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ISSN 0971-0876

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Volume 24, Number 1

June 2013, Pages 1-100

Peer Reviewed Journal

yy American Family Physician yy Cardiology yy Dermatology yy Diabetology yy ENT yy Gastroenterology yy Internal Medicine yy Neurology yy Obstetrics and Gynecology yy Ophthalmology yy Orthopedics and Rheumatology yy Pediatrics yy Pulmonology yy Psychiatry yy Surgery yy Urology yy Medifinance yy Medilaw

“IJCP’s Annual Issue 2012-13” Full text online: http://ebook.ijcpgroup.com/ijcp/

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Online Submission

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

Volume 24, Number 1, June 2013 from the desk of group editor-in-chief

5

Dr Veena Aggarwal MD, Group Executive Editor

IJCP Editorial Board Obstetrics and Gynaecology Dr Alka Kriplani Dr Thankam Verma, Dr Kamala Selvaraj Cardiology Dr Praveen Chandra, Dr SK Parashar Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses, Dr Sidhartha Das Dr A Ramachandran, Dr Samith A Shetty ENT Dr Jasveer Singh Dentistry Dr KMK Masthan Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar Dermatology Dr Hasmukh J Shroff Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan

7

Asian Journal of Orthopedics Dr J Maheshwari Anand Gopal Bhatnagar Editorial Anchor Advisory Bodies Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

This journal is indexed in IndMED (http://indmed.nic.in) and full-text of articles are included in medIND databases (http://mednic.in) hosted by National Informatics Centre, New Delhi.

Twenty-six Percent Doctors Suffer from Severe Mobile Phone-induced Anxiety: Excessive use of Mobile Phone can be Injurious to your Health KK Aggarwal

10 Twenty-six Percent School Girls Say they would Never Marry a Smoker

KK Aggarwal

American Family Physician

11 Practice Guidelines Cardiology

16 CAD: A True Pandemic and a Comprehensive Surveillance System is the Need of the Hour

G Kannan, NN Rajendran, JSN Murthy, GB Tharani

Dermatology

22 A Study of Beetle Dermatitis

Asit Mittal, Sharad Mehta, Anubhav Garg, Lalit Gupta, CM Kuldeep, Ashok Kumar Khare, Sarin Nistha

Diabetology

25 Assessment of Hypogonadism with Reference to Clinical Features and Serum Testosterone Levels in Asian-Indian Male Type 2 Diabetics

Ibraheem Khan, Chandra Kant, Anil Samaria

ENT

33 Basaloid Carcinoma: An Unusual Presentation

Sanjana V Nemade, VV Rokade

Gastroenterology

39 Role of Liv.52 HB Capsules in the Management of Hepatitis B Infection: A Review

Journal of Applied Medicine & Surgery Dr SM Rajendran, Dr Jayakar Thomas

KK Aggarwal

Community Health

Padma Shri and Dr BC Roy National Awardee

Dr KK Aggarwal Group Editor-in-Chief

All about Depression

Asim Maji, Dibyendu Goutam, Padmanabha Rugvedi

Internal Medicine

47 Probiotics: The Friendly Microbes

Manoj Goyal, Monika Bansal, Shailesh Yadav, Kriti Malhotra

NEurology

53 False Localizing Signs in Neurology

Jobin V Joseph

Obstetrics and Gynecology

58 A Study of Hyperinsulinemia and Waist-hip Ratio in Patients with Chronic Anovulation

Aruna Verma, Abhilasha Gupta, A Sarup

Ophthalmology

62 Evaluation of a Case of Penetrating Ocular Injury

Jitender Phogat, Vivek Gagneja, Sumit Sachdeva, Mukesh Rathi


Orthopedics and Rheumatology

65 An Unusual Swelling at Ankle: An Osteochondroma in Adult?

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

Vivek AN

Pediatrics

69 Clinico-etiological and EEG Profile of Neonatal Seizures

Printed at IG Printers Pvt. Ltd., New Delhi E-mail: igprinter@rediffmail.com, printer_ig@yahoo.com

Shwetal Bhatt, Nita Raju, Supriya Phanse, Sangita V Patel, Geetika Madan, Sanjeev Mehta, Chetan Trivedi

Pulmonology

76 Pulmonary Alveolar Microlithiasis: A Clinicoradiological

© Copyright 2013 IJCP Publications Ltd. All rights reserved.

Dissociation

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.

Debaprasad Chakrabarti, Prabhat Debbarma, Amrit Kumar Bhattacharyya

Psychiatry

78 Personality Characteristics in the Patients of Obsessive Compulsive Disorder

Editorial Policies 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.

Krishan Kumar, Gurpreet Kaur, Brahmdeep Sindhu, Rajneesh Kumar, Sachin

Surgery

84 A Rare Case of Superior Mesenteric Vein Aneurysm

Anjana V Trivedi, Maulik C Jethva, Jatin G Bhatt, Daxa L Chavda

Urology

86 Phytotherapy for Lower Urinary Tract Symptoms due to Benign Hyperplasia of Prostate

Tapas Maitra

Medifinance

89 Financial Advisory Team Medilaw

91 Proof of Age

MC Gupta

Confederation of Medical Associations in Asia and Oceania

94 Be Human Stop Child Abuse eMedinewS Inspiration

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.

95 Alexander The Great’s Last 3 Wishes

GM Singh

Lighter Reading

96 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 National Vice President, Elect, IMA 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)

All about Depression ÂÂ

Depression is a major public health problem as a leading predictor of functional disability and mortality.

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Optimal treatment of depression improves outcome for most patients.

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Most adults with clinically significant depression never see a mental health professional but they often see a primary care physician.

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A nonpsychiatrist physician misses the diagnosis of the depression 50% of times.

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All depressed patients must be enquired specifically about suicidal ideations.

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Suicidal ideation is a medical emergency.

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Risk factors for suicide are either known psychiatric disorders, medical illnesses, prior history of suicidal attempts or family history of attempted suicide.

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Major risk factors for attempted suicide are psychiatric disorders, hopelessness and prior suicidal attempts or threats.

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High impulsivity or alcohol or other substance abuse increase the risk.

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The demographic reasons include older age, male gender, marital status (widowed or separated) and living alone.

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World over, one million people commit suicide every year.

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Seventy-nine percent of patients who commit suicide contact their primary care provider in the last one year before their death and only one-third contact their mental health service provider.

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Twice as many suicidal victims had contacted their primary care provider as against the mental health provider in the last month before suicide.

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Suicide is the 10th leading cause of death worldwide and account for 1.2% of all deaths.

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In the US, suicide rate is 10.5 per 1,00,000 people.

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In America, suicide is increasing in middle-aged adults.

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There are 10-40 nonfatal suicide attempts for every one completed suicide.

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The majority of completed suicides in US are accomplished with firearms (57%); the second leading method of suicide in US is hanging for men and poisoning in women.

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Patients with prior history of attempted suicide are 5-6 times more likely to make another attempt.

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Fifty percent of successful victims have made prior attempts.

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One of every 100 suicide attempt survivors will die by suicide within one year of the first attempt.

Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

5


from the desk of group editor-in-chief ÂÂ

The risk of suicide increases with increase in age; however, younger and adolescents attempt suicide more than the older.

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Females attempt suicide more frequently than males but males are three times more often successful.

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The highest suicidal rate is amongst those individuals who are unmarried followed by widowed, separated, divorced, married without children and married with children in descending order.

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Living alone increases the risk of suicide.

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Unemployed and unskilled patients are at higher risk of suicide than those who are employed.

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A recent sense of failure may lead to higher risk.

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Clinicians are at higher risk of suicide.

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The suicide rate in male clinicians is 1.41 and in female clinicians, it is 2.27.

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Childhood abuse and adverse childhood experiences increase the risk of suicidal attempts.

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The first step in evaluating risk of suicide is to determine presence of suicidal thoughts including their content and duration.

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Management of suicidal individual includes reducing mortality risk, managing underlying factors, monitoring and follow-up.

6

Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013


Community Health

Twenty-six Percent Doctors Suffer from Severe Mobile Phone-induced Anxiety: Excessive use of Mobile Phone can be Injurious to your Health KK Aggarwal

Abstract The association between mobile phones and cancer has been well-studied, though the results still remain controversial. However, there are other future health problems caused by use of mobile phones, especially smartphones. Besides the physical health problems, cellphone addiction is becoming a growing problem. The Heart Care Foundation of India conducted a survey, which included 25 nurses of one hospital, 25 office staff of one public company, 25 media desk executives of one electronic TV media house and 87 family physicians from all across Delhi to find out their cellphone habits.

Keywords: Mobile phone, smartphone, cellphone addiction

W

hile people are concerned about the association of cancer and mobile phones, which still remains a controversial issue, there are other future health problems caused by use of mobile phones especially smartphones. Prolonged use of mobile phone can cause neck pain, dry eyes, computer vision syndrome, anxiety (ringxiety), phobias (nomophobia) and insomnia. In India, radiation hazards are much more than in West because of active and passive mobile phone radiations and also due to combined use of other sources of radiations - computers, microwaves and frequent x-rays done by doctors. Fifty crore people in the world use mobile phones. These phones release low power radiofrequency waves, which transmit radio frequency radiations from 500 to 800 mGH through the antenna placed near the head. Heart Care Foundation of India (HCFI) conducted a survey, which included 25 nurses of one hospital, 25 office staff of one public company, 25 media desk executives of one electronic TV media house and 87 family physicians from all across Delhi. The observations were as follows: Use of Smartphones ÂÂ

Ten percent office staff, 20% nurses and 60% media house desk executives and 31% family physicians used smartphones. Amongst family physicians, 11.5% spent <30 minutes on their phone daily; 7% for 30-60 minutes; 3% for 60-90 minutes; 2% for

Padma Shri & Dr BC Roy National Awardee President Heart Care Foundation of India E-mail: emedinews@gmail.com

90-120 minutes; 4% for 120-240 minutes and 9% >240 minutes. ÂÂ

Eighty percent office staff, 80% nurses, 80% media desk executives and 41% family physicians are on Facebook. Amongst family physicians, 26% used it for <15 minutes; 7% for 15-30 minutes; 9% between 30-60 minutes; 2% between 60-90 minutes and 5% >120 minutes. Twenty-five percent family physicians connected to Facebook from their phones.

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Twenty percent office staff, 30% nurses, 70% media desk executives and 25% family physicians have a Twitter account. Among family physicians, only 50% used it regularly and 25% used it daily. Of the daily users, 90% used it for <5 minutes.

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Only 7% family physicians blogged.

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Thirty-six percent family physicians retrieved emails from their phone.

Smartphone addiction, a new disease ÂÂ

On an average, nurses recharged their phone battery twice in a day; media desk executives and doctors did it three times in a day.

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Sixty-one percent doctors find someone to call as soon as they leave their office or their flight lands.

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Seventy percent family physicians keep their cellphone with them constantly. Even at home they keep it in their pocket or right next to them. zz

Forty-three percent of them fiddle with their cellphone whenever they have downtime

Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

7


Community Health (even when they are not on the phone or have very few minutes to kill). zz

Thirty-three percent of them always feel anxious about their cellphone, especially when they are unable to use it (meeting, plane, class, church).

zz

Twenty-eight percent of them are uncomfortable and fidgety when they are not using their cellphone.

zz ÂÂ

Seven percent family physicians feel the need to talk on the phone almost all the time.

Sixty-three percent family physicians sleep with their cellphone under the pillow/on a night stand right next to the bed. This number is 20-50% for nurses, office staff and media desk executives.

Nomophobia Sixty percent of youth aged 20-30 years fear losing their mobile phone; this number was 43% in family physicians. Cellphone anxiety ÂÂ

Forty-three percent family physicians had high levels of anxiety, stress, or insecurity, when they were without their cellphone.

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Fifty percent of mobile phone users experienced ringxiety.

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Twenty-five percent family physicians sometimes believed their phone was ringing, but when they answered it or listened longer they found that it wasn’t ringing at all (phantom ringing).

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Fifteen percent family physicians reported feeling stressed upon receiving their cellphone bill and then experienced shock once they actually saw the amount.

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Twenty-two percent family physicians reported being unable to resist special offers on the latest cellphone models.

Severity of anxiety The mean social media addiction score (calculation based on 17 dependence questions) for doctors was 5.5. (A score >8 requires social media curfew and social media holidays along with counseling). Only 6% family physicians reported feeling no anxiety at all. Mild anxiety (score <4) was present in 43% family physicians (average score 3); moderate anxiety (score 5-7) was present in 25% of family physicians (average score 6); 26% family physicians scored >8 indicating social media addiction (average score 10). The mean social media addiction score (calculation based on 17 dependence questions) was 6.3 for office staff, 9 for desk executives and 8 for nurses.

8

Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

Mobile phone as a cause of conflict ÂÂ

Twenty-six percent family physicians had been teased because they had their cellphones even while working out or doing some other activity.

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Forty-eight percent doctors said that their personal cellphone use had increased significantly.

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Facebook was the cause of conflict in 20% of situations for a family conflict (second to TV).

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Twenty-three percent family physicians experienced problems at work because of their cellphone use; 18% family physicians had had problems with family or friends because of the cellphone use.

Mobile phone as a cause of disturbed sleep On an average, office staff spent 20 minutes, nurses 30 minutes and media house desk executives 60 minutes surfing on their smartphones on the bed; 26% family physicians were disturbed by a smartphone alert in the night; 7% reported getting disturbed daily (average 3 times). Only 40% doctors and 30% of nurses, hospital staff and media executives would stop using their mobile phones 30 minutes before sleep. Fifty percent mobile phone users woke up in the night because of smartphone alerts; 40% had disturbed sleep due to smartphone use. Mobile phone use while driving Sixteen percent of doctors used their mobile phone daily while driving, 14% used it sometimes and 6% rarely used it; 34% family physicians reported being warned by police for using their phone while driving: 20% of calls received were marketing calls; 30% reported receiving emergency calls from their patients. Using/ talking on a mobile phone while driving is more dangerous than driving under the influence of alcohol. It reduces reaction time by 30% versus people under the influence of alcohol and by 50% versus persons without alcohol. The reaction time under the influence of mobile phone is half a second longer. This amounts to a car traveling with a speed of 70 miles/hour to cover a distance of 46 feet before stopping. Mobile phone as cause of day time distraction Thirty-two percent family physicians reported being distracted by a smartphone alert during a meeting. Thirty percent of nondoctors said that they got distracted in a meeting because of an SMS or email alert. Mobile phone breaks and holidays Only 48% family physicians took cellphone breaks while at work.


Community Health Use of mobile phone in the Operation Theater In a US survey of cardiopulmonary bypass technicians published in the journal Perfusion, 50% used a smartphone during surgery, 43% in cardiac operation theater (OT), 50% talked on cellphone and 50% texted on their phones. In cardiac OT, 20% perfusionists accessed emails, 15% used internet and 3% checked/posted on social networking sites during surgery. HCFI conducted a similar survey in a corporate hospital in Delhi. ÂÂ

Ninety percent of nurses in the OT (unscrubbed) and 50% of OT technicians (unscrubbed) answered their cellphones during the surgery.

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Ten percent doctors (anesthetists), 20% nurses (unscrubbed) and 50% technicians (unscrubbed) would check their messages (SMSes) even during surgery.

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No doctor (anesthetists) or nurse (unscrubbed) tweeted during the surgery, but 50% of the OT technicians (unscrubbed) who have a Twitter account, said that they do use Twitter and tweet during the surgery.

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None of the doctors (anesthetists), OT nurses (unscrubbed) or technicians (unscrubbed) used their emails or accessed their Facebook accounts during surgery.

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Doctors (operating surgeons) do talk and attend to their mobile phones while surgery is going on but they communicate through a nurse (unscrubbed) or a junior (unscrubbed) who works as a bridge between the surgeon and the caller.

The reason given for picking up the phone was to rule out emergency calls, but the reason for use of SMS or Twitter was boredom.

refers to a form of repetitive strain injury caused by the frequent use of thumbs to press buttons on PDAs, smartphones or other mobile devices. Thumb lacks the dexterity of the other four fingers. This is especially common in those who use these devices for such activities at high speeds comparable to that of touch typing. It is also called wiiitis, nintendinitis, playstation thumb or cellphone thumb. Symptoms include aching and throbbing pain in the thumb or sometimes other fingers and in the wrist. Other diseases ÂÂ

Wii knees, Touch-Screen Finger, Text Neck and the dreaded Smartphone Saggy Face, Phantom Vibration syndrome.

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Wii knees: Tenderness or soreness in the knees from excessive use of the Nintendo Wii Fit. Similar in nature to tennis elbow.

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Saggy face (saggy jowls, double chins and ‘marionette lines’ often develop from the angles at which people use their trendy new mobile devices. Leaning your head to hold your mobile phone in between your face and shoulder is believed to cause facial skin and muscle to lose its elasticity more quickly than normal).

HCFI and IMA suggestions to prevent and treat mobile phone addictions ÂÂ

Facebook holidays: Take a full one week Facebook holiday if one is suspected to have social media addiction.

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Electronic curfew: Have 30 minutes of electronic curfew before sleep. (Electronic curfew means not using mobile phones/other mobile devices for 30 minutes before sleep).

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Use mobile only when mobile: Limit talk time to <2 hours/day. If battery is discharged, call it a day for mobile use.

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Follow the formula of ‘20-20-20’ to prevent dry eyes: Every 20 minutes, focus the eyes on an object 20 feet (6 meters) away for 20 seconds or close the eyes for 20 seconds, at least every half hour.

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To prevent computer vision syndrome, spend <3 hours on a computer.

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Using other fingers to press buttons on handheld device can prevent BlackBerry thumb.

Computer vision syndrome Computer vision syndrome is a temporary condition resulting from focusing the eyes on a computer display for protracted and uninterrupted periods of time. Some symptoms are headaches, blurred vision, neck pain, redness in the eyes, fatigue, eye strain, dry eyes, irritated eyes, double vision, vertigo/dizziness, polyopia and difficulty refocusing the eyes. These symptoms can be further aggravated by improper lighting conditions (glare or bright overhead lighting) or air moving past the eyes (overhead vents, direct air from a fan). Computer vision syndrome affects some 90% of the people who spend ≥3 hours a day at a computer. BlackBerry thumb Overuse of the thumb to operate a mobile device may lead to BlackBerry thumb. It is a neologism that

These are preliminary observations and need to be validated by similar surveys at other places in the country.

Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

9


Community Health

Twenty-six Percent School Girls Say they would Never Marry a Smoker KK Aggarwal

Abstract Earlier women were attracted to men who smoked. But, now this trend has changed. A prospective survey was carried out by Heart Care Foundation of India among 195 school girls, belonging to Class X-A, aged 15-16 years, from 16 Convent Schools in Delhi. While 72% girls would insist upon their would-be partner to stop smoking before the marriage, 26% girls said that they would never marry a smoker. All students were convinced that smoking is injurious to health.

