Thorax 2001;56(4):296-301.

3.

Austrian R. Pneumococcus: the first one hundred years.

Rev Infect Dis 1981;3(2):183-9.

4.

Goldblatt D. Recent developments in bacterial conjugates vaccines. J Med Microbiol 1998;47(7):563-7.

5.

Zettler EW, Scheibe RM, Dias CAG, Santafe P, Moreira JS, Santos DS, et al. Polymerase chain reaction used to detect Streptococcus pneumoniae resistance to penicillin. J Bras Pneumol 2004;30(6):521-7.

6.

Burman LA, Norrby R, Trollfors B. Invasive pneumococcal infections: incidence, predisposing factors and prognosis.

Rev Infect Dis 1985;7(2):133-42.

7.

Butler JC, Dowel SF, Breiman RF. Epidemiology of emerging pneumococcal drug resistance: implications for treatment and prevention. Vaccine 1998;16(18):1693-7.

8.

Murphy TF, Parameswaran GI. Moraxella catarrhalis, a human respiratory tract pathogen. Clin Infect Dis 2009;49(1):124-31.

9.

Ahmed A, Hafiz S, Rafiq M, Tariq N, Abdulla EM, Hussain S, et al. Determination of antimicrobial activity of Cefaclor on common respiratory tract pathogens in Pakistan. J Pak Med Assoc 2002;52(1):7-11.

10. Meyers BR. Cefaclor revisited. Clin Ther 2000;22(2): 154-66.

11. Rodriguez WJ, Ross S, Schwartz R, Goldenberg R, Khan W. Cefaclor in the treatment of susceptible infections in infants and children. Postgrad Med J 1979; 55 Suppl 4:35-8.

12. Knothe H. In vitro activity of cefaclor (author’s transl).

Infection 1979;7 Suppl 6:518-26.

13. Derry JE. Evaluation of cefaclor. Am J Hosp Pharm 1981;38(1):54-8.

14. Bill NJ, Washington JA 2nd. Comparison of in vitro activity of cephalexin, cephradine, and cefaclor.

Antimicrob Agents Chemother 1977;11(3):470-4.

15. Drehobl M, Bianchi P, Keyserling CH, Tack KJ, Griffin TJ. Comparison of cefdinir and cefaclor in treatment of community-acquired pneumonia. Antimicrob Agents Chemother 1997;41(7):1579-83.

16. Omidvari K, de Boisblanc BP, Karam G, Nelson S, Haponik E, Summer W. Early transition to oral antibiotic therapy for community-acquired pneumonia: duration of therapy, clinical outcomes, and cost analysis. Respir Med 1998;92(8):1032-9.

17. Haczyński J, Bardadin J, Gryczyńska D, Gryczyński M, Gołabek W, Kawalski H, et al. A comparative study of cefaclor vs. amoxicillin/clavulanate in tonsillopharyngitis.

Med Sci Monit 2001;7(5):1016-22.

18. Esposito S, De Ritis G, D’Errico G, Noviello S, Ianniello F. Clinical comparison of cefaclor twice daily versus amoxicillin-clavulanate or erythromycin three times daily in the treatment of patients with streptococcal pharyngitis.

Clin Ther 1998;20(1):72-9.

19. Aggarwal M, Sinha R, Murali MV, Trihan P, Singhal PK. Comparative efficacy and safety evaluation of cefaclor vs amoxycillin + clavulanate in children with Acute Otitis Media (AOM). Indian J Pediatr 2005;72(3):233-8.

20. Catania S, Gallo A. Clinical efficacy and tolerability of short course therapy with cefaclor compared with long-term therapy for treatment of acute otitis media in children. Infez Med 2004;12(4):259-65.

21. Bandak SI, Bolzon LD, Turnak MR, Johns D, Henle SK, Allen BS. Cefaclor AF versus amoxycillin/clavulanate in acute bacterial exacerbations of chronic bronchitis: a randomised multicentre study. Int J Clin Pract 1999;53(8):578-83.

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Detection of Fetal Malnutrition by CAN Score at Birth and its Comparison with other Methods of Determining Intrauterine Growth Vikram Singhal, Prashant Agal, Nutan Kamath*

Abstract Background: Fetal malnutrition (FM) and the terms ‘small for gestational age’ (SGA) and ‘intrauterine growth retardation’ (IUGR) are not synonymous, one may occur without the other. FM can be clinically assessed by using the Clinical Assessment of Nutritional Status (CAN) score. CAN score can assess the prevalence of FM among term newborns and is comparable to anthropometric criteria used to assess fetal growth. Methodology: A prospective cohort study was carried out at a tertiary referral hospital affiliated to a medical college, consisting of 200 singleton full-term neonates over a period of two months.

In all neonates complete anthropometric assessment as per standard procedures and determination of weight for gestation was done. On the basis of Alexander and Associates intrauterine growth curves, newborns were classified into SGA and appropriate for gestational age (AGA). FM was assessed using CAN score as a standard and compared with weight for gestation age and Ponderal index (PI) Results: CAN score identified 17.5% (n = 35) malnourished neonates and 82.5% (n = 165) of babies as well-nourished by keeping the cut-off value of <25. Eight percent of AGA babies and 76.8% of SGA babies were found to be well-nourished on comparing weight for gestation age with CAN score. Sixteen (8%) babies were found to have FM using PI but by applying CAN score only 10 babies were found to have FM. The sensitivity and specificity of weight for gestational age were found to 82.85% and 41.81%, respectively and that of PI 28.57% and 96.36%, respectively, when CAN score was taken as standard. Conclusion: This implies that CAN score can identify fetal malnourishment in those neonates, which are missed by other methods.

Keywords: CAN, anthropometry, fetal malnutrition

F

etal growth is a function of growth potential of the fetus, the availability of intrauterine nutrition and placental function. The net result of these factors is a wide distribution of birth size at any given gestational age and a wide variation in the state of nutrition at birth. The concept of fetal malnutrition (FM) was initially developed by Clifford1 and was defined by Scott and Usher2 as a clinical state of infants characterized by obvious intrauterine loss of failure to acquire normal amount of subcutaneous fat and muscle. FM and the terms ‘small for gestational age’ (SGA) and ‘intrauterine growth retardation’ (IUGR) are not synonymous, one may occur without the other.3,4

FM can be clinically assessed by using the Clinical Assessment of Nutritional Status (CAN) score.3 There are various other methods, which are used to determine nutritional status of newborns at birth like weight for gestational age, Ponderal index (PI) and mid arm/head circumference ratio. But each has its own drawbacks.5,6 Detection of FM at birth is thus useful for identifying those newborns who are at higher risk for metabolic complications associated with abnormal fetal growth.3 The aim of this study was detection of FM by CAN score of term neonates at birth and its comparison with other methods of determining intrauterine growth.

Material and Methods

*Professor and Unit Head Dept. of Pediatrics, Kasturba Medical College, Mangalore Manipal University, Mangalore Address for correspondence Dr Nutan Kamath Professor and Unit Head Dept. of Pediatrics KMC Hospital, Attavar, Mangalore - 575 001 E-mail: nutankamath@yahoo.com

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A prospective cross-sectional study was carried out at a tertiary referral hospital affiliated to a medical college after taking the prior approval of the Institutional Ethics Committee. Two hundred singleton full-term neonates (38-42 weeks of gestation) whose hospital stay exceeded 24 hours of age were enrolled in the study after taking informed consent from the parents. Neonates

clinical study (both sexes), born as a result of multiple pregnancies and/or having major congenital malformations were excluded. The study was carried out over a period of two months. Before starting the study, the interand intra-observer variations of the CAN score were tested and found to be within acceptable limits (p > 0.05). Neonatal anthropometry measurements (weight, length, head circumference) were carried out between 24-48 hours of newborn age using standard guidelines and instruments. PI was calculated as weight (grams)/Length3 (cm) × 100; and values below 2.2 were taken as indicative of growth retardation.7 Infant’s age was assessed by using New Ballard score8 and it was further correlated with last menstrual period (LMP) and ultrasonic measurements taken antenatally.

If in disagreement for over two weeks, the clinical score was taken as the final gestational age (GA). All these data were recorded on the predesigned form, for each baby. On the basis of normograms of the Alexander and associates intrauterine growth curves,9 newborns were classified as SGA and appropriate for gestational age (AGA). Infants, whose weights were below the 10th percentile for their GA, were classified as SGA, whereas those with birth weight between 10th-90th percentiles for their GA were designated as AGA babies.9 CAN score4 has nine superficial readily detectable signs, which are rated from 1 (worst-severe FM) to 4 (best well-nourished). The highest possible score is 36

and lowest possible score is.9 A CAN score of ≤24 was taken as fetally malnourished.4 CAN score is presented in Table 1.

Data were statistically analyzed with test of significance, calculated by chi-square test. Anthropometric measurements were expressed as percentiles. Sensitivity, specificity, positive and negative predictive values were also calculated, wherever required. A ‘p’ value of <0.05 was considered significant.

Results In this study, 200 singleton term neonates were analyzed to detect FM. Mean birth weight of study population was 2.73 ± 0.35 kg and the mean length was 45.43 ± 2.02 cm. In our study, when nutritional status of newborns was detected by CAN score, 82.5% newborns were well-nourished but 17.5% newborns had malnutrition. When nutritional status of newborns was detected on the basis of weight for GA, we found that 62.5% babies were SGA, while 37.5% were AGA. When PI was used for detection of nutritional status in newborns, it was found that 92% newborns were wellnourished but 8% were malnourished (Fig. 1).

In our study, 35 of 200 term neonates, were malnourished in utero (FM). Thus, 96 out of 125 SGA babies were small but not malnourished and six out of 75 AGA were fully grown but were malnourished. Sixteen babies

Table 1. The Nine signs for CAN Status in the Newborn4 Hair

Large amount, smooth, silky, easily groomed (4).

Thinner, some straight, ‘staring’ hair (3).

Still thinner, more straight, ‘staring’ hair which does not respond to brushing (2).

Straight ‘staring’ hair with depigmented strip (flag sign) (1).

Cheeks

Progression from full buccal pads and round face (4); to significantly reduced buccal fat with narrow, flat face (1)

Neck and Chin

Double or triple chin fat fold, neck not evident (4); to thin chin. No fat fold, neck with loose, wrinkled skin, very evident (1).

Arms

Full, round, cannot elicit ‘accordion’ folds or lift folds of skin from elbow or tricep area (4); to a striking ‘accordion’ folding of lower arm, elicited when examiner’s thumb and fingers of the left hand grasps the arm just below the elbow of the baby and thumb and fingers of the examiners right hand circling the wrist of the baby are moved towards each other; skin is loose and easily grasped and pulled away from the elbow.

Legs

Like arms.

Back

Difficult to grasp and lift skin in the interscapular are (4); to skin loose, easily lifted in a thin fold from the interscapular area (1).

Buttocks

Full round gluteal fat pads (4); to virtually no evident gluteal fat and skin of the buttocks and upper posterior high loose and deeply wrinkled (1).

Chest

Full, round, ribs not seen (4); to progressively prominence of the ribs with obvious loss of intercostal tissues (1).

Abdomen

Full, round, no loose skin (4); to distended or scaphoid, but with very loose skin, easily lifted, wrinkled and ‘accordion’ folds demonstrable.

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clinical study Table 2. Distribution of SGA and FM Diagnoses in 200 Neonates and Comparison of CAN Score with PI p value

CAN score

Weight for gestational age

FM

Nourished

Total

AGA

6 (8%)

69 (94%)

75 (37.5%)

SGA

29 (23.2%)

96 (76.8%)

125 (62.5%)

Total

35 (17.5%)

165 (82.5%)

200 (100%)

FM

Nourished

Total

<2.2

10 (62.5%)

6 (37.5%)

16 (8%)

>2.2

25 (13.58%)

159 (86.41%)

184 (92%)

Total

35 (17.5%)

165 (82.5%)

200 (100%)

Ponderal index

for Detection of FM 62.5%

Well-nourished Malnourished AGA SGA

37.5% 17.5%

CAN score

8% Weight for gestational age

PI

Figure 1. Comparison of CAN score, weight for GA and PI.

were found to have FM using PI but by applying CAN score only 10 babies were found to have FM. Out of the 184 babies found to be well nourished by using PI, 25 babies were found to be malnourished in utero by applying CAN score (Table 2). PI has low sensitivity in comparison to CAN score for diagnosis FM (Table 3). Also, using PI alone for diagnosing FM, some SGA babies may be misdiagnosed as FM and some AGA babies may be misdiagnosed as normal.

Discussion It is important to recognize babies with FM because of high incidence of neonatal morbidity and long-term sequelae-like metabolic syndrome.2,10,11 Depending on the period of gestation, when the malnutrition started, the clinical manifestations of FM vary.

FM adversely affects body composition, including reduced muscle mass and protein content, organ structure and composition, bone, chemical composition and metabolic, and enzyme functions.4 The perinatal problems and/or central nervous system sequelae, occurred primarily in fetally malnourished

578

<0.01 highly significant

Table 3. Comparison of CAN Score with other Methods

92%

82.5%

Percentage (%)

100 90 80 70 60 50 40 30 20 10 0

< 0.01 highly significant

Indian Journal of Clinical Practice, Vol. 22, No. 11, April 2012

Value

Birth weight for gestational age

Ponderal index

Sensitivity (%)

82.85%

28.57%

Specificity (%)

41.81%

96.36%

Positive predictive value (%)

23.2%

62.5%

Negative predictive value (%)

92%

86.41%

babies, whether AGA or SGA, but not those who were simply SGA but not malnourished was found in a study done by Hill et al.12 In utero growth restriction is not a uniform condition with respect to its severity and duration, the underlying pathogenesis and the developmental stage of the fetus at the time of its occurrence. If malnutrition happens early in the second trimester, length, head circumference and weight are significantly all reduced, whereas if length and head circumference are less affected but baby is small and underweight mostly the malnutrition happened in the beginning of the third trimester.

If length and head circumference are within the normal range, and weight significantly less than the GA, an insufficient or unbalanced nutrient supply most likely occurred in the late third trimester.4,13,14 For the last two categories, weight, may be above the tenth percentile for GA. FM adversely affects body composition, including reduced muscle mass and protein content, organ structure and composition, bone, chemical composition and, metabolic and enzyme functions.4 FM is clinically characterized by obvious

clinical study intrauterine loss of subcutaneous fat and muscle.

Weight, length and head circumference may or may not be affected.15 Irrespective of cause, fetuses with inadequate nutrition will not deposit fat as long as their basic metabolic needs are not met, whereas a baby with abundant subcutaneous fat cannot have suffered from in utero malnutrition. On the basis of this principle, the evaluation of fat deposits is an appropriate means for the distinction between IUGR and non-IUGR neonates. Neither SGA nor IUGR are synonymous with FM. The current anthropometric criteria used to assess fetal nutritional status of newborn, have their shortcomings.4,16 A simple, clinically applicable scoring system was developed by Metcoff4 to differentiate the malnourished from appropriate nourished babies irrespective of birth weight or clinical classification as IUGR, SGA, or AGA. This scoring system rated clinical evidences of malnutrition in term babies determined by inspection and hands on estimates of loss of subcutaneous tissue and muscle and is independent of common confounding factors which affect weight of the baby.4

83 (54%) of 153 SGA babies; nearly half 45.8% of the SGA infants were not malnourished in utero. Our data and previous reports4,15,16 suggest that using weight for gestation classification to identify malnourished neonates may not be entirely accurate, because it may identify many well-nourished neonates as SGA, or miss a proportion of malnourished AGA neonates.

The CAN score is much simpler to learn and easy to do, particularly with the aid of cartoon illustrations of the signs and scores as described by Metcoff.4 Its major drawback is its subjective nature, like all other scoring methods used in the evaluation of neonates. The method could be used as a screening or confirmatory test.