Keywords: Smoking, school girls, marriage

I

n a prospective survey, conducted by Heart Care Foundation of India among school-going girls, 26% girls said that they would never marry a smoker. The survey included 195 school girls, belonging to class X-A, aged 15-16 years, from 16 Convent Schools in Delhi. Data was collected using a questionnaire, which each participant was asked to answer. Seventy-two percent girls answered that if they come to know that their would-be partner was a smoker, they would insist upon the partner to stop smoking before the marriage. Only 2% said that they would agree to marry as the fact that their partner smoked did not matter to them. None of the girls smoked cigarettes or consumed tobacco products. However, 26% were exposed to passive smoking in their house. Of these, 80% had objected about it to their family members. The remaining 20% said that though they wanted to intervene but could not because of fear. Fifty-eight percent girls agreed that they would object if someone was smoking in public in front of them. However, 38% girls said that instead of objecting they would rather remove themselves from the smoking area and move to a nonsmoking place. Only 4% girls said that they did not care if somebody around them was smoking. All the girls agreed that they would not begin to smoke on peer pressure from a friend or a boyfriend, even if they insisted on a single casual cigarette smoking. But, 5% girls said that they would be willing to do so to show their friends and their

boyfriends that they too were modern. One hundred percent participants were convinced that smoking is injurious to health. But, 14% girls felt that smoking helps in reducing depression. Also, 2% girls said that if they see doctors smoking in public, they would change their perception that smoking is bad for the health. Table. Observations of the Survey Variables

Percentage of participants (n = 195)

If you were asked to marry someone who smokes, you would: Never marry him/her

26% (n = 50)

Ask him/her to first stop smoking

72% (n =140)

Does not matter

2% (n = 4)

Do you smoke? Active smoking

0% (n = 0)

Does anyone in your family smoke? Passive smoking

26% (n = 50) Objected to family: 80% Could not object due to fear: 20%

Smoking in public place Would object to the person smoking

58% (n = 113)

Would not object but displace yourself from that place

38% (n = 74)

Do not mind

4% (n = 8)

Would you smoke to keep your friends happy? No

100% (n = 195)

Is smoking injurious to health? Padma Shri & Dr. BC Roy National Awardee President Heart Care Foundation of India E-mail: emedinews@gmail.com

10

Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

Yes

100% (n = 195)

Smoking reduces depression

14% (n = 27)


American Family Physician

Practice Guidelines

ACC and AHA Update on Chronic Heart Failure Guidelines In 2009, the American College of Cardiology (ACC) and the American Heart Association (AHA) published a focused update of the ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult. The guidelines writing committee reviewed recent trial data and other clinical information in the revision process for the 2009 update. The 2005 guidelines described four stages (i.e., stages A, B, C, and D) in the development of heart failure (Figure 1). Patients in stages A and B do not have heart failure, but have risk factors that predispose them toward the development of heart failure. Patients in stage C comprise the majority of patients with heart failureâ&#x20AC;&#x201D;those who have current or past symptoms of heart failure associated with underlying structural heart disease. Patients in stage D have refractory heart failure and may be eligible for specialized, advanced treatments (e.g., mechanical circulatory support, fluid removal procedures, continuous inotropic infusions, cardiac transplantation) or end-of-life care, such as hospice.

Updated Recommendations Updates to the 2005 guidelines are included in sections about the evaluation of patients presenting with heart failure; patients with reduced left ventricular ejection fraction (LVEF); patients with refractory end-stage heart failure; and the treatment of special population groups (e.g., blacks). The updated guidelines also contain a new section with recommendations about heart failure in the hospitalized patient. Evaluation of Heart Failure Updates to the section on the evaluation of patients presenting with heart failure were made to clarify the role of functional assessment beyond the New York Heart Association (NYHA) classification, and to expand on the use of brain natriuretic peptide (BNP) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) testing for patient evaluation. According

to the update, patients with left ventricular dysfunction or heart failure generally present in one of three ways: with a syndrome of decreased exercise tolerance; with a syndrome of fluid retention; or with no symptoms, or symptoms of another cardiac or noncardiac disorder. 2009 updated recommendation: Measurement of natriuretic peptides (i.e., BNP and NT-proBNP) can be useful in the evaluation of patients presenting in the urgent care setting in whom the clinical diagnosis of heart failure is uncertain. Measurement of natriuretic peptides can be useful in risk stratification. (Level of Evidence: A) The 2005 guidelines also recommended measurement of BNP for evaluating patients who present in the urgent care setting with possible heart failure; the 2009 update expanded this recommendation to include the measurement of NTproBNP. The level of evidence remained the same for this recommendation. The 2009 update warns that, although elevated natriuretic peptide levels may help confirm a suspected diagnosis of heart failure, the results of this testing alone should not be used to confirm or exclude a heart failure diagnosis. Reduced LVEF The section of the guidelines on patients with reduced LVEF included minor updates on recommendations about the use of angiotensin-II receptor blockers (ARBs) and exercise testing. 2009 updated recommendation: Use of ARBs is recommended in patients with current or previous symptoms of heart failure and reduced LVEF who have an intolerance to angiotensinconverting enzyme (ACE) inhibitors. (Level of Evidence: A) For this recommendation, the 2009 update modified the text in the 2005 guidelines by eliminating mention of specific agents tested. 2009 updated recommendation: Maximal exercise testing with or without measurement of respiratory gas exchange is reasonable to facilitate prescription of an appropriate exercise program for patients presenting with heart failure. (Level of Evidence: C)â&#x20AC;ŻThe 2009 update changed the class of recommendation from class I (i.e., treatment should be performed) to class IIa (i.e., treatment is reasonable to perform).

Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

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American Family Physician

At risk of heart failure

Management of Patients who have or are at Risk of Heart Failure Stage A: At high risk of heart failure, but without structural heart disease or symptoms of heart failure Includes patients with: Atherosclerotic disease Diabetes mellitus Hypertension Metabolic syndrome Obesity Or patients: Using cardiotoxins With a family history of cardiomyopathy

Therapy Goals: Control metabolic syndrome Discourage alcohol intake and illicit drug use Encourage regular exercise Encourage smoking cessation Treat hypertension Treat lipid disorders Drugs: ACE inhibitors or ARBs in appropriate patients for vascular disease or diabetes

Structural heart disease

Stage B: Structural heart disease but without signs or symptoms of heart failure Includes patients with: Asymptomatic valvular disease Left ventricular remodeling, including left ventricular hypertrophy and low ejection fraction Previous myocardial infarction

Therapy Goals: All measures under stage A Drugs: ACE inhibitors or ARBs in appropriate patients Beta blockers in appropriate patients Devices in selected patients: Implantable cardioverter-defibrillators

Development of symptoms of heart failure

Heart failure

Stage C: Structural heart disease, with previous or current symptoms of heart failure Includes patients with: Known structural heart disease and Shortness of breath and fatigue, reduced exercise tolerance

Therapy Goals: Drugs in selected patients: All measures under stages A and B Aldosterone antagonists Restrict dietary sodium ARBs Digitalis Drugs for routine use: Hydralazine/nitrates ACE inhibitors Beta blockers Devices in selected patients: Diuretics for fluid retention Biventricular pacing Implantable cardioverterdefibrillators

Refractory symptoms of heart failure at rest

Stage D: Refractory heart failure requiring specialized interventions Includes patients who have marked symptoms at rest despite maximal medical therapy (e.g., those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions)

Therapy Goals: All measures under stages A, B, and C Decide appropriate level of care Options: Compassionate end-of-life care, hospice Extraordinary measures (e.g., chronic inotropes, experimental drugs or surgery, heart transplant, permanent mechanical support)

Figure 1. Algorithm of the stages in the development of heart failure, with recommended therapy for patients by stage. ACE = Angiotensin-converting enzyme; ARB = Angiotensin-II receptor blocker.

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American Family Physician The section on patients with reduced LVEF also included several changes to recommendations concerning implantable cardioverter-defibrillator therapy and cardiac resynchronization therapy. 2009 updated recommendation: Implantable cardioverterdefibrillator therapy is recommended for the primary prevention of sudden cardiac death to reduce total mortality in patients with non-ischemic dilated cardiomyopathy or ischemic heart disease at least 40 days after myocardial infarction (MI); an LVEF of 35 percent or less; and NYHA functional class II or III symptoms while receiving chronic optimal medical therapy, and who have reasonable expectation of survival with a good functional status for longer than one year. (Level of Evidence: A) This recommendation was modified in the 2009 update to be consistent with the 2008 Device-Based Therapy guidelines from the ACC, AHA, and Heart Rhythm Society (HRS). It replaces recommendations from the 2005 guidelines on implantable cardioverter-defibrillator therapy for patients with ischemic heart disease at least 40 days after MI (2005 Level of Evidence: A) or nonischemic cardiomyopathy (2005 Level of Evidence: B) with an LVEF of 30 percent or less, and for patients with an LVEF of 30 to 35 percent of any origin (2005 Level of Evidence: B). In two of the major trials reviewed by the guidelines committee, no survival benefit was observed from implantable cardioverter-defibrillator therapy until after the first year of recovery from an acute coronary event. Patients with heart failure and low ejection fraction are typically older than 70 years, although this patient population was not well represented in the trials. Physicians should consider common comorbidities in older adults (e.g., previous stroke, chronic pulmonary disease, arthritic conditions) when discussing this type of therapy with patients. Medication may substantially improve LVEF; therefore, consideration of implantable cardioverterdefibrillator therapy should follow documentation of sustained reduction of LVEF despite a course of beta blockers and ACE inhibitors or ARBs. Implantable cardioverter-defibrillator therapy is not warranted in patients with refractory heart failure (stage D) or in those with concomitant diseases that would shorten their life expectancy independent of heart failure. Before implantation, physicians should inform patients of the effectiveness, safety, and mortality risks of implantable cardioverter-defibrillator therapy; of the morbidity associated with an implantable cardioverterdefibrillator shock; and that the therapy does not improve clinical function or delay progression of heart failure.

2009 updated recommendation: Patients with LVEF of 35 percent or less, sinus rhythm, and NYHA functional class III or ambulatory class IV symptoms despite recommended, optimal medical therapy and who have cardiac dyssynchrony (i.e., a QRS duration of 0.12 seconds or more) should receive cardiac resynchronization therapy, with or without an implantable cardioverter-defibrillator, unless contraindicated. (Level of Evidence: A) The 2009 recommendation was updated to clarify that cardiac resynchronization therapy may be indicated for patients with or without an implantable cardioverter-defibrillator. Evidence shows that cardiac resynchronization therapy can improve symptoms, exercise capacity, quality of life, LVEF, and survival; it can also decrease hospitalizations in patients with persistently symptomatic heart failure receiving optimal medical therapy who have cardiac dyssynchrony. The use of an implantable cardioverterdefibrillator in addition to cardiac resynchronization therapy should be based on the indications for implantable cardioverter-defibrillator therapy. End-stage Heart Failure The section of the guidelines on patients with refractory end-stage heart failure (stage D) included a modified recommendation on intermittent infusions. 2009 updated recommendation: Routine intermittent infusions of vasoactive and positive inotropic agents are not recommended for patients with refractory end-stage heart failure. (Level of Evidence: A) The 2009 update changed the level of evidence from B to A for this recommendation, based on evidence from an additional multicenter trial. Intermittent outpatient infusions of vasoactive medications (e.g., nesiritide) or positive inotropic medications have not been shown to improve symptoms or survival in patients with advanced heart failure.

New Recommendations Hydralazine/Nitrates New recommendation to 2009 update: The combination of hydralazine and nitrates is recommended to improve outcomes for patients with reduced LVEF whose ethnicity is self-described as African American and who have moderate to severe symptoms on optimal therapy with ACE inhibitors, beta blockers, and diuretics. (Level of Evidence: B) Analysis of vasodilator trials showed effectiveness of treatment with isosorbide dinitrate and hydralazine in black participants. Adding these medications to standard therapy with an ACE inhibitor, a beta blocker, or both proved to be beneficial in a subsequent trial.

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American Family Physician Accordingly, this combination is recommended for black patients who remain symptomatic despite optimal medical therapy. However, patient compliance with this combination may be low because of the large number of tablets required and the high incidence of adverse reactions. The combination treatment should not be prescribed in patients who have not previously used an ACE inhibitor, nor should it be substituted for ACE inhibitors in those who are tolerating them without difficulty. It is unclear if this combination is beneficial in non-black patients. Atrial Fibrillation and Sinus Rhythm New recommendation to 2009 update: It is reasonable to treat patients who have atrial fibrillation and heart failure with strategies to maintain sinus rhythm or to control ventricular rate alone. (Level of Evidence: A)â&#x20AC;ŻFour trials evaluated the effectiveness and safety of restoring and maintaining sinus rhythm in patients with atrial fibrillation. There were equivalent outcomes for restoring and maintaining sinus rhythm by electrical or pharmacologic conversion compared with controlling ventricular rate in patients with atrial fibrillation. Most patients quickly relapse to atrial fibrillation unless they are treated with a class I or III antiarrhythmic medication, but patients with heart failure are not likely to respond favorably to class I medications. Class III antiarrhythmic medications (e.g., sotalol, dofetilide, amiodarone) can maintain sinus rhythm in some patients, although treatment is associated with an increased risk of organ toxicity (amiodarone) and proarrhythmia (dofetilide). Cardiac Resynchronization Therapy New recommendations to 2009 update: For patients who have LVEF of 35 percent or less, a QRS duration of 0.12 seconds or more, and atrial fibrillation, cardiac resynchronization therapy, with or without an implantable cardioverter-defibrillator, is reasonable for the treatment of NYHA functional class III or ambulatory class IV heart failure symptoms on optimal recommended medical therapy. (Level of Evidence: B) Cardiac resynchronization therapy is reasonable for patients with LVEF of 35 percent or less with NYHA functional class III or ambulatory class IV symptoms who are receiving optimal recommended medical therapy and who have frequent dependence on ventricular pacing. (Level of Evidence: C)â&#x20AC;ŻCardiac resynchronization therapy recommendations were added to be consistent with the ACC/AHA/HRS 2008 Guidelines for DeviceBased Therapy of Cardiac Rhythm Abnormalities. New Section: The Hospitalized Patient The 2009 update includes a new section on the evaluation and treatment of heart failure in patients who are hospitalized. Patients may require

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hospitalization if they develop acute or progressive symptoms of heart failure. Generally there are three clinical profiles for these patients: those who have volume overload (manifested by pulmonary and/ or systemic congestion and often precipitated by an acute increase in chronic hypertension); those with profound depression of cardiac output (manifested by hypotension, renal insufficiency, and/or a shock syndrome); and those with signs and symptoms of fluid overload and shock. Patients with heart failure and preserved LVEF are just as likely to be admitted to the hospital as those with heart failure and low LVEF. Patients are usually admitted to the hospital following a concomitant cardiovascular or cerebrovascular event, and admission often is related to medical or dietary noncompliance. Other common factors that precipitate hospitalization for heart failure include acute myocardial ischemia; uncorrected high blood pressure; atrial fibrillation and other arrhythmias; recent addition of negative inotropic medications; pulmonary embolus; use of nonsteroidal anti-inflammatory drugs; excessive alcohol or illicit drug use; endocrine abnormalities (e.g., diabetes mellitus, hyperthyroidism, hypothyroidism); and concurrent infections (e.g., pneumonia, viral illnesses). Inpatient Evaluation and Diagnosis The diagnosis of heart failure in hospitalized patients should be based primarily on signs and symptoms, including volume status, the adequacy of circulatory support or perfusion, and consideration of precipitating factors or comorbidities. Many of the evaluation steps are identical to those used in the initial evaluation of heart failure. For an uncertain diagnosis of heart failure, plasma BNP or NT-proBNP concentrations should be considered in patients being evaluated for dyspnea who have signs and symptoms compatible with heart failure. In patients who have already been diagnosed with heart failure, it is important to understand what has caused the clinical symptoms to worsen. Acute MI is an important cause of worsening or new-onset heart failure, and criteria for an acute coronary event that might indicate the need for further intervention may be present in up to 20 percent of patients hospitalized for heart failure. However, several other patients may have low levels of detectable troponins that do not meet criteria for an acute ischemic event, but that are typical of chronic heart failure with an acute exacerbation. For patients with newly discovered heart failure, physicians should keep in mind the causative role of coronary artery disease in heart failure and be certain that coronary structure and function are well delineated. Therefore,


American Family Physician coronary visualization may be an important step in the evaluation of patients hospitalized with heart failure. Inpatient Treatment A careful review of each patientâ&#x20AC;&#x2122;s maintenance medications for heart failure is important, and medication adjustments may be necessary as a result of the hospitalization. The majority of patients should continue taking their medications during hospitalization, and most are able to tolerate the continuation of beta blockers, which results in better outcomes. Patients with substantial fluid overload on hospital admission should be treated with loop diuretics, initiated upon arrival to the emergency department. After admission, careful and frequent evaluation and monitoring are important and include assessing volume status and circulatory support; monitoring daily weight and vital signs; managing daily fluid input and output; and assessing daily electrolyte levels and renal function, which should be performed while intravenous diuretics or active heart failure medication titration is being done. Optimal dosing of diuretics should produce a rate of diuresis that will benefit volume status and relieve signs and symptoms of congestion without inducing an excessively rapid reduction in intravascular volume, possibly resulting in hypotension, renal dysfunction, or both. Limiting sodium intake and dosing the diuretic multiple times daily can enhance diuresis effectiveness. Patients who present with congestion and moderate to severe renal dysfunction may have a blunted response to diuretics, requiring higher initial doses. If all diuretic strategies are unsuccessful, ultrafiltration or another renal replacement strategy may be considered, as well as consultation with a kidney subspecialist. Intravenous vasodilators may be added to the treatment regimen in patients who have adequate blood pressure and ongoing congestion that does not adequately respond to diuretics and standard oral therapy. The goals of vasodilator therapy include a more rapid resolution of congestive symptoms; relief of anginal symptoms while awaiting coronary intervention; control of hypertension; and improvement of hemodynamic abnormalities before beginning oral medications for heart failure. Patients presenting with predominantly low output syndrome or combined congestion and low output may be considered for intravenous inotropes (e.g.,

dopamine, dobutamine, milrinone), which may help relieve symptoms caused by poor perfusion and preserve end-organ function in those with severe systolic dysfunction and dilated cardiomyopathy. These medications are most beneficial in patients with relative hypotension and who have intolerance or no response to vasodilators and diuretics. However, the use of inotropes indicates a poor prognosis, and a thorough hemodynamic assessment is necessary. There is no evidence of benefit for routine use of these agents in patients with acute heart failure caused by congestion only; therefore, inotropes should be limited to carefully selected patients with low blood pressure and reduced cardiac output, who will require close monitoring of blood pressure and heart rhythm. Routine invasive hemodynamic monitoring is not indicated for most patients hospitalized with symptoms of worsening heart failure, but should be considered in those whose volume and filling pressures are uncertain or who are refractory to initial therapy, particularly when filling pressures and cardiac output are unclear. Routine invasive hemodynamic monitoring also may be beneficial in patients with clinically significant hypotension (i.e., systolic blood pressure typically less than 90 mm Hg or symptomatic low systolic blood pressure) or worsening renal function during initial therapy. Invasive hemodynamic monitoring should be performed in patients with presumed cardiogenic shock that requires escalating pressor therapy and consideration of mechanical support; those with severe clinical decompensation in whom therapy is limited by uncertainty regarding relative contributions of elevated filling pressures, hypoperfusion, and vascular tone; those with apparent dependence on intravenous inotropic infusions after initial clinical improvement; or those with persistent, severe symptoms despite adjustment of recommended treatments. As patients stabilize and volume status normalizes, oral therapy for heart failure should be initiated or resumed. Caution should be used when starting beta blockers in patients who were treated with inotropes while hospitalized, or when initiating ACE inhibitors in patients who had marked azotemia. Before discharge, patients should be fully transitioned off all intravenous therapy, and oral therapy should be adjusted and maximized. Patients should be given written discharge instructions or educational materials that address activity level, diet, discharge medications, follow-up appointments, weight monitoring, and what to do if symptoms worsen. Source: Adapted from Am Fam Physician. 2010;81(5):654-665.