Deodhar et al22 state that CAN score is a simple and rapid clinical scoring system for diagnosing FM. All AGA infants are not well-nourished and not all SGA babies are malnourished and those without FM have a better outcome and faster catch-up growth. In a developing country like India, CAN score can be used as a simple and effective tool to identify FM. The limitation of our study was small sample size and inability for long-term follow-up to assess development of these babies. Undoubtedly, further research is needed, using a greater range of confirmatory information. Search and evaluation of alternative indices or other simple indicators of growth restriction might also contribute to a more accurate identification of IUGR babies.

In a study by Deodhar et al,16 FM was present in 19.6% babies (84.2% of the SGA, 12.9% of AGA babies) while Metcoff4 reported FM in 5.5% of AGA and 54% of SGA babies. This variability in the results may be because of type of growth charts used to differentiate AGA/SGA babies. Several fetal growth curves have been developed from various populations and geographic locations.9,17,18 In the study by Hill et al,12 32.6% of FM infants would have been misclassified as AGA, if only birth weights, lengths and head circumferences were considered for detection of growth retardation. In our study, using CAN score, 76.8% of SGA infants were not malnourished and 8% of AGA infants were fetally malnourished. Hill et al12 have showed that 39% of later neurologic and intellectual handicaps occur predominantly in FM babies. This would have been missed if only a birth weight of less than the 10th percentile was used. Thus, apart from 23% of the SGA, 8% of the AGA malnourished babies are also at risk. Metcoff4 established. CAN score as a good indicator of FM. In a large sample of 1,382 term neonates, a simple brief CAN status revealed that 151 (10.9%) were FM, including 5.5% of 1,229 AGA and

To classify IUGR infants, PI has been used by various authors.19,20 PI relies on the principle that length spared at the expense of weight during period of acute inflammation; weight and length velocities may be proportionately impaired so infants with chronic insult in utero may be misclassified by PI. The other drawback of PI is that any error in calculating length is cubed in the calculation of the PI.2 In our study, 16 infants (8%) were found growth retarded according to PI (<2.2); out of these only 10 infants were fetally malnourished on using CAN score. When CAN score was compared with PI, it gave a sensitivity of 28.57% and a specificity of 96.36% in the present study.

Haggarty et al21 indicate that PI is a poor predictor of in utero growth retardation.5,21

Conclusion Our study concluded that SGA and IUGR are not synonymous with FM. CAN score, which is a simple clinical index for identifying FM, is a good indicator for the same in comparison to other methods of determining IUGR-like weight for gestational age and PI. This implies that CAN score can identify fetal malnourishment in those neonates, which are missed by other methods.

References 1.

Clifford SH. Postmaturity, with placental dysfunction; clinical syndrome and pathologic findings. J Pediatr 1954;44(1):1-13.

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clinical study 2.

Scott KE, Usher R. Fetal malnutrition: its incidence, causes, and effects. Am J Obstet Gynecol 1966;94(7):951-63.

3.

Georgieff MK, Sasanow SR. Nutritional assessment of the neonate. Clin Perinatol 1986;13(1):73-89.

4.

Metcoff J. Clinical assessment of nutritional status at birth.

Fetal malnutrition and SGA are not synonymous. Pediatr Clin North Am 1994;41(5):875-91.

5.

Georgieff MK, Sasanow SR, Chockalingam UM, Pereira GR. A comparison of the mid-arm circumference/head circumference ratio and ponderal index for the evaluation of newborn infants after abnormal intrauterine growth.

Acta Paediatr Scand 1988;77(2):214-9.

6.

Kumari S, Jain S, Sethi GR, Yadav M, Saili A, Lal UB. A simple method of screening for intrauterine growth retardation at birth. Indian J Pediatr 1988;55(2):283-6.

7.

Use of a simple anthropometric measurement to predict birth weight. WHO Collaborative Study of Birth Weight Surrogates. Bull World Health Organ 1993;71(2):157-63.

8.

Singh M. Care of the newborn. 5th edition, Sagar Publications, New Delhi, 1999.

9.

Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth.

Obstet Gynecol 1996;87(2):163-8.

10. van Wassenaer A. Neurodevelopmental consequences of being born SGA. Pediatr Endocrinol Rev 2005;2(3):372-7.

11. Gluckman PD, Hanson MA, Morton SM, Pinal CS. Lifelong echoes - a critical analysis of the developmental origins of adult disease model. Biol Neonate 2005;87(2):127-39.

12. Hill RM, Verniaud WM, Deter RL, Tennyson LM, Rettig GM, Zion TE, et al. The effect of intrauterine malnutrition on the term infant. A 14-year progressive study. Acta Paediatr Scand 1984;73(4):482-7.

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13. Lubchenco LO, Hansman C, Dressler M, Boyd E. Intrauterine growth as estimated from liveborn birthweight data at 24 to 42 weeks of gestation. Pediatrics 1963;32:793-800.

14. Urrusti J, Yoshida P, Velasco L, Frenk S, Rosado A, Sosa A, et al. Human fetal growth retardation. I. Clinical features of sample with intrauterine growth retardation. Pediatrics 1972;50(4):547-58.

15. Mehta S, Tandon A, Dua T, Kumari S, Singh SK. Clinical assessment of nutritional status at birth. Indian Pediatr 1998;35(5):423-8.

16. Deodhar J, Jarad R. Study of the prevalence of and high risk factors for fetal malnutrition in term newborns. Ann Trop Paediatr 1999;19(3):273-7.

17. Brenner WE, Edelman DA, Hendricks CH. A standard of fetal growth for the United States of America. Am J Obstet Gynecol 1976;126(5):555-64.

18. Overpeck MD, Hediger ML, Zhang J, Trumble AC, Klebanoff MA. Birth weight for gestational age of Mexican American infants born in the United States. Obstet Gynecol 1999;93(6):943-7.

19. Mohan M, Prasad SR, Chellani HK, Kapani V. Intrauterine growth curves in north Indian babies: weight, length, head circumference and ponderal index. Indian Pediatr 1990;27(1):43-51.

20. Miller HC, Hassanein K. Diagnosis of impaired fetal growth in newborn infants. Pediatrics 1971;48(4):511-22.

21. Haggarty P, Campbell DM, Bendomir A, Gray ES, Abramovich DR. Ponderal index is a poor predictor of in utero growth retardation. BJOG 2004;111(2):113-9.

22. Gardosi J, Chang A, Kalyan B, Sahota D, Symonds EM. Customised antenatal growth charts. Lancet 1992;339(8788):283-7.

case report

Solitary Cysticercus Granuloma: A Re-disappearing CT Lesion Shubha Laxmi Margekar*, Venu Gopal Margekar**, Ashok Kumarâ&#x20AC;

Abstract Majority of disappearing computed tomography (CT) lesions in India have been most likely linked to infectious etiology.

Neurocysticercosis (NCC) is among the common infections of the central nervous system (CNS) and seizures are the most common clinical manifestation. A patient who presented with seizures was evaluated with serial imaging studies, which revealed a small mass lesion that disappeared twice which is not a common presentation, hence this case has been reported.

Keywords: Neurocysticercosis, disappearing CT lesion, seizures

I

n India, upto 40% of patient with epilepsy of recent onset have solitary, small, contrast-enhancing lesions in the cerebral hemisphere.1 The remarkable feature of these lesions is that most undergo spontaneous resolution within six months. The cause of these disappearing lesions remains controversial. An infectious etiology is most likely and evidence favors cysticercosis.2 Neurocysticercosis (NCC) is among the most common parasitic infections of the central nervous system (CNS). It is acquired by the ingestion of food contaminated with Taenia solium eggs. The cysticerci may invade the brain, subarachnoid space, ventricular space or spinal cord, producing an inflammatory response.3 Seizures are the most frequent clinical manifestations and occur with all the evolutionary stages.4 Majority of these lesions disappear in repeat imaging studies. We report a case in which the lesion appeared twice and disappeared twice, which is infrequent in previously reported cases.

Computed tomography (CT) scan head revealed a ringenhancing lesion in left posterior parietal lobe (Fig. 1).

He was put on phenytoin sodium, albendazole and prednisolone. A further scan after four months showed complete resolution of the lesion. He was asymptomatic for four years and then he presented with recurrent headaches. Magnetic resonance imaging (MRI) brain revealed rounded T2 hyperintense lesion with mild perilesional edema (Fig. 2) exactly at the same site as in initial CT scan. He was again put on the same treatment.

A repeat scan three months later showed complete resolution of the lesion. Anticonvulsants were tapered off. There was no recurrence of seizures. MRI scan of brain was repeated after one and half years and it was within normal limits. Enzyme-linked immunosorbent assay (ELISA) for tuberculosis was negative and he had never consumed pork.

Case report A 46-year-old male presented after a single tonicclonic seizure. There was no neurological deficit. *Assistant Professor **PG Student Dept. of Medicine GR Medical College, Gwalior â&#x20AC; Assistant Professor Dept. of Medicine Santosh Medical and Dental College, Hospital, Ghaziabad Address for correspondence Dr Shubha Laxmi Margekar Dept. of Medicine Room No. 41, Senior Girls Hostel, Near Kamla Raja Hospital JA Hospital Campus, GR Medical College, Gwalior - 474 009 E-mail: dr_shubhalaxmi@rediffmail.com

Figure 1. CT scan head showing ring-enhancing lesion in the left posterior parietal region.

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case report of the lesion. The re-appearance of the CT lesion at the same site can be explained by a hypothesis that the later lesion was in fact a small additional cyst adjacent to involuting cyst. Re-appearance of lesions may thus be explained by the co-localization of a shower of cysts, which involute at different time.5 Rajashekhar believed that periodic release of parasitic antigen within the cyst results in episodic symptoms.10 This may be the cause of recurrence of symptom in this case.

Conclusion

Figure 2. MRI brain showing a rounded T2 hyperintense lesion with mild perilesional edema in left posterior parietal region.

Discussion

Strict follow-up of every patient of SSECTL with repeat imaging studies should be done whenever a patient presents with any symptom pertaining to it to avoid missing the diagnosis of re-appearance of lesion, as seizures are likely to recur as long as the lesion remain in the brain and the time for resolution of CT lesion is variable. This follow-up would enable early initiation of management and prevention of recurrence of seizures.

Neurocysticercosis (NCC) is a major public health problem in developing countries and seizures are the most frequent clinical manifestation. Single CT enhancing lesion, measuring <20 mm, commonly seen in patient with seizures in countries endemic to NCC represents solitary cysticercus granuloma.4 In Indian reports, single lesion is a common presentation of cysticercosis.2,5 These were variously referred to as ‘disappearing CT lesion’, ’vanishing lesion’ or more appropriately, ’single, small enhancing CT lesion’ (SSECTL).2,5

References 1.

Kennedy A, Schon F. Epilepsy: disappearing lesions appearing in the United Kingdom. BMJ 1991;302(6782): 933-5.

2.

Ahuja GK, Behari M, Prasad K, Goulatia RK, Jailkhani BL. Disappearing CT lesions in epilepsy: is tuberculosis or cysticercosis the cause? J Neurol Neurosurg Psychiatry 1989;52(7):915-6.

3.

Carpio A, Hauser WA. Prognosis for seizure recurrence in patients with newly diagnosed neurocysticercosis.

Neurology 2002;59(11):1730-4.

In a study of 150 cases of simple partial epilepsy, significant CT abnormality were found in 68%.

The commonest lesion noted was a hypodense lesion on unenhanced scan, with a ring- or disc-like enhancement on contrast scan, and surrounding hypodensity.6 Singh et al reported re-appearance of CT lesion in four patients in whom the lesion disappeared and later appeared at the same or different site.5 Sethi et al also reported 11 cases of seizures with CT abnormalities, which resolved completely within 6-24 weeks of the initial presentation.7 In another study of 75 patients, the follow-up CT scan showed either disappearance or regression in the size of single enhancing CT lesion in 84% of patient.8 Chandy et al reported the result of excision biopsy specimen of 15 patients, which helped in establishing the diagnosis of cysticercosis in seven of these cases.9 In a study of series of 35 patients, 12 were positive for serological investigations of cysticercosis.2

4.

Murthy JM, Rajshekar G. Economic evaluation of seizures associated with solitary cysticercus granuloma. Neurol India 2007;55(1):42-5.

5.

Singh G, Bhatia RS, Khurana D, Khurana SB. Reappearing CT lesions: 4 cases. Neurol India 1999;47(1):47-50.

6.

Wadia RS, Makhale CN, Kelkar AV, Grant KB. Focal epilepsy in India with special reference to lesions showing ring or disc-like enhancement on contrast computed tomography. J Neurol Neurosurg Psychiatry 1987;50(10):1298-301.

7.

Sethi PK, Kumar BR, Madan VS, Mohan V. Appearing and disappearing CT scan abnormalities and seizures.

J Neurol Neurosurg Psychiatry 1985;48(9):866-9.

8.

Singh MK, Garg RK, Nath G, Verma DN, Misra S. Single small enhancing computed tomographic (CT) lesions in Indian patients with new-onset seizures. A prospective follow-up in 75 patients. Seizure 2001;10(8):573-8.

9.

In our case, the lesion re-appeared at the same site while repeat imaging revealed complete disappearance

Chandy MJ, Rajshekhar V, Prakash S, Ghosh S, Joseph T, Abraham J, et al. Cysticercosis causing single, small CT lesions in Indian patients with seizures. Lancet 1989;1(8634):390-1.

10. Rajashekhar V. Solitary cerebral cysticercus granuloma.

Epilepsia 2003;44 Suppl 1:25-8.

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case report

Isolated Duodenal Metastasis of Hepatocellular Carcinoma: A Rare Presentation N Priyathersini*, S Rajendiran**, RB Sudagar Singhâ&#x20AC; , J Thanka**

Abstract Hematogenous metastasis to the duodenum from any primary tumor is rare. Hepatocellular carcinoma (HCC) frequently metastasizes to lung and regional lymph nodes. Involvement of small intestines by HCC is mostly via direct invasion of the contiguous neoplasm. We report a case of isolated noncontiguous duodenal metastasis of HCC because of its rarity.

Keywords: Duodenal metastasis, hepatocellular carcinoma, a-fetoprotein

H

epatocellular carcinoma (HCC) is the most common primary tumor of the liver. Metastasis is frequent in these aggressive tumors and is commonly to the lungs, regional lymph nodes and/or bones. Involvement of small intestine is generally by direct invasion and spread. Isolated noncontiguous metastatic involvement of the duodenum is very rare.

Case report A 52-year-old male presented to the outpatient department with icterus, pallor, pedal edema, abdominal distension, hepatomegaly (upto 8 cm below the costal margin) and splenomegaly. He had been a chronic alcoholic and smoker for the past 15 years. Laboratory investigations revealed a raised bilirubin level (3.15 mg/dl) and SGOT level (89 U/l). His viral markers were negative. a-fetoprotein (AFP) level was high (5225.9 ng/ml), normal value being <20 ng/ml.

Ultrasound abdomen showed cirrhosis of liver with portal vein thrombosis, ascites and splenomeagaly.

Upper gastrointestinal endoscopy revealed Grade I esophageal varices with an ulcer at D1/D2 junction.

*Assistant Professor **Professor Dept. of Pathology â&#x20AC; Associate Professor Dept. of General Medicine Sri Ramachandra Medical College and University, Porur, Chennai Address for correspondence Dr N Priyathersini Dept. of Pathology P2A3A, La Celeste Apartments,1/22, Netaji Street Rajarajeswarinagar, Madandapuram, Porur, Chennai - 600 116 E-mail: nagarajan.priyathersini@gmail.com

Biopsy from the duodenal ulcer showed small intestinal mucosa with submucosal collection of tumor cells arranged in a sinusoidal pattern. The tumor cells were large with abundant granular eosinophilic cytoplasm with vesicular mildly pleomorphic nuclei (Figs. 1-3). There was no evidence of mitosis or necrosis.

The overlying small intestinal mucosa was ulcerated and the adjacent mucosa was free of dysplasia or carcinoma. The differential diagnoses considered by hematoxylin and eosin (H&E) features were: Neuroendocrine tumors (carcinoid) and metastatic HCC. The sinusoidal pattern was highlighted by CD34 on immunohistochemistry (Fig. 4). Stains for S100, synaptophysin and chromogranin were negative.