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Cardiology

CAD: A True Pandemic and a Comprehensive Surveillance System is the Need of the Hour G Kannan*, NN Rajendran**, JSN Murthy†, GB Tharani‡

Abstract Coronary artery disease (CAD) occurs when the arteries that supply blood to the heart muscle harden and narrow. According to the Global Burden of Disease Study, the developing countries contributed 3.5 million of the 6.2 million global deaths from CAD in 1990. The prevalence of CAD in India has more than doubled in the past two decades. India topped the world with 1,531,534 cardiovascular disease-related deaths in 2002, and based on WHO report, 2009, CAD currently occupies the first place in cause of death. A comprehensive surveillance system of risk factors and CAD will be an invaluable public health research tool for monitoring population health status, guiding resource allocation and policy, identifying and prioritizing interventions for subpopulations at particular risk that would help to bring down the true pandemic which is on the climb.

Keywords: Coronary artery disease, pandemic, surveillance system, health status

C

oronary artery disease (CAD) occurs when the arteries that supply blood to the heart muscle harden and narrow (Bhati K, 2011; Heart Diseases, 2011). The result is the loss of oxygen and nutrients to myocardial tissue because of diminished coronary blood flow (Springhouse, 2005). This reduction in blood flow can lead to acute coronary syndrome (angina or myocardial infarction). CAD is on the climb and has become a true pandemic that respects no borders.

Prevalence of CAD

Global Scenario The term ‘prevalence’ of CAD usually refers to the estimated population of people who are managing CAD at any given time (American Heart Association, 2004). The proportion of deaths due to CAD is projected to rise from 59% in 2002 to 69% in 2030 (Mathers and

*Assistant Professor Dept. of Pharmacy Practice, Faculty of Pharmacy Sri Ramachandra University, Porur, Chennai **Professor Swami Vivekananda College of Pharmacy, Erode, Chennai †Professor and Head Dept. of Cardiology, Sri Ramachandra University, Porur, Chennai ‡Professor and Head Saveetha Medical College, Thandalam, Chennai Address for correspondence Dr G Kannan Assistant Professor, Dept. of Pharmacy Practice, Faculty of Pharmacy Sri Ramachandra University, Porur, Chennai - 600 116 E-mail: kannagg2@yahoo.ca

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Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

Loncar, 2006). The WHO (2006) estimates that at least 20 million people survive CAD-related heart attacks and strokes every year around the world; many require continuing costly clinical care. By 2030, almost 23.6 million people will die from CADs, mainly from heart disease and stroke. These are projected to remain the single leading causes of death (WHOCardiovascular Disease: Prevention and Control, 2006). A recent evaluation of WHO in the cause of death in 2009, CAD and stroke were placed as first (7,185,353 deaths) and second (5,704,843 deaths) in rank among total deaths (6,830,586,985) of all kind of diseases. Moreover, the rate of death is rising more in the underdeveloped countries than the developed countries, because of their lifestyle and socioeconomic factors (WHO, 2009). According to the Global Burden of Disease Study, the developing countries contributed 3.5 million of the 6.2 million global deaths from CAD in 1990. The projections estimate that these countries will account for 7.8 million of the 11.1 million deaths due to CAD in 2020 (Murray et al, 1996). Disability-adjusted life years (DALYs) lost can be thought of as ‘healthy years of life lost’. They indicate the total burden of a disease, as opposed to simply the resulting deaths. Murray et al (1996) calculate that in India and China, a spectacular rise in the number of DALYs is expected in the coming years - from a figure of <25 million DALYs in each country in 1990, to 30 million and 35 million in India and China, respectively, in 2020. CAD is decreasing


Cardiology in many developed countries, but is increasing in developing and transitional countries, partly as a result of increasing longevity, urbanization and lifestyle changes. CAD is responsible for 10% of DALYs lost in low and middle-income countries and 18% in highincome countries (Global Burden of Coronary Heart Disease, 2002). CAD is the most common cause of death (and premature death) in the UK. One in 5 men and one in 7 women die from CAD. There are 94,000 deaths from CAD in the UK each year (Greenlund et al, 2006). With regard to incidence, data from the Atherosclerosis Risk In Communities (ARIC) and Cardiovascular Health Study indicate that annually, 7,85,000 Americans have a new coronary attack and 4,70,000 have a recurrent attack; in addition, approximately 1,95,000 silent myocardial infarctions occur each year. This assumes that 21% of the 9,35,000 first and recurrent myocardial infarctions are silent (Thom et al, 2001; Boland et al, 2002). Tables 1 and 2 depict the CAD prevalence in urban and rural population of developed countries and developing countries.

in urban than in rural population, with a greater prevalence in affluent groups (Chadha et al, 1990; Enas et al, 1992; Singh et al, 1997). Enas et al (1996) and Enas et al (1999). It is estimated that 9.2 million productive years of life were lost in India in 2000, with an expected increase to 17.9 million years in 2030. Table 3 depicts the CAD prevalence with respect to age group, sample size of the study population in different parts of India. Salient features of the CAD epidemic in India: ÂÂ

Incidence of CAD in young Indians is about 12-16%, which is higher than any other ethnic group (Mammi et al, 1991).

ÂÂ

Age-standardized estimates for DALYs lost due to CAD per 1,000 population in India are three times higher than in developed countries (Negus et al, 1994).

ÂÂ

About 5-10% of heart attacks occur in Indian men and women younger than 40 years (Mackay and Mensah, 2004).

ÂÂ

India topped the world with 1,531,534 cardiovascular disease-related deaths in 2002, and occupied first place in cause of death in current moment based on WHO report, 2009 (Yusuf et al, 2004; WHO, 2009).

ÂÂ

Median age of first heart attack in Indians is 53 years (WHO, 2009).

ÂÂ

1,55,88,000 DALYs (WHO, 2009).

Indian Scenario The prevalence of CAD in India has more than doubled in the past two decades. This has occurred both in the rural and urban populations, although it is higher

Table 1. CAD in Urban and Rural Population of Developed Countries Author

Year

Age group

Place

Sample size

CAD prevalence (%)

Calvet et al.

2010

45-75

France

300

50.0

Arzamendi et al.

2010

20-65

Developed countries

1,260

49.0

Iwasaki et al.

2011

30-70

Japan

135

9.20

Icaza et al.

2009

35-74

USA

General population

6.95

Kivimaki et al.

2011a

30-70

UK

5,533

0.70

Jain et al.

2011

35-75

London (UK)

2,369

22.0

Kivimaki et al.

2011b

30-70

London (UK)

7,095

0.027

Ong et al.

2011

30-70

UK

698

5.00

Stansby et al.

2011

68

UK

473

30.0

Ebrahim et al.

2011

20-70

UK

1,63,471

4.35

Secrest et al.

2011

24-32

USA

317

2.50

Oizumi et al.

2008

30-70

Japan

2,938

3.19

Idris et al.

2008

30-70

UK

1,087

50.0

Konishi et al.

1990

40-59

Japan

8,835

88.0

Urban population

Rural population

Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

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Cardiology Table 2. CAD in Urban and Rural Population of Developing Countries (Excluding India) Author

Year

Age group

Place

Sample size

CAD prevalence (%)

Grau et al.

2010

30-70

France + Spain

420 + 562

0.98

Chin et al.

2009

30-70

Malaysia

2,030

10.35

Hatmi et al.

2007

20-45

Iran

3,000

25.75

Hariharan et al.

2010

30-70

Trinidad + Tobago

1,082

1.20

Sadeghi et al.

2006

35-70

Iran

6,498

29.90

Kalra et al.

2011

35-86

Nepal

142

38.00

Icaza et al.

2009

35-74

Chile

General population

1.80

Icaza et al.

2009

35-74

China

General population

0.85

Icaza et al.

2009

35-74

Spain

General population

3.70

Ozdemir et al.

2010

30-70

Turkey

24

33.33

Vaidya et al.

2009

35 - <

Eastern Nepal

-

5.70

Onat et al.

2010

45-74

Turkey

1,655

11.50

Pitsavos et al.

2008

30-70

Greek

2,172

1.36

PavloviÄ&#x2021; et al.

2004

37-56

Croatia

3,544

3.70

Urban population

Rural population

Table 3. Prevalence of CAD in Population of India Author

Year

Age group

Place

Sample size

CAD prevalence (%)

South India Geetha et al.

2011

30-70

Chennai (Tamil Nadu)

2,350

2.93

Mohan et al.

2010a

30-70

Chennai (Tamil Nadu)

-

5.40

Mohan et al.

2010b

30-70

Chennai (Tamil Nadu)

-

11.0

Kumaran et al.

2002

30-70

Mysore

435

21.75

Mohan et al.

2001

20-70

Chennai (Tamil Nadu)

1,262

11.0

Stein et al.

1996

Mysore

517

10.0

Begom et al.

1995

25-65

South India (Urban)

506

13.9

Singh et al.

2011

<15

Chandigarh

196

0.000045

Kumar et al.

2006

>35

North India (Urban + Rural)

7,169

3.96

Ahmad et al.

2005

25-70

Delhi (Urban)

14,000

0.2-0.9

Ahmad et al.

2005

25-70

Delhi (Rural)

14,000

0.1-0.4

North India

Singh et al.

1997

25-64

Moradabad

3,575

1.5-3.0

Chadha et al.

1997

25-64

Delhi (Urban + Rural)

13,723

96.7 (Urban) + 27.1 (Rural)

Begom et al.

1995

25-65

North India (Urban)

506

61.6

Lanjewar et al.

2005

25-70

Mumbai

3,871

4.20

Rastogi et al.

2004

30-70

Western India

350

1.88

Pinto et al.

2004

35-64

Goa

371

13.2

Hazarika et al.

2002

30-70

Assam

1,015

61.0

Bhattacharyya

2003

30-70

Kolkata

28 + 62

39 + 60

West India

East India

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Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013


Cardiology Need of the Hour Prospective studies on the relative role and importance of traditional and newer risk factors are urgently needed in Indians within the subcontinent as much of the knowledge of risk factors for CAD has been acquired from studies conducted in the Western population. It is widely believed that the association of these risk factors with CAD in different subpopulations needs to be ascertained, and there is speculation that differences might range from the frequency of presence of classical risk factors to their total absence or irrelevance in these populations. A cost-effective preventive strategy will need to focus on reducing risk factors both in the individual and in the population at large. Effective screening, evaluation and management strategies for CAD are well-established in high-income countries, but these strategies have not been fully implemented in India which was noted by Mohan et al (2001). A key factor that hampers the development of such preventive strategies in developing countries such as India is the meager amount (8%) of published literature on CAD research available from these countries (Mackay and Mensah, 2004). Of particular concern to India is not only the high burden of CAD, but also the effects of these diseases on the productive workforce aged 35-65 years. Heart diseases are rising in Asian Indians 5-10 years earlier than in other populations around the world. The mean age for first presentation of acute myocardial infarction in Indians is 53 years. CAD that manifests at a younger age can have devastating consequences for an individual, the family and society. Prevention of these deaths in young people is a nationâ&#x20AC;&#x2122;s moral responsibility (Sharma and Ganguly, 2005). A strategy involving prevention of CADs long before their onset will be more costeffective than providing interventions at a stage when the disease is well-established. Therefore, it is imperative to undertake large populationbased, prospective studies in developing countries such as India to identify CAD risk factors, both conventional and novel. Careful scrutiny of available scientific evidence for modifiable CAD risk factors (elevated serum total and LDL-C, low HDL-C, smoking, diabetes, hypertension, low level of physical activity and central obesity) in association with genetically predisposing factors like Lp(a) in Indian population may be helpful in formulating a more immediate CAD prevention strategy. Given the explosion of diabetes and CAD in India and in view of the differences in race, culture, way of life,

diet, stress and strain and the myriad other factors, increased emphasis on lifestyle modification, including diet, exercise, weight reduction and whenever relevant, stress reduction, is urgently needed. A comprehensive surveillance system of risk factors and CAD will be an invaluable public health research tool for monitoring population health status, guiding resource allocation and policy, identifying and prioritizing interventions for subpopulations at particular risk, identifying disparities in outcomes and planning and evaluating health programs. Carefully planned prevention programs with intervention strategies by catching the vulnerable individuals at an early age could also be taken up in different parts of the country to prevent the twin epidemic of diabetes and CAD; as both have common causative factors, and prevention strategies could also be combined judiciously to prevent both disorders, as this would make it more cost-effective. Resources should be directed towards applying the existing knowledge base to tackle the CAD epidemic in policy, capacity building and research arenas. Control of the CAD epidemic in the Indian subcontinent is tenable in the foreseeable future, provided that policy makers, health professionals and the lay public in the Indian subcontinent acknowledge its potential impact and promptly act to address to make a major step towards CAD free society. Suggested Reading 1. Ahmad N, Bhopal R. Is coronary heart disease rising in India? A systematic review based on ECG defined coronary heart disease. Heart 2005;91(6):719-25. 2. American Heart Association, 2004. Prevalence of Coronary heart disease. http://www.wrongdiagnosis. com/c/coronary_heart_disease/prevalence.htm. 3. Arzamendi D, Benito B, Tizon-Marcos H, Flores J, Tanguay JF, Ly H, et al. Increase in sudden death from coronary artery disease in young adults. Am Heart J 2011;161(3):574-80. 4. Bhattacharyya M. Coronary heart disease prevention in Kolkata, India. J R Soc Promot Health 2003;123(4): 222-8. 5. Begom R, Singh RB. Prevalence of coronary artery disease and its risk factors in the urban population of South and North India. Acta Cardiol 1995;50(3):227-40. 6. Bhati K. Causes and herbal remedies for coronary artery disease or heart problem. Available at: http://www. sooperarticles.com/health-fitness-articles/heart-diseasearticles/causes-herbal-remedies-coronary-artery-diseaseheart-problem-368593.html. Published on 28th Mar. 2011. 7. Boland LL, Folsom AR, Sorlie PD, Taylor HA, Rosamond WD, Chambless LE, et al. Occurrence of

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Cardiology unrecognized myocardial infarction in subjects aged 45 to 65 years (the ARIC study). Am J Cardiol 2002;90(9): 927-31.

21. Heart diseases (2011). The Heart and Stroke Foundation. Available at: http://www.heartandstroke.com/site/c.ikI QLcMWJtE/b.3483991/k.34A8/Statistics.htm.

8. Calvet D, Touzé E, Varenne O, Sablayrolles JL, Weber S, Mas JL. Prevalence of asymptomatic coronary artery disease in ischemic stroke patients: the PRECORIS study. Circulation 2010;121(14):1623-9.

22. Icaza G, Núñez L, Marrugat J, Mujica V, Escobar MC, Jiménez AL, et al. Estimation of coronary heart disease risk in Chilean subjects based on adapted Framingham equations. Rev Med Chill 2009;137(10):1273-82.

9. Chadha SL, Radhakrishnan S, Ramachandran K, Kaul U, Gopinath N. Epidemiological study of coronary heart disease in urban population of Delhi. Indian J Med Res 1990;92:424-30.

23. Idris I, Deepa R, Fernando DJ, Mohan V. Relation between age and coronary heart disease (CHD) risk in Asian Indian patients with diabetes: a cross-sectional and prospective cohort study. Diabetes Res Clin Pract 2008;81(2):243-9.

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24. Iwasaki M, Kuroda S, Nakayama N, Hokari M, Yasuda H, Saito H, et al. Clinical characteristics and outcomes in carotid endarterectomy for internal carotid artery stenosis in a Japanese population: 10-year microsurgical experience. J Stroke Cerebrovasc Dis 2011;20(1):55-61.

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26. Kivimäki M, Batty GD, Hamer M, Ferrie JE, Vahtera J, Virtanen M, et al. Using additional information on working hours to predict coronary heart disease: a cohort study. Ann Intern Med 2011b;154(7):457-63.

14. Enas EA, Yusuf S, Mehta JL. Prevalence of coronary artery disease in Asian Indians. Am J Cardiol 1992;70(9): 945-9.

27. Kivimäki M, Nyberg ST, Batty GD, Shipley MJ, Ferrie JE, Virtanen M, et al. Does adding information on job strain improve risk prediction for coronary heart disease beyond the standard Framingham risk score? The Whitehall II study. Int J Epidemiol 2011a May 9. (Epub ahead of print)

15. Geetha L, Deepa M, Anjana RM, Mohan V. Prevalence and clinical profile of metabolic obesity and phenotypic obesity in Asian Indians. J Diabetes Sci Technol 2011; 5(2):439-46. 16. Grau M, Bongard V, Fito M, Ruidavets JB, Sala J, Taraszkiewicz D, et al; REGICOR, GENES Investigators. Prevalence of cardiovascular risk factors in men with stable coronary heart disease in France and Spain Arch Cardiovasc Dis 2010;103(2):80-9. 17. Greenlund KJ, Giles WH, Keenan NL, et al. Heart disease and stroke mortality in the 20th century. In: Silent Victories: The History and Practice of Public Health in 20th Century America. Ward J, Warren C (Eds.), Oxford University Press: Oxford, England; 2006.