Histopathological and immunohistochemical features with the markedly elevated levels of AFP in a cirrhotic patient were in favor of duodenal metastasis of HCC. Further radiological investigation was suggested.

A contrast-enhancing computer tomography (CECT) abdomen revealed multiple hypodense lesions in both lobes of liver showing enhancement in arterial phase with early washout in the venous phase (Fig. 5). The portal vein was dilated at the hilum and showed echogenic thrombus within. There was mild splenomegaly, moderate ascites and multiple splenorenal, perigastric and gallbladder collaterals. The radiological features were that of multicentric HCC. There was no direct invasion of the small intestine by the lesion. No other primary lesion was identified on thorough endoscopic and radiological investigations.

Since, the patient had portal vein thrombosis, chemoembolization was not recommended and the patient was put on palliative chemotherapy with cisplatin and 5-fluorouracil. He responded to the treatment and

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case report

Figure 1. Shows small intestinal mucosa with submucosal collection of tumor cells (H&E 100x).

Figure 2. Tumor cells arranged in a sinusoidal pattern (H&E 100x).

Figure 3. Tumor cells have abundant granular eosinophilic cytoplasm and vesicular mildly pleomorphic nuclei (H&E 400x).

Figure 4. IHC for CD34 highlights the sinusoidal pattern (IHC 100x).

the first follow-up radiological investigation showed reduction in the size of hepatic lesions.

Discussion Hematogenous metastasis to the duodenum from any primary malignancy is rare. The usual primary tumors include carcinoma of the lung, breast and malignant melanoma.1-3 However, most of these cases had metastatic deposits in other sites also.

Figure 5. CECT abdomen shows multiple hypodense lesions in both lobes of liver.

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HCC is the most common primary tumor of the liver worldwide. This aggressive neoplasm frequently metastasizes to lungs and regional lymph nodes.

Involvement of the small intestine is usually by direct invasion and spread by the primary tumor.4-8 Hematogenous or lymphatic metastasis is very rare.

Even among those rare instances of isolated metastatic lesions of duodenum, the primary origin from liver appears to be exceedingly rare.9

case report With the histopathological picture of submucosal collection of tumor cells in nests, a differential diagnosis of carcinoid tumor was considered. The immunohistochemical markers for the neuroendocrine neoplasm, namely synaptophysin, chromogranin and S100 were negative. The sinusoidal pattern highlighted on CD34 on immunohistochemistry, raised AFP levels and radiological picture of hepatic lesions in a cirrhotic background favor the diagnosis of duodenal metastasis of HCC. With no involvement of other organs by radiological study, this is a unique presentation of HCC with isolated noncontiguous duodenal metastasis.

Involvement of the duodenum indicates advanced nature of the disease with a very grave prognosis.

2.

Hashimoto M, Miura Y, Matsuda M, Watanabe G. Concomitant duodenal and pancreatic metastases from renal cell carcinoma: report of a case. Surg Today 2001;31(2):180-3.

3.

Houghton AD, Pheils P. Isolated duodenal metastasis from breast carcinoma. Eur J Surg Oncol 1987;13(4):367-9.

4.

Chen LT, Chen CY, Jan CM, Wang WM, Lan TS, Hsieh MY, et al. Gastrointestinal tract involvement in hepatocellular carcinoma: clinical, radiological and endoscopic studies.

Endoscopy 1990;22(3):118-23.

5.

Del Natale M, Druez P, Brenard R. Images in hepatology.

Fistulization of a hepatocellular carcinoma into the duodenum. J Hepatol 2001;34(1):172.

6.

Hatano E, Ikai I, Shimizu M, Maetani Y, Konda Y, Chiba T, et al. Resection for hepatocellular carcinoma with duodenal invasion: report of a case. Hepatogastroenterology 2003;50(52):1034-6.

7.

Lin CP, Cheng JS, Lai KH, Lo GH, Hsu PI, Chan HH, et al.

Gastrointestinal metastasis in hepatocellular carcinoma: radiological and endoscopic studies of 11 cases.

J Gastroenterol Hepatol 2000;15(5):536-41.

8.

Mohamed AO, Joshi S, Czechowski J, Branicki F. Hepatocellular carcinoma directly invading the duodenum. Saudi Med J 2005;26(3):478-80.

9.

Chung C, Al Ali J, Owen DA, Weiss AA, Yoshida EM, Tai IT. A rare case of isolated duodenal metastases from hepatocellular carcinoma associated with p53 and ki-67 expression: a case report. Cases J 2009;2:9344.

Conclusion Isolated noncontiguous duodenal metastasis of HCC is a rare and unique presentation. This condition poses differential diagnostic problems and should be kept in mind. Close clinical and radiological correlation is very essential for the correct diagnosis of this rare presentation.

References 1.

Bender GN, Maglinte DD, McLarney JH, Rex D, Kelvin FM. Malignant melanoma: patterns of metastasis to the small bowel, reliability of imaging studies, and clinical relevance. Am J Gastroenterol 2001;96(8):2392-400.

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case report

Delayed Diagnosis of Fetus Papyraceous with Microcephaly of Surviving Co-Twin Rekha Chaudhary*, Suniti verma**, Shaifali Dadhich*, Asha Meena†, Ram narayan sehra‡

Abstract Fetus papyraceous is a relatively rare complication in twin pregnancy. Ultrasound detection is not always possible due to anatomical position and technical difficulties. It is very important to make a diagnosis in time to prevent severe complications.

Keywords: Fetus papyraceous, microcephaly, diamniotic dichorionic

F

etus papyraceous is a relatively rare complication in twin pregnancy, its occurrence making antenatal diagnosis of this condition desirable.

Ultrasound (USG) detection is not always possible due to anatomical position and technical difficulties.

A case of twin pregnancy, which was diagnosed at 32 weeks of gestation during USG of an unbooked pregnant women with first twin fetus papyraceous and second surviving co-twin with microcephaly is reported here.

Case report A 28-year-old pregnant woman with eight months amenorrhea presented at our hospital on 22nd December, 2010 in the labor room with preterm labor pains.

She was G2P1 with one live and healthy 2-year-old male child delivered at full-term by lower segment cesarean section. The indication of cesarean section was premature rupture of membrane with nonprogress of labor. Her date of last menstrual period was not known. She had taken her tetanus toxoid at seven months and was taking iron supplementation since four months. Her antenatal period till now had

*Senior Resident **Associate Professor †Resident Dept. of Obstetrics and Gynecology ‡Associate Professor, Dept. of Pediatrics SP Medical College and Attached Group of Hospital, Bikaner, Rajasthan Address for correspondence Dr Rekha Chaudhary Dept. of Obstetrics and Gynaecology SP Medical College and Attached Group of Hospitals, Bikaner, Rajasthan E-mail: rekhatappu@gmail.com

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been uneventful. Her baby had been fully immunized according to the national immunization schedule.

Clinical and Laboratory Examination General physical examination was normal. On per abdominal examination, fundal height corresponded to 32 weeks of gestational age in cephalic presentation with regular fetal heart sound 160/minute. Uterus was acting mildly, regular uterine contractions occured every 10 minutes. On per vaginal examination, cervix was 50% effaced 1 cm dilated. All routine antenatal investigations were normal. C-reactive protein (CRP) was within normal limits. She had two USGs, done at a private nursing home one month back.

The first USG was done on 13-11-10, which showed a single live fetus of 28 weeks in cephalic presentation, placenta posterior wall upper segment, adequate liquor.

Second was done on 22-11-10 and showed a single live fetus with biparietal diameter corresponding to 25 weeks and femur length corresponding to 28 weeks, placenta was fundoposterior, liquor was adequate.

The sonography was done again at our center. A very surprising finding was seen - twin pregnancy with one live fetus with biparietal diameter corresponding to 27 weeks and femur length corresponding to 32 weeks, head circumference 27 weeks (microcephaly) and abdominal circumference to 31 weeks in cephalic presentation with placenta upper segment early Grade 3 and liquor in lower limit of normal. The other twin was fetus papyraceous stuck to anterior uterine wall corresponding to gestational age of 16 weeks.