28. Konishi M, Iso H, Iida M, Naito Y, Sato S, Komachi Y, et al. Trends for coronary heart disease and its risk factors in Japan: epidemiologic and pathologic studies. Jpn Circ J 1990;54(4):428-35. 29. Kumar R, Singh MC, Singh MC, Ahlawat SK, Thakur JS, Srivastava A, et al. Urbanization and coronary heart disease: a study of urban-rural differences in northern India. Indian Heart J 2006;58(2):126-30. 30. Kumaran K, Fall CH, Martyn CN, Vijayakumar M, Stein CE, Shier R. Left ventricular mass and arterial compliance: relation to coronary heart disease and its risk factors in South Indian adults. Int J Cardiol 2002;83(1):1-9.

18. Hariharan S, Chen D, Vialva M, Exeter H, Billingy I, Bobb KA, et al. Outcome evaluation of coronary artery bypass grafting surgery applying the EuroSCORE in a Caribbean developing country. Heart Surg Forum 2010;13(5):E287-91.

31. Lanjewar C, Jolly S, Mehta SR. Effects of aspiration thrombectomy on mortality in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention: a meta-analysis of the randomized trials. Indian Heart J 2009;61(4):335-40.

19. Hatmi ZN, Tahvildari S, Gafarzadeh Motlag A, Sabouri Kashani A. Prevalence of coronary artery disease risk factors in Iran: a population based survey. BMC Cardiovasc Disord 2007;7:32.

32. Mackay J, Mensah G. The atlas of heart disease and stroke. World Health Organization, Centers for Disease Control and Prevention; 2004.

20. Hazarika NC, Biswas D, Narain K, Kalita HC, Mahanta J. Hypertension and its risk factors in tea garden workers of Assam. Natl Med J India 2002;15(2):63-8.

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33. Mammi MV, Pavithran K, Abu Rahiman P, Pisharody R, Sugathan K. Acute myocardial infarction in north Kerala. A 20-year hospital based study. Indian Heart J 1991;43(2):93-6.


Cardiology 34. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3(11):e442. 35. Mohan V, Deepa R, Rani SS, Premalatha G; Chennai Urban Population Study (CUPS No. 5). Prevalence of coronary artery disease and its relationship to lipids in a selected population in South India: The Chennai Urban Population Study (CUPS No. 5). J Am Coll Cardiol 2001;38(3):682-7. 36. Mohan V, Vassy JL, Pradeepa R, Deepa M, Subashini S. The Indian type 2 diabetes risk score also helps identify those at risk of macrovascular disease and neuropathy (CURES-77). J Assoc Physicians India 2010a; 58:430-3. 37. Mohan V, Venkatraman JV, Pradeepa R. Epidemiology of cardiovascular disease in type 2 diabetes: the Indian scenario. J Diabetes Sci Technol 2010;4(1): 158-70. 38. Murray CJL, Lopez AD. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Disease, Injuries and Risk Factors in 1990 and Projected to 2020. Harvard University Press: Boston, Ma; 1996. 39. Oizumi T, Daimon M, Jimbu Y, Wada K, Kameda W, Susa S, et al. Impaired glucose tolerance is a risk factor for stroke in a Japanese sample - the Funagata study. Metabolism 2008;57(3):333-8. 40. Onat A, Uğur M, Ciçek G, Ayhan E, Doğan Y, Kaya H, et al. The Turkish Adult Risk Factor survey 2009: similar cardiovascular mortality in rural and urban areas. Turk Kardiyol Dern Ars 2010;38(3):159-63. 41. Ong P, Athanasiadis A, Borgulya G, Voehringer M, Sechtem U. 3-year follow-up of patients with coronary artery spasm as cause of acute coronary syndrome: the CASPAR (coronary artery spasm in patients with acute coronary syndrome) study follow-up. J Am Coll Cardiol 2011;57(2):147-52. 42. Ozdemir H, Ciftçi E, Tapisiz A, Ince E, Tutar E, Atalay S, et al. Clinical and epidemiological characteristics of children with Kawasaki disease in Turkey. J Trop Pediatr 2010;56(4):260-2. 43. Pavlović M, Corović N, Gomzi M, Simić D, Jazbec A, Tiljak MK. Smoking habits, signs of chronic diseases and survival in inland and coastal regions of Croatia: a followup study. Coll Antropol 2004;28(2):689-700. 44. Pinto RJ, Bhagwat AR, Loya YS, Sharma S. Coronary artery disease in premenopausal Indian women: risk factors and angiographic profile. Indian Heart J 1992;44(2):99-101. 45. Pitsavos C, Kavouras SA, Panagiotakos DB, Arapi S, Anastasiou CA, Zombolos S, et al; GREECS Study Investigators. Physical activity status and acute coronary syndromes survival The GREECS (Greek Study of Acute Coronary Syndromes) study. J Am Coll Cardiol 2008; 27;51(21):2034-9. 46. Rastogi T, Vaz M, Spiegelman D, Reddy KS, Bharathi AV, Stampfer MJ, et al. Physical activity and risk of coronary heart disease in India. Int J Epidemiol 2004;33(4):759‑67.

47. Secrest AM, Costacou T, Gutelius B, Miller RG, Songer TJ, Orchard TJ. Associations between socioeconomic status and major complications in type 1 diabetes: the Pittsburgh epidemiology of diabetes complication (EDC) Study. Ann Epidemiol 2011;21(5):374-81. 48. Sharma M, Ganguly NK. Premature coronary artery disease in Indians and its associated risk factors. Vasc Health Risk Manag 2005;1(3):217-25. 49. Singh RB, Rastogi SS, Rao PV, Das S, Madhu SV, Das AK, et al. Diet and lifestyle guidelines and desirable levels of risk factors for the prevention of diabetes and its vascular complications in Indians: a scientific statement of The International College of Nutrition. Indian Consensus Group for the Prevention of Diabetes. J Cardiovasc Risk 1997;4(3):201-8. 50. Singh S, Aulakh R, Bhalla AK, Suri D, Manojkumar R, Narula N, et al. Is Kawasaki disease incidence rising in Chandigarh, North India? Arch Dis Child 2011;96(2): 137-40. 51. Springhouse (2005). Professional Guide to Diseases 8th edition, Lippincott Williams and Wilkins; 2005. 52. Stansby G, Mister R, Fowkes G, Roughton M, Nugara F, Brittenden J, et al; Prospective Registry and Evaluation of Peripheral Arterial Risks, Events and Distribution Investigators. High risk of peripheral arterial disease in the United Kingdom: 2-year results of a prospective registry. Angiology 2011;62(2):111-8. 53. Stein CE, Fall CH, Kumaran K, Osmond C, Cox V, Barker DJ. Fetal growth and coronary heart disease in South India. Lancet 1996;348:1269-73. 54. Thom TJ, Kannel WB, Silbershatz H, D’Agostino RB. Cardiovascular disease in the United States and preventive approaches. In: Hurst’s The Heart, Arteries and Veins. 10th edition, Fuster V, Alexander RW, O’Rourke RA (Eds.), McGraw-Hill: New York, NY 2001:3-7. 55. Vaidya A, Pokharel PK, Nagesh S, Karki P, Kumar S, Majhi S. Prevalence of coronary heart disease in the urban adult males of eastern Nepal: a population-based analytical cross-sectional study. Indian Heart J 2009;61(4):341-7. 56. WHO. Cardiovascular Disease: Prevention and Control. 2006.‑http://www.who.int/mediacentre/factsheets/fs317/ en/index.html. 57. World Health Organisation. Disease and injury regional estimates for 2004. Geneva, Switzerland. Available at: http://www.who.int/healthinfo/global_burden_disease/ estimates_regional/en/index.html. Accessed 5 September 2009. 58. Yusuf S, Hawken S, Ôunpuu S, Dans T, Avezum A, Lanas F, et al; INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937-52.

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Dermatology

A Study of Beetle Dermatitis Asit Mittal*, Sharad Mehta**, Anubhav Garg**, Lalit Gupta*, CM Kuldeep†, Ashok Kumar Khare‡, Sarin Nistha¶

Abstract Background: Beetle dermatitis is a common condition seen in regions with warm and tropical climate. The condition causes significant morbidity and can be misdiagnosed. Aim: The study was conducted to know the clinical profile of beetle dermatitis and to increase awareness among nondermatologist physicians about this condition. Methods: All clinically diagnosed cases of beetle dermatitis were included in the study. Detailed history was taken and a thorough clinical examination was conducted in all the cases. Clinical photographs were taken in all the cases. Results: A total of 70 cases comprising of 46 males and 24 females were studied. The age of the patients ranged from 5 to 60 years. Majority of the cases presented during the post monsoon months (September-November), indicating a distinct seasonal trend. Morphology of lesions was mainly linear, but kissing and bizarre lesions were also observed. Head, neck and upper extremities were the most commonly involved sites. Fever and malaise was observed in a few cases. Conclusion: Beetle dermatitis should be included in differential diagnosis while examining erythematous vesicular lesions of sudden onset, especially on exposed parts during rainy and post rainy season. Awareness of this condition and its clinical features among the physicians will prevent misdiagnosis. Preventive measures can be undertaken based on the behavioral pattern of this beetle.

Keywords: Beetle dermatitis, kissing lesion

B

eetle dermatitis is a specific form of acute irritant contact dermatitis caused by a vesicant chemical present in the body fluid of the beetle belonging to the order coleopteron.1 The beetle does not bite or sting but accidental brushing against or crushing over the skin provokes the release of its coelomic fluid, which is a potent vesicant.1 The disease is characterized by sudden onset of erythematous, vesiculobullous lesions on the exposed body parts and associated with burning, stinging and itching.2 The dermatitis is most commonly seen in regions with warm tropical climate3 and is common in various parts of India, but may not be easily diagnosed by nondermatologists due to lack of awareness and familiarity about this condition. There have been reports of outbreak of beetle dermatitis from various

*Associate Professor **Assistant Professor †Professor ‡Professor and Head ¶Dept. of Dermatology, Venereology and Leprosy RNT Medical College, Udaipur, Rajasthan Address for correspondence Dr Asit Mittal Associate Professor, Dept. of Dermatology, Venereology and Leprosy, RNT Medical College, Udaipur, Rajasthan - 313 001 E-mail: asitmittal62@gmail.com

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Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

regions of India.3,4 We undertook this study to know the various clinical patterns of beetle dermatitis and to raise the awareness about this entity among medical professionals. Material and Methods This study was carried out at the Dept. of Skin and VD, RNT Medical College and Associated Group of Hospitals, Udaipur, Rajasthan. A total of 70 cases of beetle dermatitis were seen over a period of three months from September to November. A detailed history was taken regarding age, sex, occupation, locality (rural or urban), duration, symptoms like itching, burning, pain, fever, malaise, living conditions, sleeping habits, history of exposure to insects, etc. A thorough clinical examination was done to record the sites, distribution, morphology of lesions, residual post inflammatory pigmentary changes and systemic features, if any. Clinical photographs of all cases were taken. Patients were treated according to severity of lesions. Mild cases were treated with topical corticosteroidantibiotic combination and oral antihistamines. For severe cases, oral corticosteroids were prescribed. Where secondary infection was seen, systemic antibiotics were also added.


Dermatology Results A total of 70 cases of beetle dermatitis were included in this study. Age of the patients ranged from 5 to 60 years. Out of 70 cases, 46 (65.71%) were males and rest 24 (34.29%) were females. Duration of lesions was less than one week in 60 (85.71%) patients. Maximum number of patients 55 (78.57%) had burning and itching at the site of lesion, while 15 (21.43%) cases were asymptomatic. Systemic features such as fever and malaise were observed in 10 (14.29%) cases. Face was the commonest site in 32 (45.71%) patients. Other sites of involvement were trunk, upper extremities and lower extremities (Table 1). Maximum number of patients 40 (57.14%) showed linear pattern (Table 2).

Figure 1. Kissing lesion over cubital fossa.

All cases responded well to therapy; however, residual hyperpigmentation and persistent exfoliation (Fig. 3), which were very distressing to the patient, were seen in a few cases. Discussion Beetle dermatitis is a distinctive seasonal vesicobullous skin disorder caused by three major families of blister beetles of the order coleoptera: Meloidae, edemeridae and staphylinidae. The vesicant chemical Table 1. Sites of Involvement of Beetle Dermatitis Sites of involvement

No. of cases

% (n = 70)

Face

32

45.71

Upper extremities

18

25.71

Trunk

10

14.29

Lower extremities

10

14.29

Total

70

100

Figure 2. Beetle dermatitis mimicking herpes zoster.

Table 2. Pattern of Lesions of Beetle Dermatitis Morphology of lesions

No. of cases

% (n = 70)

Linear

40

57.14

Kissing (Fig.1)

12

17.14

Bizarre

10

14.29

Herpetiform (Fig. 2)

8

11.43

Total

70

100

Figure 3. Persistent exfoliation.

in both meloidae and edemeridae is cantharidin, while it is pederin in the third family staphylinidae, which includes the genus Paederus.1 The genus paederus consists of more than 622 species, which are widely

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23


Dermatology distributed.2 Cantharidin dermatitis is characterized by noninflammatory vesicle and bullae whereas, Paederus dermatitis is characterized by vesicle and pustules arising from intensely inflamed skin.2 Blister beetle can fly but they prefer to run and live in moist habitats, and may appear in large numbers following heavy rains and hot weather.1 They are attracted to white light at night, a feature that commonly brings them into contact with humans. In our study, exposed body parts such as head, neck and upper extremities were most commonly affected. A similar observation was made in a study on 77 cases of beetle dermatitis in Punjab by Handa et al3 and in a study on 54 cases at Jodhpur by Kalla et al.4 Most common pattern of lesions seen in our study was linear. Similar pattern has been reported in other studies also.2-5 The lesions are commonly linear due to crushing and whipping an insect off the skin. Mirror image or ‘kissing lesions’ are seen in skin flexures where an insect has been inadvertently crushed with transfer of chemical to the opposing surface.5-7 Ocular involvement was seen in a few of our patients. It is usually secondary to transfer of toxic chemicals by fingers from elsewhere on skin. Ocular involvement as a relatively common finding was also reported by Zargari et al.2 We observed diffuse and persistent exfoliation (desquamative lesions) as an uncommon finding in a few of our patients. Such atypical variants of beetle dermatitis have been reported in other studies also.2,8 Clinically beetle dermatitis mimics many common skin conditions like herpes simplex, herpes zoster, thermal burns, bullous impetigo, phyto-photodermatitis and acute allergic or irritant contact dermatitis.2,6-9 Herpes zoster is particularly a condition often confused with beetle dermatitis on account of symptom of burning, pain and vesico-bullous lesions. Grouped vesicles and bullae strictly in a dermatomal pattern is characteristic of herpes zoster. The diagnosis of beetle dermatitis should be suspected by the sudden onset of linear and mirror image lesions, predominant involvement of exposed sites and seasonal incidence.

Conclusion Awareness about this condition amongst the medical practitioner will aid in early diagnosis and prompt treatment and prevent the sequelae of persistent hyperpigmentation, which can be particularly distressing in some patients. Therefore, an early diagnosis and treatment would prevent this complication. In addition awareness among the public at large may also help decrease the incidence of beetle dermatitis. The patients should also be counseled about the benign and self-limiting nature of the disease. Various preventive measures like changing the light source, using kerosene or petrol to kill the larva in stagnant water and spraying pesticides and insecticides particularly in breeding areas are often helpful.8 References 1. Nicholls DS, Christmas TI, Greig DE. Oedemerid blister beetle dermatosis: a review. J Am Acad Dermatol 1990;22 (5 Pt 1):815-9. 2. Zargari O, Kimyai-Asadi A, Fathalikhani F, Panahi M. Paederus dermatitis in northern Iran: a report of 156 cases. Int J Dermatol 2003;42(8):608-12. 3. Handa F, Sharma P, Gupta S. Beetle dermatitis in Punjab (a study of 77 cases). Indian J Dermatol Venereol Leprol 1985;51(4):208-12. 4. Kalla G, Batra A. Blister beetle dermatitis. Indian J Dermatol Venereol Leprol 1996;62(4):267-8. 5. Vegas FK, Yahr MG, Venezuela C. Paederus dermatitis. Arch Dermatol 1996;94:175-83. 6. Banney LA, Wood DJ, Francis GD. Whiplash rove beetle dermatitis in central Queensland. Australas J Dermatol 2000;41(3):162-7. 7. Kamaladasa SD, Perera WD, Weeratunge L. An outbreak of paederus dermatitis in a suburban hospital in Sri Lanka. Int J Dermatol 1997;36(1):34-6. 8. Singh G, Yousuf Ali S. Paederus dermatitis. Indian J Dermatol Venereol Leprol 2007;73(1):13-5. 9. Gnanaraj P, Venugopal V, Mozhi MK, Pandurangan CN. An outbreak of Paederus dermatitis in a suburban hospital in South India: a report of 123 cases and review of literature. J Am Acad Dermatol 2007;57(2):297-300.

■■■■

Umbrellas may Shield you from more than Rain: Study If it’s streaming sunshine outdoors and the sunscreen isn’t handy, an umbrella could help shield skin from ultraviolet (UV) rays, according to a new study by dermatologists at Emory University in Atlanta. They found that any fully-functioning handheld umbrella can block more than three-quarters of UV light on a sunny day. Black ones seem to do the job especially well, blocking at least 90% of rays. (Source: Medscape)

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Diabetology

Assessment of Hypogonadism with Reference to Clinical Features and Serum Testosterone Levels in Asian-Indian Male Type 2 Diabetics Ibraheem Khan*, Chandra Kant**, Anil Samaria†

Abstract Objective: To assess the prevalence of hypogonadism in Asian-Indian males with type 2 diabetes (T2DM) with reference to clinical feature and total serum testosterone levels. Material and methods: In the cross-sectional study of 50 diabetics of 30-76 years age group preferably without chronic illness, total testosterone, body mass index (BMI) and waist circumference (WC) were measured. Overt hypogonadism was defined as the presence of clinical symptoms of hypogonadism and low testosterone level (total testosterone <8 nmol/l). Borderline hypogonadism was defined as the presence of symptoms and total testosterone of 8-12 nmol/l. Results: A low serum testosterone level was common in diabetic men and a significant proportion of these men had symptoms of hypogonadism. Overt hypogonadism was seen in 30% of men with total testosterone levels <8 nmol/l and borderline hypogonadism was found in 28% of men with total testosterone levels 8-12 nmol/l. Total serum testosterone levels significantly and negatively correlated with both BMI (r = –0.334, p < 0.05) and WC (r = –0.443, p < 0.001), with the association being stronger for WC. HbA1C also significantly and negatively correlated with serum testosterone levels (r = –0.503, p < 0.001). Conclusions: Testosterone levels are frequently low in men with T2DM and the majority of these men have symptoms of hypogonadism, even in the younger age group (early-onset hypogonadism). Obesity and BMI are also associated with low testosterone levels in Asian-Indian diabetic men.

Keywords: Type 2 diabetes, serum testosterone, overt hypogonadism, obesity

D

iabetes mellitus (DM) comprises a group of common metabolic disorders that share the phenotype of hyperglycemia, factors may include reduced insulin secretion, decreased glucose utilization and increase glucose production depending upon the etiology of DM. Metabolic dysregulation associated with DM causes secondary pathophysiologic changes in multiple organ systems. DM, with its attendant acute and long-term complications and the myriad of disorders associated with it, is a major health hazard.1 India has an estimated population of 44 million diabetic subjects, which is chiefly contributed by the urban population.2 Type 2 diabetes (T2DM) in Indians differs from that in Europeans in several aspects: The onset is

*Postgraduate **Professor †Associate Professor Dept. of Medicine, Jawaharlal Nehru Medical College, Ajmer Address for correspondence Dr Ibraheem Khan Samraya, Weir, Bharatpur, Rajasthan - 321 408 E-mail: imedicine2008@gmail.com

at a younger age,3 obesity is less common4 and genetic factors appear to be stronger.5 Insulin resistance (IR) is an common feature of T2DM.6 It is now increasingly being recognized that low testosterone level in men is associated with reduced insulin sensitivity and T2DM.7 An inverse relationship has been seen between testosterone levels and insulin concentrations in healthy men.8 Testosterone was inversely related to the degree of hyperglycemia.9 IR and risk of diabetes development was more in patient with low testosterone levels.10 Low testosterone was also associated with diabetic dyslipidemia.9 A recent study has demonstrated that free testosterone levels, which are independent of sex hormone-binding globulin (SHBG), are low in onethird of diabetics.11 Hypogonadism is defined as the presence of clinical symptoms and low testosterone levels (total testosterone <8 nmol/l). Although there is no uniform definition of classical hypogonadism, various guidelines for the diagnosis of hypogonadism are available, for example from Bhasin and colleagues.12 Recently published recommendations that patients with total testosterone <8 nmol/l should be treated with testosterone therapy, those with testosterone 8-12 nmol/l and hypogonadal

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Diabetology symptoms should be given a trial of testosterone therapy, and those with total testosterone >12 nmol/ l are not hypogonadal and should not be treated.13 Overt hypogonadism is the presence of clinical symptoms of hypogonadism and low testosterone levels (total testosterone <8 nmol/l). Borderline hypogonadism is the presence of symptoms along with total testosterone 8-12 nmol/l. The major symptoms of hypogonadism are reduced libido, reduced duration of erection, fatigue, reduced physical strength and mood changes. Questionnaires have been developed to assess hypogonadism. Androgen deficiency in the aging male (ADAM) questionnaire is one of them. It lacks specificity (66%) but it has reasonable sensitivity (88%) in the presence of low testosterone levels. This is a 10-item screening questionnaire used to evaluate ADAM.14 Normal testosterone production rates by the Leydig cells vary considerably between healthy young individuals and range from 3 to 10 mg/day.15 It is thought that most testosterone in the blood, about 65%, is strongly bound to SHBG; about 35% is relatively loosely to albumin and only 1-2% is free. Free and albumin-bound testosterone is called bioavailable testosterone because both fractions comprise the biologically active component that is readily available to the tissues, whereas SHBG-bound testosterone is tightly bound and thus considered inactive. Testosterone concentrations vary considerably between individuals. The normal range of total testosterone in young adult men being 12-35 nmol/l and bioavailable Testosterone testosterone is 2.5-4.2 nmol/l.16 concentrations also follow a diurnal rhythm with highest levels in morning and falling by as much as 35% in the afternoon and evening.17 A confounding factor is that SHBG rises with age, and thus free testosterone decreases more rapidly than total testosterone in older men. Thus, it is important to measure bioavailable or free testosterone in men with diabetes. Erectile dysfunction (ED) is best defined as persistent failure to generate sufficient penile body pressure to achieve vaginal penetration and/or the inability to maintain this degree of penile rigidity until ejaculation.18 Symptomatically, ED is common in diabetic men,19 although the etiology may be vascular disease, autonomic neuropathy, hypogonadism or a combination of these.20

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Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

Erection is a complex process mediated by combination of neurotransmission and vascular smooth muscle responses due to increase arterial inflow and signaling by endothelial cavernosal sinusoids and underlying smooth muscle cells. Cholinergic parasympathetic pathways, nonadrenergic, noncholinergic pathways and endothelial cells, all release nitric oxide (NO) that triggers a molecular cascade result in the relaxation of smooth muscle cell and occluding venous return through venous compression of the subtunical venules resulting in an erection. Parasympathetic outflow is impaired in diabetics and causes reduction in NO resulting in smooth cell apoptosis and decrease in sinusoidal compliance leading to ED.21 Loss of Libido Libido is defined as the biological need for sexual activity (the sex drive) and frequently is expressed as sex-seeking behavior. Evidence for a role of androgens in regulation of sexual behavior in the human male has been reviewed by Mooradian and colleagues.22 In a study, withdrawal of androgen therapy in hypogonadal males led to a decline of libido in 3-4 weeks, and untreated hypogonadal men have impairment in spontaneity of erection.23 According to Kapoor et al 63% diabetic men had loss of libido. Testosterone levels inversely correlate with waist circumference (WC) and body mass index (BMI). A plausible explanation for this is the hypogonadal - obesity cycle, which was first described by Cohen.24 Essentially, visceral adipocytes have a high activity of the enzyme aromatase, which converts testosterone to estrogen. Testosterone inhibits the enzyme lipoprotein lipase, which takes up free fatty acids into adipocytes.25 Lower testosterone levels result in increased triglyceride levels in adipocytes, which promote further adipocyte proliferation and hence higher aromatase activity. Testosterone levels are further lowered as a result of leptin resistance at the hypothalamic-pituitary and testicular levels, causing reduced luteinizing hormone (LH) release and testosterone secretion.26 It is known that a reduction in the degree of obesity results in an elevation of testosterone levels. Dhindsa and colleagues conducted some tests with gonadotropin-releasing hormone (GnRH) in T2DM patients with ED and demonstrated a normal LH, and follicle-stimulating hormone (FSH) rise, suggesting a hypothalamic rather than a pituitary defect.11 The existence of a hypothalamic defect resulting in hypogonadotropic hypogonadism in T2DM is of


Diabetology interest in view of its association with insulin resistance. Neuron-specific insulin receptor knockout (NIRKO) mice with a specific knockout of the insulin receptor in neurons exhibit hypogonadotropic hypogonadism.27 Plasma LH levels were decreased by 60-90% in NIRKO mice compared with controls. When these mice were injected with lupron, a GnRH receptor agonist, they displayed a normal to 2-fold increase in LH levels compared with control mice. These mice also had increased adipose tissue and IR. Metabolic syndrome, IR and visceral obesity have all been associated with low total testosterone levels in men.28 Data from literature in humans and NIRKO mice and from the study by Dhindsa and colleagues, seem to suggest that obesity/IR is associated with hypogonadism and that the hypogonadism appears to be hypogonadotropic in nature. Obesity is associated with increased plasma levels of proinflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin (IL)-6, C-reactive protein and adhesion molecules.29,30 In this regard, it is interesting to note that TNF-a and IL-1b have been shown to reduce hypothalamic GnRH and LH secretion in animals and in vitro.31 So, it may be worthwhile to know the status of testosterone level in diabetic patients. Testosterone level is affected by factors like obesity, BMI and age of patient.19 Bioavailable testosterone appears to represent reliable index of biologically readily available testosterone, but is not well-suited for clinical routine, being too time-consuming and expensive. Hypogonadism was defined in many studies13,19 by total testosterone levels, so total testosterone levels can be used for the study. Very few studies have been done so far on this topic so an assessment of clinical hypogonadism in 50 patients of T2DM was done. AIM AND OBJECTIVES ÂÂ

To estimate serum testosterone levels in T2DM.

ÂÂ

To correlate the serum testosterone levels with clinical hypogonadism in T2DM.

MATERIAL AND METHODS The study was conducted at Jawaharlal Nehru Medical College and Associated Group of Hospitals, Ajmer, Rajasthan to evaluate clinical and biochemical hypogonadism in men with T2DM (≥5 years duration) attending medical OPD and various medical wards.

Inclusion Criteria ÂÂ

Male patients with T2DM in 30-76 years age group.

ÂÂ

Patients with T2DM ≥5 years.

Normal value was taken as control for that age group.

Exclusion Criteria ÂÂ

Patients taking drugs which are known to interfere e.g., glucocorticoids, hormone replacement therapy, ketoconazole, opiods, alcohol, methadone, heroin and marijuana.

ÂÂ

Patients with features associated with congenital GnRH deficiency (midline facial defects, synkinesis or a family history of GnRH deficiency or anosmia).

ÂÂ

History of tumor, exposure to radiation, history of head trauma, spinal cord injuries, history of pelvic trauma and surgery.

ÂÂ

Any disease other than diabetes known to cause autonomic dysfunction.

ÂÂ

Any other chronic disease such as human immunodeficiency virus (HIV), end-stage renal disease, cirrhosis of liver and psychiatric disease.

Special Investigations ÂÂ

Total testosterone was measured by electrochemilumiscence immunoassay by ECLIA kit.

ÂÂ

In patient with diabetes, blood sample was collected always between 8 a.m. and 10 a.m.

ÂÂ

Serum sample was obtained by centrifugation. Sample remained stable for one week at 2-8°C, for six month at –20°C, though it was not needed to freeze the serum sample for storage.

Examination of the Patients’ History Total 50 patients were taken. A detailed history of present illness was recorded including duration of the onset of symptoms (Table 1). Complete ADAM questionnaire, past history and family history for hypertension, and DM and history of medications was asked. Personal history like early morning erection, smoking, alcohol consumption, decrease in libido, lack of energy, decrease in strength and/or endurance, loss of height, decreased enjoyment of life, feeling of sadness and/or grumpy, decrease strength of erection, recent deterioration in ability to play sports and a recent deterioration in work performance were noted. Positive response was based on decreases in loss of libido, strength of erections or any three nonspecific

Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

27


Diabetology questions that include fatigability, mood changes and loss of height.

Clinical Examination A detailed clinical examination was done. General examination including height, weight, WC (defined as the point midway between the iliac crest and the costal margin) and blood pressure (BP). Systemic examination included cardiovascular, respiratory, gastrointestinal and neurological examination (Table 1). Clinically ED (organic or psychogenic) was assessed by ÂÂ

Stamp test

ÂÂ

Testicular sensation test

ÂÂ

Interruption of urination.

OBSERVATION and RESULTS

Statistical Analysis Values were expressed as a percentage of each group or as mean ± SE (standard error) unless otherwise stated. The impact of clinical variables on testosterone levels was determined by correlation. Comparisons between groups were made using X2 test. The unpaired ‘t’ test was used to compare testosterone levels in men with ED and without ED (Table 2). Student test was also used to compare testosterone in others variables like glycosylated hemoglobin (HbA1C), BMI, WC, smokers and nonsmokers, hypertension. Results were considered statistically significant at p < 0.05. Prevalence of low testosterone levels: Thirty percent (15 men) had testosterone level <8 nmol/l and 28% (14 men) had testosterone between 8 and 12 nmol/l. Prevalence of low testosterone levels was not uncommon in all age groups but it was maximum (80%) in old age >69 years and 43% in young adults (<40 years). Percentage of diabetic men with low testosterone per decade is shown in Figure 1. Prevalence of symptoms and low testosterone levels (hypogonadism): Prevalence of overt hypogonadism in diabetic patients with positive ADAM score was 30% (15 men) and borderline hypogonadism was 28% (14 men) based on symptoms as suggested by ADAM questionnaire and low serum testosterone levels. Incidence of positive symptoms in men with low testosterone by decade of age is shown in Figure 2. ED and loss of libido were the common symptoms, 46% and 52%, respectively, in these patients with low testosterone levels (<12 nmol/l), while the incidence of these symptoms were 60% and 64%, respectively in the diabetic study group. Only 16% patient had other symptoms.

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Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

Association of body composition and testosterone levels in diabetic Asian-Indian adults: Total serum testosterone levels significantly and negatively correlated with both BMI (r = –0.334, p < 0.05) and WC (r = –0.443, p < 0.001). Patients having BMI >23 kg/m2, 37% diabetic men had low testosterone <8 nmol/l and adding the value 8-12 nmol/l, it was increased to 78% (p < 0.01). In patients with WC, Table 1. The Baseline Characteristics of Subjects Parameter

Sample range

Age (years) Serum testosterone (nmol/l)

SD

35-76

54.3

±12.9

3.51-27.10

12.14

±6.04

5.6-12.4

8.27

±1.52

HbA1C (%) (kg/m2)

Average

18.75-33.89

23.54

±3.71

Waist circumference (cm)

75-105

87.2

±6.88

Systolic blood pressure (mmHg)

110-160

136.32

±14.51

Diastolic blood pressure (mmHg)

70-100

83.88

±6.70

5-17

7.48

±3.52

Body mass index

Duration (years) Smoking Others (occupation and residence) SD = Standard deviation

Table 2. Comparisons of Testosterone Levels in Men with and without Variables by Unpaired ‘t’ Test Variable

Mean

SD`

t

P

4.13

<0.001

4.42

<0.001

3.80

<0.001

2.38

<0.05

1.07

>0.05

0.122

>0.05

Serum testosterone levels With ED

9.48

4.24

Without ED

16.10

6.26

With HbA1C ≤9

13.75

6.24

With HbA1C >9

8.75

3.97

With WC <85 cm

15.02

6.47

With WC >85 cm

9.26

3.91

kg/m2

14.30

5.99

With BMI >23 kg/m2

10.30

5.54

In hypertensive

13.49

6.16

In nonhypertensive

11.51

5.97

In smokers

12.01

6.42

In nonsmokers

12.23

5.89

With BMI <23

ED = Erectile dysfunction; WC = Waist circumference; BMI = Body mass index.


Percentage of men with low testosterone

Diabetology Table 3. Association of Low Testosterone Level with Clinical Variable

90 80

Parameter (n)

70 60 50 Testosterone <8 nmol/l

40 30

Testosterone <12 nmol/l

20 10 0

<40 40-49 50-59 60-69 >69 Age in years

Percentage of men with low testosterone

Figure 1. Percentage of diabetic men with low testosterone and borderline testosterone levels as per decade.

90 80

<8 nmol/l 8-12 nmol/l >12 nmol/l (15) (14) (21)

P

BMI >23 kg/m2 (27)

10

11

6

<0.01

WC >85 cm (25)

9

11

5

<0.001

HbA1C >9% (16)

8

6

2

<0.01

Hypertension (16)

3

4

9

>0.05

Smoking (20)

7

4

9

>0.05

Erectile dysfunction (23)

11

12

<0.001

Loss of libido (26)

12

14

<0.001

Other symptoms (8)

5

3

<40 (7)

2

1

4

40-49 (10)

4

2

4

50-59 (14)

3

5

6

60-69 (14)

3

5

6

>69 (5)

3

1

1

Age

70 60

duration, smoking and history of hypertension could not be established (p > 0.05).

50 40

DISCUSSION

30

Hypogonadism, a clinical condition comprising both symptoms and biochemical evidence of testosterone deficiency is associated with T2DM.

20 10 0

<40 40-49 50-59 60-69 >69 Age in years

Figure 2. Incidence of positive symptoms in men with low testosterone by decade of age.

>85 the serum testosterone levels were â&#x2030;¤12 nmol/l in 80% cases (p < 0.001) (Table 3). Correlation between HbA1C and low testosterone: HbA1C significantly and negatively correlated with serum testosterone levels (r = â&#x20AC;&#x201C;0.503, p < 0.001). Eighty-six percent patients with HbA1C >9% had low testosterone levels, while 44% diabetics with HbA1C <9% had serum testosterone <12 nmol/l showing statistical significance (p < 0.001). Hypertension, smoking duration, socioeconomic factor and serum testosterone: Statistical correlation and significance between hypogonadism and diabetes

The purpose of this study was to determine the prevalence of clinical hypogonadism based on both symptoms and biochemical available measure of testosterone deficiency in men of T2DM in Indian perspectives. In present study, we observed that there is a high prevalence of symptomatic hypogonadism in men with T2DM. Previous studies11 have shown that about one-third of men with T2DM have low serum testosterone levels. In our study, we found that a high proportion of diabetic men had low levels of serum testosterone. There is no widely accepted consensus as to what constitutes the levels of testosterone below which treatment is to be considered. But on the basis of normal ranges and international recommendations overt hypogonadism <8 nmol/l and borderline hypogonadism 8-12 nmol/l serum testosterone level was considered. In the present study, 30% subjects with T2DM had symptoms and

Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

29


Diabetology associated serum testosterone level <8 nmol/l, which was called as overt hypogonadism. Further 28% of diabetic men had symptoms of hypogonadism with testosterone level in the range of borderline hypogonadism i.e. 8-12 nmol/l. These findings support the study done by Kapoor and colleagues.19 Aging is associated with decline in testosterone levels even in healthy men according to Nieschlag, Behre and colleagues.32 In the Baltimore Longitudinal Study on aging, 8, 12, 19 and 28% of men aged >40, 50, 60 and 70 years, respectively had serum total testosterone levels below the normal range of <11.3 nmol/l in that study.33 Using the criteria in that study, we found a higher prevalence of hypogonadism across all age group 43% in <40, 60% in 40-49, 57% in 50-59, 57% in 60-69 and 80% in >69 years. Kapoor et al19 also found similar results in all diabetic age groups (42, 44, 39 and 56% in the age-groups 40-49, 50-59, 60-69 and 70-79 years, respectively). Although hypogonadism increases with age, it is also common in younger diabetic age groups. Dhindra and colleagues11 have shown low testosterone level in T2DM. Frequency of symptoms in all defined groups of their study was studied. It is important to note that the ADAM questionnaire lacks specificity and this questionnaire is useful only in the presence of a biochemical evidence of low level of serum testosterone. Asian-Indians are known to have a lower BMI than Europeans. For any given BMI, Asian-Indians have a greater waist-to-hip ratio than Europeans. To clarify the issue, Ramachandran and colleagues performed a case-control study in 82 subjects with T2DM and 82 sex- and age-matched nondiabetic controls from the Chennai Urban Rural Epidemiology Study.34 Visceral, subcutaneous and total abdominal fat were measured by computed tomography (CT), while dual-energy X-ray absorptiometry (DEXA) was used to measure central abdominal and total body fat. Diabetic subjects had significantly higher visceral and central abdominal fat compared to controls. Both measurements correlated well with each other as well as with the WC. Therefore, WC is a valid measure of visceral adiposity in this population. To clarify the anthropometric variables in Asian-Indian adults, 19,025 adults over 20 years of age were given an oral glucose tolerance test using World Health Organization (WHO) criteria.35 The calculations were done to stratify subjects with diabetes against subjects without diabetes using multiple logistic analyses. The upper limit of the stratum in which the risk became

30

Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

clinically significant was considered the cut-off for normal values. The normal cut-off for BMI was 23 kg/m2 in both sexes. The cut-off for WC was 85 cm for men and 80 cm for women. The present study showed that there is strong negative correlation between WC and hypogonadism in cases of diabetes (r = â&#x20AC;&#x201C;0.443, p < 0.001) and between BMI and hypogonadism in these cases (r = â&#x20AC;&#x201C;0.334, p < 0.05). The study supports the results of previous study done by Kapoor and colleagues according to which there was strong correlation between body composition and total testosterone levels. We observed that serum testosterone decreased more in uncontrolled diabetic men showing correlation and statistical significance (r = â&#x20AC;&#x201C;0.503, p < 0.001). In this study, we did not find any association between the duration of diabetes, socioeconomic status and history of smoking with hypogonadism. The previous study did not show any clear cut relation with these findings. Further studies with a large number of subjects may determine the clear cut association. Testosterone therapy has important role in treatment of ED and also in management of IR. Men with ED who fail to respond to phosphodiesterase inhibitors have been shown to have low testosterone levels.36 Testosterone replacement therapy in two studies was found to convert sildenafil nonresponders to responders.37 Interventional studies have shown a beneficial effect of testosterone replacement therapy on IR. A study in healthy men with low total testosterone reported an improvement in insulin sensitivity with testosterone or dihydrotestosterone treatment.38 Testosterone treatment has also been shown to reduce IR in obese men, men with heart failure and T2DM subjects. Studies on T2DM men have shown an improvement in glycemic control with testosterone replacement therapy.39 Conclusion Testosterone levels are frequently low in men with T2DM and the majority of these men have symptoms of hypogonadism, even in the younger age group (early-onset hypogonadism). Obesity and BMI are also associated with low testosterone levels in Asian-Indian diabetic men. Control of diabetes and associated risk factor should be the goal of therapy. More studies are required to establish the benefit of testosterone replacement therapy on quality-of-life and the diabetic state in Indian men.