Diagnosis She was a case of diamniotic dichorionic twin pregnancy of 32 weeks of gestation with one twin fetus

case report day in a healthy state after an uneventful post-delivery course. Patient was called after six weeks for postnatal check-up. The baby was examined thoroughly by the pediatrician. Immunization was done according to national schedule. Till date, follow-up of the baby has been perfectly normal.

Discussion

Figure 1. Preterm baby and papyraceous fetus with shriveled cord attached to placentae.

papyraceous corresponding to gestational age 16 weeks and microcephaly of surviving co-twin corresponding to 32 weeks of gestation with preterm labor pains.

Treatment Complete hemogram and coagulation profile was done.

Prothrombin time, activated plasma thromboplatin time, fibrin degradation products and serum fibrinogen levels were all within normal limits. After proper counseling and discussion with the patient, expectant management was planned. She was kept in the maternity ward, tocolytics were given and two doses of injection betamethasone 12 mg were given intramuscularly at an interval of 24 hours. She was comfortable; uterine contractions had subsided.

Patient was discharged after proper counseling. She came for regular antenatal check-up every seven days; complete coagulation profile was done at each visit along with USG surveillance. Coagulation profile remained normal. As per USG, growth of surviving cotwin was normal but discrepancy of head circumference was persistently present. At 36 weeks, she was again admitted in labor room with true labor pains. Her vitals were stable, coagulation profile was normal and her per vaginal examination showed favorable Bishop scoring. She delivered vaginally a full-term female child of 2.2 kg, 47 cm length, head circumference 29 cm.

Pediatrician attended the baby immediately. Baby cried soon after delivery with an Apgar score of 9 at 1-minute after birth. It was a diamniotic dichorionic multiple gestation with one of the sacs having papyraceous fetus with shriveled cord.

The papyraceous fetus had a crown-heel length of 11 cm, head circumference of 5 cm and weight of 75 g (Fig. 1). Breastfeeding was started immediately after delivery. Mother and baby were discharged on third

The term fetus papyraceous is used to describe a flattened, mummified fetus associated with a viable twin or multiple gestations. The incidence of fetus papyraceous is reported as one in 17,000 to one in 20,000 singleton pregnancies. In twin pregnancy, it is one in 184 to one in 200.1 Fetus papyraceous can occur in both uniovular and binovular twins but is more common in uniovular twins. A tiny flattened fetus may be discovered within the membranes and/or in the placenta after delivery. Searching for a fetus papyraceous should be a routine part.

Attributable causes that have been cited in the etiology of intrauterine death of fetus in twin pregnancy include twin-twin transfusion syndrome, velamentous cord insertion, true cord knot, cord stricture, placental insufficiency and congenital anomalies. Cord complications have been found in 30%, congenital anomalies have been present in 25% of cases and birth weight discordance has been responsible in 11-12% of cases.2 The primary concern of fetus papyraceous is its effect on mother and surviving co-twin.

Morbidity and mortality are mainly related to the gestational age of fetus papyraceous. When vanishing twin syndrome occurs during the first trimester, morbidity is limited and the mother is most likely to develop mild vaginal bleeding and cramping. If the event occurs later in the pregnancy, the morbidity is high. Surviving fetus can have problems due to twin embolization syndrome (TES).

Maternal complications include preterm labor, infection from a retained fetus, severe puerperal hemorrhage, consumptive coagulopathy and obstruction of labor by a low-lying fetus papyraceus causing dystocia leading to cesarean delivery. In about 90% cases, there is precipitation of pre- term labor and thus risk of prematurity. The effects on surviving twin include risk of cerebral palsy, congenital abnormalities like neural tube defects (NTDs), optic nerve hypoplasia, hypoxic ischemic lesions of white matter, microcephaly, post hydrocephalus, bilateral renal cortical necrosis, unilateral absence of kidney, gastrointestinal tract atresia,

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case report gastroschisis, hemifacial microsomia and aplasia cutis.3 Single fetal death in twin pregnancies exposes mother to the risk of DIC, where breach between maternal and fetal circulation allows passage of tissue thromboplastin from dead fetus and its placenta into maternal circulation leading to hemostasis impairment depending on the intensity of stimulus, incidence being 25%.4 But the risk of cerebral impairment is the greatest. Anand et al reported that surviving co-twins had poorer scores on the Griffiths Mental and Development Scales when compared to singleton.5 Okamura et al observed that survival difference due to chorionicity is because of frequency of vascular connections in monochorionic placentae (85-98%) leading to vascular disruption injury by hemodynamic fluctuation and transchorionic embolization and coagulopathy.6 Fetus papyraceous or vanishing twin has been shown to increase pregnancy associated plasma protein-A and free b-human chorionic gonadotropin.7

References 1.

Woo HH, Sin SY, Tang LC. Single foetal death in twin pregnancies: review of the maternal and neonatal outcomes and management. Hong Kong Med J 2000;6:293-300.

2.

Karl WM. Intrauterine death in a twin: implications for the survivor. In: Multiple pregnancy. Ward RH, Whittle M (Eds.), RCOG Press: London 1995:218-30.

3.

Akbar M, Ikram M, Talib W, Saeed R, Saeed M. Fetus papyraceous; demise of one twin in second trimester with successful outcome of second twin at term. Professional Med J 2005;12(3):351-3.

4.

Pritchard JA, Ratnoff OD. Studies of fibrinogen and other hemostatic factors in women with intrauterine death and delayed delivery. Surg Gynecol Obstet 1955;101(4): 467-77.

5.

Anand D, Platt MJ, Pharoah PO. Comparative development of surviving co-twins of vanishing twin conceptions, twins and singletons. Twin Res Hum Genet 2007;10(1): 210-5.

6.

Okamura K, Murotsuki J, Tanigawara S, Uehara S, Yajima A. Funipuncture for evaluation of hematologic and coagulation indices in the surviving twin following co-twin’s death. Obstet Gynecol 1994;83(6):975-8.

7.

Chasen ST, Perni SC, Predanic M, Kalish RB, Chervenak FA. Does a “vanishing twin” affect first-trimester biochemistry in Down syndrome risk assessment? Am J Obstet Gynecol 2006;195(1):236-9.

Conclusion Fetus papyraceous, although rare, is a well-known entity. It is very important to make a diagnosis in time to prevent severe complications. An ultrasound proves to be of great benefit.

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medilaw

Insight on Medicolegal MC Gupta

Q

A

Please answer the following questions related to the PC & PNDT Act, 1994.



a. What is the difference between PNDT rule 9(1) & rule 9(4)? b. Is it against law to keep Form F not as a hard bound register but in an electronic form? (I maintain electronic record as per rule 9(7). I have also taken hard copies of “FORM F” & signed the same arranged them in the form of a box file and submitted the same to the PNDT authority but the authority does not accept it and insists that I must maintain a regular hard bound register). 

Rule 9(1) of the Pre-Natal Diagnostic Techniques (Regulation and Prevention of Misuse) Rules, 1996, is reproduced below: “(1) Every Genetic Counselling Centre, Genetic Laboratory, Genetic Clinic, Ultrasound Clinic and Imaging Centres shall maintain a register showing, in serial order, the names and addresses of the men or women given genetic counselling, subjected to pre-natal diagnostic procedures or pre–natal diagnostic tests, the names of their spouse or father and the date on which they first reported for such counselling, procedure or test.”

“FORM F= Form for maintenance of record in respect of pregnant woman by genetic clinic/ ultrasound clinic/imaging centre.”

The foot note in Form F clearly states as follows: “Person conducting ultrasonography on a pregnant woman shall keep complete record thereof in the clinic/centre in Form F and any deficiency or inaccuracy found therein shall amount to contravention of provisions of Section 5 or Section 6 of the Act, unless contrary is proved by the person conducting such ultrasonography.” 







The record/report that is expected to be maintained by the ultrasound clinic is described in Rule 9(4) as follows:

An ultrasound clinic is a genetic clinic as per definition of the genetic clinic given in Section 2 (d) of the Act.