Diabetology References 1. Powers AC. Diabetes mellitus. Harrison’s Principles of Internal Medicine. 17th edition, Fauci AS, et al. (Eds.), McGraw Hill: New York 2008:2275-304. 2. Ramachandran A, Snehalatha C, Kapur A, Vijay V, Mohan V, Das AK, et al; Diabetes Epidemiology Study Group in India (DESI). High prevalence of diabetes and impaired glucose tolerance in India: National Urban Diabetes Survey. Diabetologia 2001;44(9):1094-101. 3. Mohan V, Ramachandran A, Snehalatha C, Mohan R, Bharani G, Viswanathan M. High prevalence of maturityonset diabetes of the young (MODY) among Indians. Diabetes Care 1985;8(4):371-4. 4. Joshi SR. Metabolic syndrome - emerging clusters of the Indian phenotype. J Assoc Physicians India 2003;51: 445-6. 5. Viswanathan M, Mohan V, Snehalatha C, Ramachandran A. High prevalence of type 2 (non-insulin-dependent) diabetes among the offspring of conjugal type 2 diabetic parents in India. Diabetologia 1985;28(12):907-10. 6. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37(12): 1595-607. 7. Kapoor D, Malkin CJ, Channer KS, Jones TH. Androgens, insulin resistance and vascular disease in men. Clin Endocrinol (Oxf) 2005;63(3):239-50. 8. Simon D, Preziosi P, Barrett-Connor E, Roger M, SaintPaul M, Nahoul K, et al. Interrelation between plasma testosterone and plasma insulin in healthy adult men: the Telecom Study. Diabetologia 1992;35(2):173-7. 9. Barrett-Connor E. Lower endogenous androgen levels and dyslipidemia in men with non-insulin-dependent diabetes mellitus. Ann Intern Med 1992;117(10):807-11. 10. Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care 2000;23(4):490-4. 11. Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab 2004;89(11):5462-8. 12. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2006;91(6):1995-2010.

for androgen deficiency in aging males. Metabolism 2000;49(9):1239-42. 15. Wu FCW. Disorder of male reproduction. In: Oxford Textbook of Medicine. Volume 11, Weatherall DJ, Ledingham JGG, Warrell DA (Eds.), Oxford University Press: Oxford 1996:p1679-87. 16. Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 1992;75(4): 1092-8. 17. Sternbach H. Age-associated testosterone decline in men: clinical issues for psychiatry. Am J Psychiatry 1998;155(10):1310-8. 18. Wagner G. Erection: physiology and endocrinology. In: Impotence: Physiological, Psychological Surgical Diagnosis and Treatment. Wagner G, Green R (Ed.), Plenum Press, New York: NY 1981:p25-36. 19. Kapoor D, Aldred H, Clark S, Channer KS, Jones TH. Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes: correlations with bioavailable testosterone and visceral adiposity. Diabetes Care 2007;30(4):911-7. 20. McCulloch DK, Campbell IW, Wu FC, Prescott RJ, Clarke BF. The prevalence of diabetic impotence. Diabetologia 1980;18(4):279-83. 21. McVary KT. Clinical practice. Erectile dysfunction. N Engl J Med 2007;357(24):2472-81. 22. Mooradian AD, Morley JE, Korenman SG. Biological actions of androgens. Endocr Rev 1987;8(1):1-28. 23. Skakkebaek NE, Bancroft J, Davidson DW, Warner P. Androgen replacement with oral testosterone undecanoate in hypogonadal men: a double blind controlled study. Clin Endocrinol (Oxf) 1981;14(1):49-61. 24. Cohen PG. The hypogonadal-obesity cycle: role of aromatase in modulating the testosterone-estradiol shunt - a major factor in the genesis of morbid obesity. Med Hypotheses 1999;52(1):49-51. 25. Mårin P, Odén B, Björntorp P. Assimilation and mobilization of triglycerides in subcutaneous abdominal and femoral adipose tissue in vivo in men: effects of androgens. J Clin Endocrinol Metab 1995;80(1):239-43. 26. Isidori AM, Caprio M, Strollo F, Moretti C, Frajese G, Isidori A, et al. Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels. J Clin Endocrinol Metab 1999;84(10):3673-80. 27. Brüning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, et al. Role of brain insulin receptor in control of body weight and reproduction. Science 2000;289(5487):2122-5.

13. Nieschlag E, Swerdloff R, Behre HM, Gooren LJ, Kaufman JM, Legros JJ, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU recommendations. Int J Androl 2005;28(3):125-7.

28. Laaksonen DE, Niskanen L, Punnonen K, Nyyssönen K, Tuomainen TP, Salonen R, et al. Sex hormones, inflammation and the metabolic syndrome: a population-based study. Eur J Endocrinol 2003;149(6):601-8.

14. Morley JE, Charlton E, Patrick P, Kaiser FE, Cadeau P, McCready D, et al. Validation of a screening questionnaire

29. Dandona P, Weinstock R, Thusu K, Abdel-Rahman E, Aljada A, Wadden T. Tumor necrosis factor-alpha in sera

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Diabetology of obese patients: fall with weight loss. J Clin Endocrinol Metab 1998;83(8):2907-10. 30. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112(12):1796-808. 31. Watanobe H, Hayakawa Y. Hypothalamic interleukin-1 beta and tumor necrosis factor-alpha, but not interleukin6, mediate the endotoxin-induced suppression of the reproductive axis in rats. Endocrinology 2003;144(11): 4868-75. 32. Nieschlag E, Behre HM, Bouchard P, Corrales JJ, Jones TH, Stalla GK, et al. Testosterone replacement therapy: current trends and future directions. Hum Reprod Update 2004;10(5):409-19. 33. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR; Baltimore Longitudinal Study of Aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001;86(2): 724-31. 34. Ramachandran A, Snehalatha C, Yamuna A, Murugesan N, Narayan KM. Insulin resistance and clustering of cardiometabolic risk factors in urban teenagers in southern India. Diabetes Care 2007;30(7):1828-33.

35. Snehalatha C, Viswanathan V, Ramachandran A. Cutoff values for normal anthropometric variables in Asian Indian adults. Diabetes Care 2003;26(5):1380-4. 36. Kalinchenko SY, Kozlov GI, Gontcharov NP, Katsiya GV. Oral testosterone undecanoate reverses erectile dysfunction associated with diabetes mellitus in patients failing on sildenafil citrate therapy alone. Aging Male 2003;6(2):94-9. 37. Shabsigh R, Kaufman JM, Steidle C, Padma-Nathan H. Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. J Urol 2004;172(2):658-63. 38. Simon D, Charles MA, Lahlou N, Nahoul K, Oppert JM, Gouault-Heilmann M, et al. Androgen therapy improves insulin sensitivity and decreases leptin level in healthy adult men with low plasma total testosterone: a 3-month randomized placebo-controlled trial. Diabetes Care 2001;24(12):2149-51. 39. Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006;154(6): 899-906.

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Umbrellas may Shield you from more than Rain: Study If it’s streaming sunshine outdoors and the sunscreen isn’t handy, an umbrella could help shield skin from ultraviolet (UV) rays, according to a new study by dermatologists at Emory University in Atlanta. They found that any fully-functioning handheld umbrella can block more than three-quarters of UV light on a sunny day. Black ones seem to do the job especially well, blocking at least 90% of rays. (Source: Medscape)

Weight Gain in Smokers who Quit is OK for the Heart Weight gained after someone quits smoking has no effect on the cardiovascular benefits of butting out, at least among people without diabetes, researchers reported. (Source: Medpage Today)

Alogliptin Wins FDA Go-ahead for Type 2 Diabetes After a long delay, the FDA approved the oral drug alogliptin (Nesina) for treatment of adults with type 2 diabetes, as well as two products combining alogliptin with other antidiabetic drugs. Approved simultaneously with Nesina were alogliptin combinations with metformin (Kazano) and with pioglitazone (Oseni). Alogliptin is the fourth dipeptidyl peptidase-4 inhibitor to win FDA approval, joining sitagliptin (Januvia), saxagliptin (Onglyza), and linagliptin (Tradjenta). (Source: Medpage Today)

Ranibizumab Fails to Beat Saline in Avoiding Vitrectomy Patients with vitreous hemorrhage from proliferative diabetic retinopathy (PDR) experienced about the same rates of vitrectomy by 16 weeks whether they received intravitreal injections of ranibizumab (Lucentis, Genentech) or saline. The results of this short-term study, published online January 31 in JAMA Ophthalmology, suggest little likelihood of a clinically meaningful difference on vitrectomy between the 2 interventions. Longer follow-up is planned. (Source: Medscape)

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Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013


ENT

Basaloid Carcinoma: An Unusual Presentation Sanjana V Nemade*, VV Rokade**

Abstract Basaloid squamous cell carcinoma (BSCC), an uncommon tumor, is a distinct variant of squamous cell carcinoma because of its unique histological features and highly aggressive malignant behavior. We report a case of pedunculated, nonaggressive basaloid cell carcinoma of the posterior pharyngeal wall in a middle-aged female treated successfully with wide local excision and postoperative radiotherapy.

Keywords: Pedunculated basaloid carcinoma, nonaggressive, squamous cell carcinoma

B

asaloid squamous cell carcinoma (BSCC) is a high grade, aggressive variant of squamous cell carcinoma (SCC) with predilection for base of tongue, floor of mouth, larynx and tonsils. It appears biologically virulent, with a propensity to aggressive local behavior, early nodal and distant metastasis and subsequent poor survival. To the authorsâ&#x20AC;&#x2122; knowledge, pedunculated, nonaggressive basaloid cell carcinoma of the posterior pharyngeal wall without nodal and distant metastasis in middle-aged women has rarely been reported. Accurate diagnosis and appropriate treatment with surgery followed by radiotherapy gave a very good prognosis in this patient.

Case Report A 56-year-old female presented in the Dept. of ENT OPD with complaints of dysphagia to solid food since six months. There was no history of weight loss, change in voice or dyspnea or any abuse of tobacco or alcohol. No other significant history was noted.

was normal. All routine investigations were within normal limits. Computerized tomography (CT) showed a 1.5 x 1.8 cm moderately enhancing soft tissue lesion in posterior pharyngeal wall at the level of vallecula. There was no evidence of lymphadenopathy (Fig. 1). Patient was posted for excision of the mass under general anesthesia. Boyle Davis mouth gag was applied. Wide elliptical incision was taken around the pedicle of the mass and the mass was excised in toto (Fig. 2). The base was cauterized. The mass was sent for histopathological examination. Postoperative period was uneventful. Histopathological examination revealed a neoplastic infiltrate, predominantly pleomorphic, basaloid appearing cells with hyperchromatic nuclei and a variable amount of eosinophilic to clear-appearing

Routine throat examination was normal. On indirect laryngoscopy, a red, irregular, pedunculated mass 2 x 1 cm, was seen on the posterior pharyngeal wall at the level of vallecula. Rest of the ENT and neck examination

*Assistant Professor **Associate Professor and Head Dept. of ENT, Smt Kashibai Navale Medical College and General Hospital Ambegaon, Narhe, Pune Address for correspondence Dr Sanjana V Nemade C/o: R Manjarekar B-6/97, Shrikrishna Clinic, Vitthal Rakhumai Society Apte Colony, Sinhgad Road, Hingane Khurd, Pune - 411 051 E-mail: drsanjana31@yahoo.in

Figure 1. CT scan showing moderately enhancing posterior pharyngeal wall at the level of vallecula.

Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

33


ENT is frequently confused with adenoid cystic carcinoma histopathologically. The presence of lobules or cords of small, closely packed basaloid cells with scanty cytoplasm, with or without small cystic spaces and hyalinized stroma, as well as an associated abnormal squamous cell component differentiates this tumor from adenoid cystic carcinoma.6

Figure 2. Showing mass excised in toto.

cytoplasm. Tumor cells showed biphasic pattern with comedo type necrosis. Squamous differentiation was seen in focal areas. These features were suggestive of basaloid variant of SCC. After confirmation of diagnosis, CT brain and abdomen was done to rule out distant metastasis and it was normal. We referred the patient for radiotherapy after six weeks. Patient is on regular follow-up and without clinical or radiological evidence of recurrence for two years. Discussion Basaloid squamous cell carcinoma (BSCC), first described in 1986 by Wain et al for the head and neck region is a rare distinct variant of SCC. It shows predilection for upper aerodigestive tract especially base or tongue, floor of mouth, larynx and tonsils.1,2 It is known for its highly aggressive malignant behavior with early nodal (64%) and distant metastases (44%).3,4 Results of a case-control study by Soriano et al found a six times higher risk of distant metastasis compared to usual type of SCC.5 Absence of cervical metastasis cannot be considered as favorable prognostic sign as the tumor might have already spread to distant sites like liver, lungs, brain and skin. Hence, extensive workup in the form of whole body CT scan is mandatory in all cases of BSCC.2 By the time they are evaluated, most of the patients are in Stage III or IV. Our patient was in Stage I with no evidence of nodal or distant metastasis. Histological characteristics of BSCC have been described by Wain in 1986, and included in WHO classification in 2005. Prior to this, these cases were classified as adenoid cystic carcinoma, small cell undifferentiated carcinoma and poorly differentiated SCC and were treated on a case-to-case basis.4 BSCC

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Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

BSCC is usually seen in males after 60 years of age. In a series of cases reported by Ferlito et al, the average age of patients at their initial evaluation was 63.33 years.7 At 45 years of age, our patient was relatively young. It is usually seen in patients who have history or abuse of tobacco and heavy consumption of alcohol.8,9 Our patient had no history of abuse of tobacco or alcohol. Some reported cases of BSCC were associated with a second primary tumor,10 and rarely with previous irradiation.11 It is usually pedunculated and has benign papilloma-like appearance. The relationship of this tumor with viral agents, Epstein-Barr virus in BSCC of the nasopharynx,12 human papillomavirus in BSCC of external genitalia and anus13 has also been suggested by some authors. Treatment consists of surgery followed by radiotherapy as this tumor is more radiosensitive as compared to SCC. Chemotherapy might have role in patients with distant metastasis.2 BSCC is associated with poor outcome. The overall 3-year survival rate of BSCC has been estimated as 28.5%.14 Thus, our case is exclusive because of BSCC occurring in middle-aged female without history of abuse of tobacco, alcohol and without distant metastasis giving a very good prognosis. Our patient had no evidence of recurrence clinically or radiologically for two years after surgery. Conclusion The exact line of differentiation or pathogenesis of BSCC is still unknown. We strongly believe that every pedunculated papilloma-like mass of the upper aerodigestive tract should be considered to be BSCC unless proved otherwise and should be investigated for nodal and distant metastases. Surgery followed by radiotherapy is the standard line of treatment, however, close follow-up is mandatory. CT is recommended at baseline and every six months during follow-up. It is important for the otolaryngologist to be aware of this benign looking malignant tumor to improve the prognosis by accurate diagnosis and appropriate treatment.


ENT References 1. Sah K, Kale A, Hallikerimath S. Basaloid squamous cell carcinoma involving floor of mouth. J Oral Maxillofac Pathol 2008;12(2):61-3. 2. Prasad KC, Kaniyur V, Devan PP, Kedakalathil J. Basaloid squamous cell carcinoma of larynx: report of a case. Ear Nose Throat J 2002;81(4):254-5. 3. Vasudev P, Boutross-Tadross O, Radhi J. Basaloid squamous cell carcinoma: two case reports. Cases J 2009;2:9351. 4. Thariat J, Badoual C, Faure C, de Mones E, Bucori C, Santini J, et al. Basaloid squamous cell carcinoma of head and neck. Bull Cancer 2009;96(10):989-1004. 5. Soriano E, Faure C, Lantuejoul S, Reyt E, Bolla M, Brombilla E, et al. Course and prognosis of basaloid squamous cell carcinoma of the head and neck: a case-control study of 62 patients. Eur J Cancer 2008;44(2):244-50. 6. Zhang XH, Sun GQ, Zhou XJ, Guo HF, Zhang TH. Basaloid squamous cell carcinoma of esophagus: a clinicopathological, immunohistochemical and electron microscopic study of sixteen cases. World J Gastroenterol 1998;4(5):397-403. 7. Ferlito A, Altavilla G, Rinaldo A, Doglioni C. Basaloid squamous cell carcinoma of larynx and hypopharynx. Ann Otol Rhinol Laryngol 1997;106(12):1024-35.

8. Coppola D, Catalano E, Tang CK. Elfenbein IB, Harwick R, Mohr R. Basaloid squamous cell carcinoma of floor of mouth. Cancer 1993;72(8):2209-305. 9. Paulino AF, Singh B, Shah JP, Huvos AG. Basaloid squamous cell carcinoma of the head and neck. Laryngoscope 2009;110(9):l479-82. 10. Seldman JD, Berman JJ, Yost BA, Iseri OA. Basaloid squamous cell carcinoma of die hypopharynx and larynx associated with second primary tumors. Cancer 1991;68(7):1545-9. 11. Wan SK,Chan JK, Tse KC. Basaloid-squamous carcinoma of the nasal cavity. J Laryngol Otol 1992;106(4):370-1. 12. Wan SK, Chan JK, Lau WH, Yip TT. Basaloid squamous cell carcinoma of nasopharynx. An Epstein-Barr virusassociated neoplasm compared with morphologically identical tumors occurring in other sites. Cancer 1995;76(10):1689-93. 13. Shroyer KR, Brookes CG, Markham NE, Shroyer AL. Detection of human papillomavirus in anorectal squamous cell carcinoma. Correlation with basaloid pattern of differentiation. Am J Clin Pathol 1995; 104(3):299-305. 14. Ereno C, Lopez Jl, Sanchez JM, Toledo JD. Basaloidsquamous cell carcinoma of larynx and hypopharynx. A clinicopathological study of 7 cases. Pathol Res Pract 1994;190(2):186-93.

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Tonsillectomy Helps Adults Too Adults who undergo a tonsillectomy have fewer symptoms of pharyngitis, visit their doctors with throat problems less often, and miss work less, researchers from the University of Oulu and Oulu University Hospital, both in Finland, reported in CMAJ (Canadian Medical Association Journal).

Tonsillectomy in Adults with Severe Recurrent Sore Throats may Benefit Some People Tonsillectomy may result in fewer severe sore throats and could benefit some adult patients, according to a randomized trial published in CMAJ (Canadian Medical Association Journal).

Light Shed on the Natural Mechanism that Protects Ears from Hearing Loss New research from the Massachusetts Eye and Ear, Harvard Medical School and Harvard Program in Speech and Hearing Bioscience and Technology may have discovered a key piece in the puzzle of how hearing works by identifying the role of the olivocochlear efferent system in protecting ears from hearing loss. The findings could eventually lead to screening tests to determine who is most susceptible to hearing loss. Their paper is published in the Journal of Neuroscience.

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Gastroenterology

Role of Liv.52 HB Capsules in the Management of Hepatitis B Infection: A Review Asim Maji*, Dibyendu Goutam**, Padmanabha Rugvedi†

Abstract Liver diseases of viral origin are a major health concern worldwide, especially in developing countries due to high endemicity. Hepatitis B causes both acute and chronic liver damage where a greater proportion of patients with chronic disease end up with liver cirrhosis and hepatocellular carcinoma (HCC). Despite advances in modern medicine, there is no effective drug available that stimulates liver function, protects the liver from damage or helps to regenerate hepatic cells. Hence, there is a need for safe and effective remedy. Various clinical trials have been carried out to evaluate the efficacy and safety of Liv.52 HB capsule, a herbal preparation, in the management of hepatitis B infection. The present article reviews the clinical data available on Liv.52 HB capsules in patients with chronic hepatitis B (CHB) infection. Six clinical trials including one case study on the product were selected for review with respect to their study design, results and conclusions. Study duration was six months in all the studies. In all the studies, alanine aminotransferase (ALT) level was taken for symptomatic analysis and hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), hepatitis B virus (HBV) DNA were considered as specific investigations to grade the condition.

Keywords: Liver diseases, Liv.52 HB, ALT

H

epatitis B is a serious and common infectious disease of the liver caused by the hepatitis B virus (HBV), an enveloped virus containing a partially double stranded, circular DNA genome and classified within the family hepadnavirus.1 The average estimated carrier rate of HBV is 4%, placing India in the intermediate range for hepatitis B endemicity2 with an approximate total of 36 million carriers.3 Among the estimated 400 million hepatitis B surface antigen (HBsAg) carriers worldwide, India alone contributes 9% of the total.4 There are wide variations in social, economic and health factors in different regions of India, which may explain the differences in HBV carrier rates reported by investigators in different parts of the country.5-8 The virus is transmitted by exposure to infectious blood or body fluids such as semen and vaginal fluids, while viral DNA has been detected in the saliva, tears and urine of chronic carriers. Perinatal infection is a major route of infection in endemic (mainly developing) countries during the preschool years.9 *Consultant Gastroenterologist ‘Complete Care’, Kolkata **Professor Dept. of Surgery, Medical College, Kolkata †Consultant Ayurvedic Physician Bangalore Address for correspondence Dr Asim Maji Consultant Gastroenterologist, ‘Complete Care’ 40/2/1-Z, Lake Road, Kolkata - 700 029

In areas of intermediate endemicity, transmission is either perinatal or horizontal.10,11 The route of transmission has important clinical implications, as there is a very high probability of developing chronic hepatitis B (CHB) if the infection is acquired perinatally or in the preschool years.12 Other risk factors for developing HBV infection include working in a healthcare setting, transfusions, dialysis, acupuncture, tattooing, extended overseas travel and residence in an institution.13-15 The virus does not spread by holding hands, sharing eating utensils or drinking glasses, kissing, hugging, coughing, sneezing or breastfeeding.16,17 The acute illness causes liver inflammation, vomiting, jaundice and, rarely, death. CHB may eventually cause cirrhosis and liver cancer - a disease with poor response to all but a few current therapies.18 The infection is preventable by vaccination.19 Extrahepatic manifestations include serum sickness-like syndrome, acute necrotizing vasculitis (polyarteritis nodosa [PAN]), membranous glomerulonephritis and papular acrodermatitis of childhood (Gianotti-Crosti syndrome).20,21 The serum sickness-like syndrome occurs in the setting of acute hepatitis B, often preceding the onset of jaundice.22 The clinical features are fever, skin rash and polyarteritis. Symptoms often subside shortly after the onset of jaundice, but can persist throughout the duration of acute hepatitis B.23 About 30-50% of people with acute necrotizing vasculitis (PAN) are HBV carriers.24 HBV-associated nephropathy

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Gastroenterology has been described in adults but is more common in children.25,26 Membranous glomerulonephritis is the most common form23 followed by other immunemediated hematological disorders, such as essential mixed cryoglobulinemia and aplastic anemia.23 If the host is able to clear the infection, the HBsAg will eventually become undetectable and will be followed by immunoglobulin G (IgG) antibodies to the HBsAg and core antigen (anti-HBs and anti-HBc IgG).24 A person negative for HBsAg but positive for anti-HBs either has cleared an infection or has been vaccinated previously. Individuals who remain HBsAg-positive for at least six months are considered to be hepatitis B carriers.25 Carriers of the virus may have CHB reflected by elevated serum alanine aminotransferase (ALT) levels and hepatic inflammation. Carriers who have seroconverted to hepatitis B e-antigen (HBeAg)-negative status, especially those who have acquired the infection as adults, have very little viral multiplication and hence may be at little risk of long-term complications or of transmitting infection to others.26 Antiviral treatment is the effective way to reduce morbidity and mortality from chronic HBV infection. Conventional interferon (IFN)-Îą and lamivudine have been the primary treatments to date. IFN-Îą produces a durable response in a moderate proportion of patients but has undesirable side effects and must be administered subcutaneously three times per week, an inconvenient regimen for patients. These disadvantages may be partially overcome with pegylated IFN (PEG-IFN). Lamivudine offers the advantages of minimal side effects and ease of administration. The major disadvantages are its modest efficacy rate, the need for long-term therapy to maintain response and its association with a high rate of viral resistance, particularly with prolonged use.26-31 However, prolonged treatment is often necessary to prevent relapse on cessation of therapy32 and continuous treatment can lead to the development of lamivudine resistance. Promising emerging treatments include adefovir,33 entecavir34 and PEG-IFN Îą-2a (40 kDa).35 The current treatment of care is costly, has significant side effects and fails to cure about half of all infections. Hence, there is a need to develop new treatment from medicinal plants, which are less toxic, more efficacious and cost-effective. The Ayurvedic viewpoint in understanding liver diseases Any disease is a cumulative effect of the altered functions of the dosha and unless arrested these

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phenomena progress to cause further damage. The consequences of the altered dosha are replicated through the programmed dispensation and try to break the barrier of the homeostatic condition with the specific causative factors that accelerate through its intensity in the susceptible zone. The concept and explanation of aganthuja vyadhis or exogenous disorders is discussed in Ayurveda as one of the basic classifications of diseases. The characteristic feature of an aganthuja disease is that it first affects the body, shows its symptoms and then spoils the internal environment further consolidating its position, if not properly treated. The generated disease is amplified with respect to the resistance mechanism of the body and therefore the causative factors of the relevant diseases are classified in different ways. Substances, which have opposite qualities to those of bodily tissues (or deha-dhatu-pratyanik bhutani), (when gain entry into the body) encounter the opposition by the dehadhatu (bodily tissues) (Charaka Samhita Sutrasthana 26/81). It points out that immune system of person attacks any antigen, which has gained entry into the body.

Understanding Liver Physiology Liver handles majority of digestion and metabolism in the human body. It is regarded as the site of origin for Raktavaha srotas. It is the place regarded as connector between Abhyantara roga marga and Bahya roga marga or sakha and koshta. It is the place for Bhutagnis as speculated by some of earlier authors on Kayachikitsa. These roles are clearly appreciated in the classical literature while explaining the agni vyapara, especially in relation to snehana karma in the context of Panchakarma and in Kaamala chikitsa. Kaamala is a disease characterized by liver cell damage or bile flow obstruction. Other diseases like Pandu, Halimaka, Udara, etc., are also related to the condition with either cause or effect relation. The dormant nature of the disease for a longer period in an immunocompetent person should be regarded as the leenatha of doshas as noted in Jwara chikitsa by Acharya Charaka. This is much in the level of Rakta dhatu as the virus seats in liver, the moola of Raktavaha srotas. The active state of the disease is the jwaravastha or Dosha ulbana avastha. When a disease is not treated in its earlier stages, it enters into Bheda avastha (complicated stage) and carries a bad prognosis. At this stage, apart from the original samprapti ghataka (elements in pathogenesis), other dhatus also involve. Even, involvement of Marma, ojas and gambhira dhatus like sukra are also involved resulting in the decline of deha bala (immunity). Ascites,


Gastroenterology fulminant hepatic failure and other metabolic and neurologic consequences of the disease are a result of compromised status of kayagni, an important state of udara roga and along with dhatu saithilya of rakta, mamsa dhatus make the condition miserable and not infrequently, fatal. As Acharya Sushrutha describes, the popular modes of transmission of a disease are prasanga (sexual transmission), gatra samsparsha (any physical contact), niswasa (aerial/droplet), saha bhojana (eating together) and saha shayya, snana, vastra, malya, anulepana (sharing of bed, utensils, clothes, bathing and anointments). The modes differ with the diseases and the commonly noted contagious diseases are kushta (major skin diseases), jwara (some types of fevers), sosha (tuberculosis), netrabhisyanda (conjunctivitis) and aupasargika rogas (diseases due to affliction of invisible things). The infectious nature of hepatitis B may well be related with the infective fevers as described above. During subclinical and early clinical stages of the disease excluding acute manifestations, the doshas can be considered to be in leenavastha. These can be treated or managed very well considering the good immunity of the person. In the acute stages, it has to be treated as per the manifestation; chhardi chikitsa, atisara chikitsa, or jwara chikitsa as the case may be, all summing upto maintenance of Kayagni with due consideration of dosha gati and avastha. Role of Liv.52 HB in the Management of Hepatitis B Infection Liv.52 HB, a multi-ingredient formulation, offers a new dimension in the management of hepatitis B infection. Various clinical studies have established the therapeutic efficacy and safety of Liv.52 HB in the management of hepatitis B. It is devoid of harmful side effects, which ensures patient compliance. The antiperoxidative activity prevents loss of functional integrity of the hepatic cell membrane, due to its effect on cytochrome P-450 system, hastens recovery period and ensures early restoration of hepatic functions in infective hepatitis. Liv.52 HB capsule protects the hepatic parenchyma and promotes hepatocellular regeneration possibly due to its antiperoxidative and antiviral activities. Pharmacological Actions and Principal Herbs

Antiviral Activity HBsAg is the main factor in pathogenesis of hepatitis B. High morbidity and mortality has been found in Asia among HBsAg-positive patients, even in the absence of

Composition Each Liv.52 HB capsule contains Sanskrit Name Botanical Name Exts.

Mustaka

Quantity (mg)

Cyperus rotundus

125 mg

Nagaramustaka Cyperus scariosus

125 mg

overt liver disease.36 The goals of treatment in chronic infection are sustained viral suppression, normalization of ALT levels and improvement in liver histology leading to reduction in the long-term risk of cirrhosis and hepatocellular carcinoma (HCC).37 Loss of HBsAg, HBeAg, normalization of ALT levels and improvement in liver histology are the usual short-term endpoints of therapy.38 Cyperus rotundus and Cyperus scariosus are therapeutically used for their antimicrobial activities.39-40 Various trials are also suggestive of the antimicrobial activity of these herbs.41 Kar et al reported that 24 weeks of medication with C. rotundus and C. scariosus extracts resulted in clinically significant virological and biochemical benefits in patients with CHB. A 6-month extended therapy gives comparatively better results in terms of viral clearance. The potential benefit of the above mentioned extracts showed viral clearance including HBsAg, HBeAg and HBV DNA viral copies, helping in managing the hepatitis B infection.42

Hepatoprotective Activity C. rotundus has hepatoprotective activity, which protects the liver from varied etiologies possibly due to antioxidant activity.40-43 In vivo trials have demonstrated that pre-treatment with the extract of C. scariosus significantly lowered (p < 0.05) alkaline phosphatase (ALP), serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels to 192 ± 31, 63 ± 9 and 35 ± 8. The hepatotoxic dose of CCl4 (1.5 ml/kg; orally) raised ALP, SGOT and SGPT levels to 328 ± 30, 493 ± 102 and 357 ± 109 IU/l (n = 10), respectively, compared to respective control values of 177 ± 21, 106 ± 15 and 47 ± 12. The same dose of plant extract (500 mg/kg) significantly prevented (p < 0.05) CCl4-induced rise in serum enzymes and the estimated values of ALP, SGOT and SGPT were 220 ± 30, 207 ± 95 and 75 ± 38, respectively. It also prevented CCl4-induced prolongation in pentobarbital sleeping time confirming hepatoprotectivity. These results rationalize the folkloric use of this plant in hepatobiliary disorders.44

Renormalization of the Liver Functions Treatment with the extracts of C. rotundus and C. scariosus renormalize liver enzymes and thus improve

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Gastroenterology hepatic functions. These extracts are also reported in improving the loss of appetite.45-47 Experiments were also conducted on Pekin ducks to assess the efficacy of the plant extract to eliminate the duck HBV in experimentally infected Pekin ducks in a duck model study and found to be effective. The molecular mechanism involved in the antihepatitis B (HBV) activity of HD-03/ES has been studied using in vitro models. The effect of HD-03/ES on HBsAg secretion and its gene expression was studied in transfected human hepatocarcinoma PLC/PRF/5 cells. The anti-HBV activity was tested based on the inhibition of HBsAg secretion into the culture media, as detected by HBsAg specific antibody-mediated enzyme assay at concentrations ranging from 125 to 1,000 mg/ml. The effect of HD-03/ES on HBsAg gene expression was analyzed using semiquantitative multiplex real-time polymerase chain reaction (RT-PCR) by employing specific primers. The results showed that HD-03/ES suppressed HBsAg production with an IC50 of 380 mg/ml in PLC/PRF/5 cells for a period of 24 hours. HD-03/ES downregulated HBsAg gene expression in PLC/PRF/5 cells. Thus, HD-03/ES exhibited strong anti-HBV properties by inhibiting the secretion of HBsAg in PLC/PRF/5 cells and this action is targeted at the transcription level.48 In another experimental study, HD-03/ES drug preparations were pre-treated with HBV and tested for the virus binding inhibition to its receptor. HD-03/ES was tested for its anti-HBV activity by HBsAg binding inhibition assay. A dose-response analysis was done to find out the optimum concentration of HD-03/ES that could completely inhibit the virus. HD-03/ES had interfered HBV binding with its receptor. Among the formulations evaluated, drug dissolved in PBS showed more anti-HBV activity. Dose response study of HD-03/ES indicated that 2.5 and 5 mg/ml concentrations were optimal upto 1.5 pg/ml of HBV. HD-03/ES inhibited HBsAg binding to its receptor suggesting its possible role in inhibiting HBV infection at entry level.49 Several clinical trials have been conducted to evaluate the safety and efficacy of Liv.52 HB capsules. Clinical Trial 1: Safety and efficacy of oral HD-03/ES given for six months in patients with chronic hepatitis B46 Aim: To investigate the safety and efficacy of HD-03/ES capsules in the management of patients with CHB. Material and methods: An open prospective controlled clinical trial was carried out in the Dept. of Gastroenterology, Lifeline Rigid Hospitals, Chennai, Tamil Nadu, India, between March 2005 and June 2006. Twenty-five (22 male and 3 female) patients aged between

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20 and 45 years (mean age 33.7 years) with a history of hepatitis B or HBsAg carriers for at least six months were recruited to the study. Inclusion criteria: Patients with a history of hepatitis B or HBsAg carriers for at least six months, who still had symptoms and signs of hepatitis B as well as abnormal liver function and positive HBsAg, were diagnosed as having CHB infection in the present study. Patients who were willing to give a written informed consent and follow the schedule and who had not participated in a similar investigation in past four weeks were enrolled. Exclusion criteria: Patients aged >60 years or <18 years, pregnant or lactating women, patients who had hepatitis C or other hepatic viral infection, autoimmune hepatitis and drug-induced hepatitis or alcoholic hepatitis; patients with severe complications of the cardiovascular, renal or hematopoietic systems and mental diseases, were excluded. Patients were excluded if they had decompensated liver disease (serum albumin ≤360 g/l, bilirubin ≥150 g/l, prothrombin time [PT] ≥2s prolonged or a history of ascites, variceal hemorrhage or hepatic encephalopathy), pancytopenia (hemoglobin [Hb] <110 g/l, total leukocyte count [TLC] <4,000/mm3 or platelets <105/mm3). Patients with a history of using IFN or antiviral agents or corticosteroids or immunosuppressive drugs and who are unwilling to give written informed consent were also excluded. Study procedure: Each patient was asked to take two capsules of HD-03/ES (The Himalaya Drug Company, Bangalore, India) twice-daily for a period of six months. The symptoms and signs of patients were recorded in detail using the ‘Clinical Observation Table’ once a month before and during the treatment. HBsAg, HBeAg and HBV DNA were estimated at baseline, four and six months after therapy using commercially available enzyme-linked immunosorbent assay (ELISA) kits from Roche. Liver function tests (LFTs) - serum proteins, total bilirubin (TB), ALT, aspartate aminotransferase (AST) - were done every month during the treatment. Results: Six months of therapy with HD-03/ES capsules was markedly effective in the majority of the patients as it relieved main clinical symptoms such as abdominal pain and poor appetite. After six months of treatment, ALT levels decreased from initial value of 66.5 ± 11.1 to 39.1 ± 5.2 (p < 0.01). In 14 of the 25 patients (56%), ALT levels were normalized. Though ALT levels were not normalized in the remaining 11 patients, there was a trend towards reduction and in none of the patients was a rise in ALT levels seen. Thirteen of the 25 patients (52%) had undetectable HBsAg at the end of treatment (p < 0.001). HBeAg loss (60%, p < 0.001) and HBV DNA loss (60%, p < 0.05) also occurred during treatment in those six patients who were positive for both HBeAg and HBV DNA initially, but were negative