Advocate and Medicolegal Consultant, New Delhi

Rule 9(7) reads:

Please note that this rule talks of records in genera and not Form F in particular. It cannot include Form F because it needs the following three signatures:  Name, Signature and Registration number of the Gynaecologist/Radiologist/Director of the Clinic  Signature/Thumb impression of pregnant woman  Name and signature of the person conducting ultrasonography/image scanning/Director or owner of genetic clinic/ultrasound clinic/ imaging centre.

Rule 9(1) is a general rule and asks for maintaining a record only in respect of the following:  Serial no.  Date  Name of the patient  Name of the spouse/father

“(4) The record to be maintained by every Genetic Clinic, in respect of each man or woman subjected to any pre-natal diagnostic procedure/technique/ test, shall be as specified in Form F.”

Nowhere in the PNDT Act or Rules is there a mention of an “F form register”. As a matter of fact, the serial no. (which can be reasonably expected to be associated with a register) is a requirement in respect of Rule 9(1) but not Rule 9(4). “(7) In case the Genetic Counselling Centre or Genetic Laboratory or Genetic Clinic maintains records on computer or other electronic equipment, a printed copy of the record shall be taken and preserved after authentication by a person responsible for such record.”

Please note that this rule is mandatory and no excuses/exemptions are permissible. Please also note that it specifically talks of a register which is serially numbered. 

An ultrasound clinic is required to maintain a register in terms of Rule 9(1) and also to fill up Form F in terms of Rule 9(4). The title of the form reads—

The above signatures/thumb impression cannot be obtained in an electronic record. 

As per the PNDT Rules, it can be concluded:  There is nothing like a hard bound Form F Register  Form F is not supposed to be maintained an electronic form.

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practice guidelines

ACCF/AHA Release Guideline for Early Cardiovascular Risk Assessment

A

therosclerotic cardiovascular disease is the leading cause of death among adults in the United States. Because coronary heart disease (CHD) has a long asymptomatic latent period, there is an opportunity for early preventive measures.

The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) have created a guideline to assist physicians with the early cardiovascular risk assessment of asymptomatic adults. The goal of this assessment is to guide targeted preventive efforts based on the patientâ&#x20AC;&#x2122;s individual risk. Initial evaluation includes broadly categorizing patients by risk. Further intervention is based on these risk assessments.

Recommendations

Global Risk Scoring Global risk scores (e.g., Framingham Risk Score) that include multiple traditional cardiovascular risk factors effectively combine individual risk factor measurements into a single quantitative estimate of risk. These scores should be used in all cardiac risk assessment evaluations to guide the initiation of targeted preventive measures.

Family History and Genomic Testing Family history of atherothrombotic cardiovascular disease should be obtained, although genotype testing is not recommended.

Laboratory Testing Lipoprotein and Apolipoprotein. Lipid measurements, including lipoprotein levels, apolipoprotein levels, and particle size/density, beyond the standard lipid profile are not recommended.

Natriuretic Peptide. Measurement of natriuretic peptide levels is not recommended.

C-Reactive Protein. Measurement of C-reactive protein levels can be useful in selecting candidates for statin therapy in the following patients: men 50 years and

Source: Adapted from Am Fam Physician. 2011;84(2):234-235.

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older and women 60 years and older with a lowdensity lipoprotein cholesterol level less than 130 mg per dL (3.37 mmol per L) who are not on lipid-lowering medications, hormone therapy, or immunosuppressant therapy and do not have clinical CHD, diabetes mellitus, chronic kidney disease, severe inflammatory conditions, or contraindications to statins. Measurement of C-reactive protein levels may be reasonable in younger patients with intermediate cardiovascular risk, but is not recommended for high-risk patients.

A1C. Measurement of A1C levels may be reasonable in patients without diabetes to assess cardiovascular risk.

Microalbuminuria. Urinalysis to detect micro-albuminuria is reasonable in patients with hypertension or diabetes, and may be reasonable in intermediate-risk patients without these conditions.

Lipoprotein-Associated Phospholipase A2. Measure-0ment of lipoprotein-associated phospholipase A2 levels may be reasonable in intermediate-risk patients.

Imaging and Other Testing Resting Electrocardiography (ECG). Resting ECG is reasonable in patients with hypertension or diabetes, and may be considered in patients without these conditions.

Transthoracic Echocardiography. Echocardiography to detect left ventricular hypertrophy may be considered in patients with hypertension, but is not recommended in those without hypertension.

Carotid Intima-Media Thickness. Measurement of carotid intima-media thickness is reasonable in intermediaterisk patients; however, high-quality results are dependent on properly performing the test.

Brachial/Peripheral Flowâ&#x20AC;&#x201C;Mediated Dilation. Peripheral arterial flowâ&#x20AC;&#x201C;mediated dilation is not recommended.

Arterial Stiffness. Measurement of arterial stiffness is not recommended outside of research settings.

Ankle-Brachial Index. Measurement of ankle-brachial index is reasonable for intermediate-risk patients.

Exercise and stress ECG. Exercise ECG may be considered in intermediate-risk patients (including sedentary

practice guidelines adults who are considering a vigorous exercise program), particularly if non-ECG markers, such as exercise capacity, are noted.

Stress Echocardiography. Stress echocardiography is not recommended in low- or intermediate-risk patients. It is used mainly in the advanced cardiac evaluation of symptomatic patients to estimate prognosis in those with known coronary artery disease and to assess those with known or suspected valvular heart disease.

Myocardial Perfusion Imaging. Stress myocardial perfusion imaging may be considered in patients with diabetes or a strong family history of CHD, or if a previous risk assessment suggested high risk of CHD. It is not indicated for patients with low or intermediate risk, and is used mainly in the advanced cardiac evaluation

of symptomatic patients and to estimate prognosis in patients with known coronary artery disease.

Calcium Scoring Methods. Measurement of cardiac calcium levels is reasonable in patients with intermediate risk (10 to 20 percent 10-year risk), may be reasonable in those with low to intermediate risk (6 to 10 percent 10year risk), and is not recommended in patients with low risk (less than 6 percent 10-year risk). Measurement of cardiac calcium levels is reasonable in patients 40 years and older with diabetes.

Coronary Computed Tomography Angiography. Coronary computed tomography angiography is not recommended.

Magnetic Resonance Imaging. Magnetic resonance imaging for detection of vascular plaque is not recommended.

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photo quiz

Arcuate, Red Plaques with Pustules on the Trunk

A

61-year-old woman presented with a waxing and waning eruption that she noticed one year prior. Initially, the eruption was characterized by annular, eczematous plaques on the extremities.

Findings from biopsies of these areas were consistent with allergic contact dermatitis; however, the lesions did not appear to be caused by contact with allergens.

The rash did not resolve after multiple courses of topical and systemic steroids. Over a short period, the eruption generalized. The patientâ&#x20AC;&#x2122;s medical history was significant for hidradenitis suppurativa, and she was allergic to penicillin and sulfa medications. She did not have constitutional symptoms or recent illness.

Physical examination revealed generalized erythematous, arcuate plaques studded with small, tense pustules (see accompanying figure) involving the flexural surfaces bilaterally. Crusts were present at the center of the plaques. Some plaques formed polycyclic lesions with serpiginous borders.

Question

Results of bacterial and viral cultures were negative.

A repeat skin biopsy was performed. Hematoxylineosin staining revealed mounds of neutrophils in the stratum corneum and superficial stratum granulosum.

Results of direct immunofluorescence were negative for immunoglobulin deposition.

B.

Based on the patientâ&#x20AC;&#x2122;s history, physical examination, and laboratory results, which one of the following is the most likely diagnosis?

A. Erythema annulare centrifugum.

Generalized pustular psoriasis.

C. Immunoglobulin A pemphigus.

D. Impetigo.

E.

Subcorneal pustular Wilkinson disease).

dermatosis

(Sneddon-

SEE THE FOLLOWING PAGE FOR DISCUSSION.

Source: Adapted from Am Fam Physician. 2011;84(12):1405-1406.

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photo quiz Discussion

Summary Table

The answer is E: subcorneal pustular dermatosis (SCPD).

Condition

Characteristics

Erythema annulare centrifugum

Arcuate or annular plaques with central clearing and a trailing collarette of scale; lesions may be polycyclic and usually involve the trunk, buttocks, or lower extremities; pustules typically are not present

Generalized pustular psoriasis

May manifest as annular plaques studded with vesicles; typically accompanied by systemic symptoms, such as fever; possible history of psoriasis

Immunoglobulin A pemphigus

Vesiculopustular lesions commonly on trunk, proximal extremities, intertriginous areas; direct immunofluorescence shows immunoglobulin A deposition in the epidermis

Impetigo

Localized vesicles that rupture to form honey-colored crusts; usually occurs in neonatal period

Subcorneal pustular dermatosis (Sneddon-Wilkinson disease)

Symmetric distribution of sterile, pea-sized pustules on erythematous plaques in the axillae, groin, and inframammary folds

SCPD, or Sneddon-Wilkinson disease, is a chronic eruption that typically affects women older than 40 years. It has a symmetric distribution of sterile, peasized pustules on erythematous plaques that are located in the axillae, groin, and inframammary folds. Scaling and crusting occur secondarily after rupture of the pustules. Histologic examination shows an accumulation of neutrophils under the stratum corneum. SCPD has a benign and chronic course. Lesions tend to wax and wane over several years.

The workup includes biopsy of perilesional skin for direct immunofluorescence to rule out immunoglobulin A (IgA) pemphigus. Repeat skin biopsies for direct immunofluorescence should be performed periodically during follow-up. In addition, screening for urine and serum monoclonal gammopathies should be performed to help exclude an underlying myeloma. Oral dapsone, 50 to 150 mg daily, is considered the first-line treatment for SCPD, but it may take several weeks to produce significant results.1 SCPD refractory to dapsone has been treated with phototherapy or acitretin, but isotretinoin is not effective.1 Erythema annulare centrifugum appears as arcuate or annular plaques with central clearing and a trailing collarette of scale. The lesions may be polycyclic and usually involve the trunk, buttocks, or lower extremities. Pustules typically are not present. Histologic examination shows a dermal lymphocytic infiltrate.2 Generalized pustular psoriasis is difficult to distinguish clinically from SCPD.1,3 Patients with generalized pustular psoriasis may have annular plaques studded with vesicles. However, patients usually present with systemic symptoms, such as fever, and may require hospitalization. Patients may have a history of psoriasis.3 IgA pemphigus is an autoimmune, blistering disease with vesiculopustular lesions commonly on the trunk, proximal extremities, and/or intertriginous areas. It is clinically indistinguishable from SCPD. Both diseases lead to neutrophil collections in the epidermis.1,4 In IgA pemphigus, direct immunofluorescence shows IgA deposition in the epidermis.1

Nobullous impetigo usually occurs during childhood and is typically characterized by localized vesicles that rupture and form honey-colored crusts. Culture is positive for staphylococcal and/or streptococcal organisms. Bullous impetigo commonly occurs in the neonatal period, often resolving within weeks.5 REFERENCES 1.

Cheng S, Edmonds E, Ben-Gashir M, Yu RC. Subcorneal pustular dermatosis: 50 years on. Clin Exp Dermatol.

2008;33(3):229-233.

2.

Tyring SK. Reactive erythemas: erythema annulare centrifugum and erythema gyratum repens. Clin Dermatol. 1993;11(1):135-139.

3.

Lyons JH III. Generalized pustular psoriasis. Int J Dermatol. 1987;26(7):409-418.

4.

Robinson ND, Hashimoto T, Amagai M, Chan LS. The new pemphigus variants. J Am Acad Dermatol. 1999; 40(5 pt 1):649-671.

5.

Cole C, Gazewood J. Diagnosis and treatment of impetigo.

Am Fam Physician. 2007;75(6):859-864.

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lighter reading

Prison help!

An old man lived alone in Minnesota. He wanted to spade his potato garden, but it was very hard work. His only son, who would have helped him, was in prison. The old man wrote a letter to his son and mentioned his situation: Dear Son,

I am feeling pretty bad because it looks like I won’t be able to plant my potato garden this year.

I hate to miss doing the garden because your mother always loved planting time. I’m just getting too old to be digging up a garden plot. If you were here, all my troubles would be over. I know you would dig the plot for me, if you weren’t in prison.

quote

An Inspirational Story

Lighter Side of Medicine Be noble minded! Our own heart, and not other men’s opinions of us, forms our true honor.

—Friedrich Schiller

Dr. Good and Dr. Bad Situation: A patient with burns came with severe pain.

It is a bad sign

It is a good sign

Love, Dad

At 4 a.m. the next morning, a dozen FBI agents and local police officers showed up and dug up the entire garden without finding any guns.

Confused, the old man wrote another note to his son telling him what had happened, and asked him what to do next. His son’s reply was: ‘Go ahead and plant your potatoes, Dad. It’s the best I could do for you, from here.’

Moral: No matter where you are in the world, if you have decided to do something deep from your heart, you can do it. It is the thought that matters, not where you are or where the person is.

—Ms Ritu Sinha

laugh a while

Child Rearing FAQs Q: Should I have a baby after 35?

A: No, 35 children is enough.

Q: I’m two months pregnant now. When will my baby move?

A: With any luck, right after he finishes college.

—Dr GM Singh

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Indian Journal of Clinical Practice, Vol. 22, No. 11, April 2012

©IJCP Academy

Shortly, the old man received this telegram: ‘For Heaven’s sake, Dad, don’t dig up the garden!! That’s where I buried the GUNS!!’

Lesson: Pain indicates that the nerves are intact.

Dr KK Aggarwal

ILLUSION

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.

Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper.

Covering letter –

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The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper.

Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors.

Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.

Manuscript – Three complete sets of the manuscript should be submitted and preferably with a CD; typed double spaced throughout (including references, tables and legends to figures).

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The manuscript should be arranged as follow: Covering letter, Checklist, Title page, Abstract, Keywords (for indexing, if required), Introduction, Methods, Results, Discussion, References, Tables, Legends to Figures and Figures.

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All pages should be numbered consecutively beginning with the title page.

departments and institutions where the work was performed, name of the corresponding authors, acknowledgment of financial support and abbreviations used.

– The title should be of no more than 80 characters and should represent the major theme of the manuscript.

A subtitle can be added if necessary.

– A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included.

– The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page.

– A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text.

Summary – The summary of not more than 200 words. It must convey the essential features of the paper.

– It should not contain abbreviations, footnotes or references.

Introduction – The introduction should state why the study was carried out and what were its specific aims/objectives.

Methods – These should be described in sufficient detail to permit evaluation and duplication of the work by others.

– Ethical guidelines followed by the investigations should be described.

Statistics The following information should be given: – The statistical universe i.e., the population from which the sample for the study is selected.

– Method of selecting the sample (cases, subjects, etc. from the statistical universe).

– Method of allocating the subjects into different groups.

– Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques.

Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors.

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Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the

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Confidence intervals for the measurements should be provided wherever appropriate.

Results These should be concise and include only the tables and figures necessary to enhance the understanding of the text.

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Discussion –

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.

References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses).

At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution.

Examples of common forms of references are: Articles

Figures – Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat.

– All photomicrographs should indicate the magnification of the print.

– Special features should be indicated by arrows or letters which contrast with the background.

– The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen.

– Color illustrations will be accepted if they make a contribution to the understanding of the article.

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Do not use clips/staples on photographs and artwork.

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Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as “Fig.”.

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected

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.

2. Total number of pages ________________________

Books

5. Special requests _____________________________

Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.

6. Suggestions for reviewers (name and postal address)

Articles in Books

2.____________

2._ _______________

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._ _______________

Tables –

These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.

Legends – These should be typed double spaces on a separate sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text.

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The legend must include enough information to permit interpretation of the figure without reference to the text.

Indian Journal of Clinical Practice, Vol. 22, No. 11, April 2012

summary, etc.)_______________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________

Indian 1.____________Foreign 1._ _______________

7. All authors’ signatures________________________ 8. Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________

Online Submission Also e- Issue @ www.ijcpgroup.com For Editorial Correspondence

Dr KK Aggarwal

Group Editor-in-Chief Indian Journal of Clinical Practice E-219, Greater Kailash, Part-1 New Delhi - 110 048. Tel: 40587513 E-mail: editorial@ijcp.com Website: www.ijcpgroup.com