Gastroenterology for the same at the end of therapy. Conclusion: This trial demonstrated that 24 weeks of HD-03/ES treatment resulted in clinically significant virological and biochemical benefits in patients with CHB. Long-term comparative trials with standard drugs with extended duration of follow-up are recommended. Clinical Trial 2: Double-blind clinical trial of HD-03/ES vs placebo in the management of chronic hepatitis B50 Aim: To evaluate the safety and efficacy of HD-03/ES in patients with hepatitis B infection. Material and methods: A double-blind, randomized, placebocontrolled clinical study was carried out in 50 patients with CHB. Patients with CHB who attended the Dept. of Medicine OPD, Rajendra Institute of Medical Sciences, Bariatu, Ranchi, India were enrolled in the present study. Inclusion criteria: Eligible patients included males and females aged 18-65 with positive HBsAg for at least six months, ALT levels within six times the upper limit of normal at the screening visit and who were willing to give a written informed consent and follow the schedule and who had not participated in a similar investigation in past four weeks were enrolled. Exclusion criteria: Patients with decompensated liver disease (serum albumin ≤36 g/dl, bilirubin ≥15 g/dl, PT ≥2 sec prolonged or a history of ascites, variceal hemorrhage or hepatic encephalopathy), pancytopenia (Hb <11 g/dl, TLC <4,000/mm3 or platelets <105/mm3), or use of IFN or antiviral agents were excluded. Women of child-bearing age as well as lactating women were also excluded. Other exclusion criteria included co-infection by hepatitis C virus, a history of HCC, serious medical illness, active substance or alcohol abuse and concurrent use of corticosteroids or immunosuppressive agents and unwilling to give written informed consent. Study procedure: Fifty patients who met the eligibility criteria were randomized to treatment with either HD-03/ES (n = 25) or placebo (n = 25). Each patient was advised to take two capsules twice-daily for six months. The symptoms and signs of patients were recorded in detail using the ‘Clinical Observation Table’ once in a month before and during the treatment. HBsAg, HBeAg and HBV DNA were estimated at baseline, 16 weeks and 24 weeks after therapy using ELISA. LFT - serum proteins, TB, ALT, AST - were done every month. Results: Of the 50 patients enrolled for the study, five in the placebo group and one in the HD-03/ES group were lost during follow-up during the final visit; remaining 44 patients completed the study as planned. HD-03/ES was more effective than placebo in normalizing ALT levels, an important follow-up marker of biochemical response. ALT normalization occurred in 17 of the 24 patients (70.8%) versus just three patients in the placebo group (15%). This occurred more significantly in those

who cleared their HBsAg than in those who did not. Ten of these 24 patients (41.75%) had undetectable HBsAg at the end of treatment versus just 5% with placebo (p < 0.001). HBeAg loss occurred more frequently during treatment with HD-03/ES in 5 of the nine patients. HBV DNA levels became undetectable after 24 weeks of therapy with HD-03/ES therapy in six patients who were positive for the same at the initiation of therapy versus just one person losing HBV DNA in the placebo group (p < 0.05). Twenty-four weeks of therapy with HD-03/ES capsules was markedly effective in majority of the patients as chief clinical symptoms such as abdominal pain and poor appetite were relieved. There was progressive weight gain in the subjects treated with HD-03/ES capsules (not significant). Jaundice had virtually disappeared in all except in two subjects after 24 weeks of therapy with HD-03/ES. Conclusion: HD-03/ES had clinically significant virological and biochemical benefits in patients with CHB. The study of potential benefits of HD-03/ES in the management of CHB in long-term comparative trials with standard drugs is recommended. Clinical Trial 3: A preliminary study on the safety and efficacy of HD-03/ES therapy in patients with chronic hepatitis B51 Aim: To evaluate the safety and efficacy of the formulation HD-03/ES capsules in the management of patients with CHB. Material and methods: An open prospective controlled clinical trial was carried out in patients attending the Dept. of Medicine, RG Kar Medical College, Calcutta, India between March 2003 and February 2005. Inclusion criteria: Patients aged 18-60 years with ALT level 41-240 IU/l, serum HBsAgpositive, those willing to give a written informed consent and follow the schedule and those who had not participated in a similar investigation in past four weeks were enrolled. Exclusion criteria: Patients aged >60 years or <18 years, pregnant or lactating women, patients who had hepatitis C or other hepatic viral infection, autoimmune hepatitis and drug-induced hepatitis or alcoholic hepatitis; patients with severe complications of the cardiovascular, renal or hematopoietic systems and those with mental diseases were excluded. Patients were excluded if they had decompensated liver disease (serum albumin ≤36 g/dl, bilirubin ≥15 mg/dl, PT ≥2 sec prolonged or a history of ascites, variceal hemorrhage or hepatic encephalopathy), pancytopenia (Hb <11 g/dl, TLC <4,000/mm3 or platelets <105/mm3). Patients with a history of using IFN or antiviral agents or corticosteroids or immunosuppressive drugs were also excluded. Study procedure: Fourteen patients (12 males and 2 females) aged between 18 and 48 years with a mean age of 32.4 years participated in this open

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Gastroenterology study. The study was carried out in 14 patients with CHB infection and was treated with HD-03/ES capsules twice-daily in the morning and evening for a period of 6 months. Signs and symptoms of hepatitis such as loss of appetite, nausea/vomiting, fatigue, weight loss, sense of well-being, jaundice and hepatomegaly were assessed at baseline as present or absent and if present the severity was noted as mild, moderate or severe. HBsAg, HBeAg and HBV DNA were estimated at baseline, 16 weeks and 24 weeks after therapy using commercially available ELISA kits from Roche. LFT serum proteins, TB, ALT, AST - were done every month. Results: All 14 patients completed the six months study as planned. The mode of transmission of HBV was unknown in most (78%); history of blood transfusion was present in 14.3%. There was a progressive weight gain in the subjects treated with HD-03/ES capsules (not significant). Clinical manifestations of hepatitis improved significantly in HD-03/ES treated patients and jaundice disappeared in all the subjects after 24 weeks of therapy. A progressive and statistically significant reduction in ALT from the initial level of 153 U/l was seen; the levels normalized in nine of the 14 patients enrolled for the study. Only five patients had elevations ranged between 41 and 88 IU/l at the end of the study. Before the treatment, HBsAg was detected in all the patients. In 10 of the 14 patients, HBsAg became negative within 3-6 months after initiation of HD 03/ES therapy. Five of the 10 patients (50%) treated with HD-03/ES had undetectable HBeAg (p < 0.05). HBV DNA loss also occurred more frequently during treatment with HD-03/ES in four patients who were positive for HBV DNA initially were negative for the same at the end of therapy. Conclusion: This controlled study showed clinically significant antiviral effect of HD-03/ES in CHB. Clinical Trial 4: Short-term HD-03/ES therapy for CHB: A randomized controlled trial45 Aim: To investigate the safety and efficacy of 24 weeks of treatment with HD-03/ES at a dosage of one capsule twice-daily in adult patients with CHB. Material and methods: Patients with CHB who attended the Dept. of Medicine OPD, Heritage Hospitals Ltd., Lanka, Varanasi, Uttar Pradesh, India between August 2003 and September 2005 were enrolled in the present study. Twenty-two patients (17 males and 5 females) aged between 21 and 54 years with a mean age of 32.6 years participated in this open study. Inclusion criteria: Eligible patients included males and females aged 18-65 with positive HBsAg for at least six months, ALT levels within six times the normal, patients who were willing to give a written informed consent and follow the schedule and who had not participated

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in a similar investigation in past four weeks were enrolled in the study. Exclusion criteria: Patients were excluded if they had decompensated liver disease (serum albumin ≤36 g/dl, bilirubin ≥15 g/dl, PT ≥2 sec prolonged or a history of ascites, variceal hemorrhage or hepatic encephalopathy), pancytopenia (Hb <11 g/dl, TLC <4,000/mm3 or platelets <105/mm3). Patients with a history of using IFN or antiviral agents, pregnant and lactating women, patients with hepatitis C virus co-infection, history of HCC, serious medical illness, active substance or alcohol abuse and concurrent use of corticosteroids or immunosuppressive agents were also excluded. Study procedure: The study medication HD-03/ES was given at a dose of two capsules twicedaily. The symptoms and signs of patients were recorded in detail using the ‘Clinical Observation Table’ once a month before and during the treatment. HBsAg, HBeAg and HBV DNA were estimated at baseline and 24 weeks after therapy using commercially available ELISA kits (Roche). LFTs - serum proteins, TB, ALT, AST - were done every month. Results: Twenty-one patients completed the six-month study as planned; one patient was lost to follow-up. There was a progressive and statistically significant reduction in ALT levels and this got normalized in 16 patients; in the remaining six, the elevations ranged between 41 and 75 IU/l only. In 11 of the 21 patients (52.4%), HBsAg became undetectable within 3-6 months after initiation of HD-03/ES therapy (p < 0.001). HBV DNA loss also occurred more frequently during treatment with HD-03/ES in that five of the 11 patients (45.5%) who were positive for HBV DNA initially were negative for the same at the end of therapy. There was progressive weight gain in the subjects treated with HD-03/ES capsules (not significant). Clinical manifestations of hepatitis improved significantly in HD-03/ES treated patients and jaundice virtually disappeared in all but one of the subjects after 24 weeks of therapy. Conclusion: This trial demonstrated that 24 weeks of HD-03/ES treatment resulted in clinically significant virological and biochemical benefits in patients with CHB. Clinical Trial 5: Reduction of HBsAg with decrease in viral load with herbal formulation, HD-03/ES: A case study52 Case history: A 29-year-old young married female presented with repeated attacks of low-grade fever, generalized weakness, headache, loss of appetite and loss of weight for more than two years. She had been treated randomly at various places for generalized weakness with tonics, vitamins and minerals as oral supplements as well as injections. She had delivered a baby boy four years ago and had suffered postpartum weakness since then and been treated


Gastroenterology conventionally from time-to-time. Patient underwent complete physical and biochemical investigations for suspected hepatitis about eight months back, which revealed mild anemia along with evidence of HBsAg. Investigations: Complete hematological, biochemical and immunological investigations were done including HBsAg, PCR, along with LFT. Patient consented for undergoing the new drug treatment along with necessary investigations from time-to-time to evaluate the response. Patient was given HD-03/ES at a dose of two capsules (500 mg), twice-daily for five months. She was monitored every month with respect to physical, biochemical and immunological investigations. Results: Patient took HD-03/ES without any hesitation, which indicates a positive compliance. She reported feeling of well-being, improvement of appetite and weight gain of about 6 kg. ELISA revealed 48.60% reduction of HBsAg and the ELISA titer was reduced from 1.442 to 0.741 OD values at the end of four months. The PCR analysis using the amplification of 523 bp HBV specific DNA fragments revealed disappearance of viral DNA at 3rd month onwards. HD-03/ES did not produce adverse effects on the liver functions. The results showed significant reduction of HBsAg along with disappearance of viral DNA suggesting positive effect of HD-03/ES. Conclusion: HD-03/ES had reduced the viral load significantly in the patient at the dose of two capsules (500 mg) twice-daily along with inhibition of HBsAg. The result corresponds with the in vitro efficacy of HD-03/ES in terms of reduction in viral load and inhibition of HBsAg. Since the patient had not received any conventional antiviral drug or IFN, this suggests that the positive effects are definitely produced by HD-03/ES. Clinical Trial 6: HD-03/ES: A promising herbal drug for HBV antiviral therapy42 Aim: To determine whether HD-03/ES administration is safe and effective for human administration in the management of CHB. Material and methods: An open-labeled clinical trial of HD-03/ES capsules was carried out in 51 patients of CHB infection aged between 19 and 51 years (mean age 35.9 years), which included 41 (80.4%) patients of chronic hepatitis and 10 (19.6%) patients of decompensated cirrhosis who were admitted in the medical wards of Lok Nayak Hospital and Associated Maulana Azad Medical College, New Delhi, between June 2005 and May 2009. Inclusion criteria: Patients aged 18-60 years, ALT levels 41-200 IU/l, positive serum HBsAg, those who were willing to give a written informed consent and follow the schedule and those who had not participated in a similar investigation in past four weeks were enrolled in the study. Exclusion criteria: Pregnant or lactating women, patients who had hepatitis C or other hepatic

viral infection, autoimmune hepatitis and druginduced hepatitis or alcoholic hepatitis; patients with severe complications of the cardiovascular, renal or hemopoietic systems and those with mental diseases, patients with a history of using IFN or antiviral agents or corticosteroids or immunosuppressive drugs were excluded. Study procedure: Each patient was asked to take two capsules of HD-03/ES twice-daily, for a period of six months. The symptoms and signs of patients were recorded in detail using the ‘Clinical Observation Table’ once a month before and during the treatment. HBsAg, IgG anti-HBc, HBeAg and HBV DNA were estimated at baseline, four and six months after therapy using commercially available ELISA kit. LFT - serum proteins, TB, ALT, AST - were done every month. Results: Six months of therapy with HD-03/ES capsules was markedly effective in the majority of the patients as it alleviated the chief clinical symptoms such as abdominal pain and poor appetite. There was a trend towards normalization of LFT in all patients treated with HD-03/ES. ALT levels decreased from initial value of 71.2 ± 16.3 to 36.4 ± 6.8 (p < 0.01). In 32 of the 51 patients (62.7%), ALT levels were normalized. Though ALT levels did not normalize in the remaining 19 patients, there was a trend towards reduction and in none of the patients was a rise in ALT levels seen. Six of the 51 patients (11.8%) at the end of treatment, who were treated with HD-03/ES, had undetectable HBsAg. Also, HBeAg loss 14/51 (27.4%) and HBV DNA loss 14/51 (27.4%) was observed during treatment with HD-03/ES in patients who were positive for both HBeAg and HBV DNA initially. The mean baseline viral load of the 14 patients who cleared the HBV DNA was log10 4.8 ± 0.79 copies/ml. Among these 14 patients, only six patients cleared the virus at the end of six months. However, in the remaining eight patients, the viral load decreased significantly at the end of six months, and they subsequently cleared the virus after 12 months therapy with HD-03/ES. Genotype D was found in 39 (76.5%) while Genotype A was found in 12 (33.5%), respectively. The mean reduction in viral load was observed from log10 7.1 ± 1.8 to log10 4.4 ± 2.1 (p < 0.01). However, a sharp decline in viral load was observed in patients infected with Genotype A (log10 6.8 ± 2.5 to log10 4.9 ± 1.8; p < 0.01) compared to genotype D (log10 7.0 ± 2.6 to log10 5.9 ± 3.5; p = 0.074). Conclusion: This trial demonstrated that 24 weeks of HD-03/ES treatment resulted in clinically significant virological and biochemical benefits in patients with CHB infection. Further, six months extended therapy has shown comparatively better results in terms of viral clearance. Hence, HD-03/ES should be studied in long-term comparative trials with standard drugs with extended duration of follow-up.

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Gastroenterology Status of Liv.52 HB capsule in management of Hepatitis B infection Liv.52 HB capsule is a polyherbal formulation with proven safety and efficacy, owing to the multipharmacological properties of its ingredients and hence can be safely used in hepatitis B infection. Liv.52 HB improved the clinical manifestations of hepatitis, normalized the elevated LFT parameters and serum markers for liver dysfunction. HBV DNA loss was also observed in the clinical studies with Liv.52 HB treatment. The effects of Liv.52 HB capsule are attributed to the synergistic action of the constituent herbs, which act in a complementary manner to potentiate the therapeutic effects of the formulation. Additionally, anti-HBV activity of Liv.52 HB was studied in in vitro (PLC/PRF/5) cell line as demonstrated by anti-HBV activity and suppression of HBsAg. No adverse effects were reported in any of the reviewed trials. It is safe for long-term use and compliance to the study drug was satisfactory. The results from the above reviewed clinical trials show that Liv.52 HB capsule is a safe, effective, practical and affordable therapeutic modality, which may be beneficial in management of hepatitis B infection.

15. Kidd-Ljunggren K, et al. J Hosp Infect 2006;64(4):352-7. 16. Hepatitis B. National Institute of Health. Available at: http:// www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001324. Retrieved 2010-11-23. 17. Hepatitis B FAQs for the Public - Transmission. U.S. Centers for Disease Control and Prevention (CDC). Available at: http://www.cdc.gov/hepatitis/b/bfaq.htm 18. Chang MH. Semin Fetal Neonatal Med 2007;12(3):160-7. 19. Pungpapong S, et al. Mayo Clin Proc 2007;82(8):967-75. 20. Dienstag JL. Semin Liver Dis 1981;1(1):45-57. 21. Trepo C, et al. J Autoimmun 2001;16(3):269-74. 22. Alpert E, et al. N Engl J Med 1971;285(2):185-9. 23. Liang TJ. Hepatology 2009;49(5 Suppl):S13-21. 24. Gocke DJ, et al. Lancet 1970;2(7684):1149-53. 25. Lai KN, et al. N Engl J Med 1991;324(21):1457-63. 26. Takekoshi Y, et al. Lancet 1978;2(8099):1065-8. 27. Zuckerman AJ. Hepatitis viruses. In: Baronâ&#x20AC;&#x2122;s Medical Microbiology. Baron S, et al (Eds.), 4th edition, University of Texas Medical Branch, 1996. 28. Lok AS, et al. Hepatology 2007;45(2):507-39. 29. Chu CM, et al. Gastroenterology 2007;133(5):1458-65. 30. Liaw YF, et al. Gastroenterology 2000;119(1):172-80. 31. Dienstag JL, et al. Hepatology 1999;30(4):1082-7. 32. Perrillo R, et al. Hepatology 2000;32(1):129-34.

References

33. Yang H, et al. Hepatology 2002;36(2):464-73.

1. Ganem D, Schneider RJ. Hepadnaviridae: The viruses and their replication. In: Fields Virology. 4th edition, Knipe DM et al. (Eds.), Lippincott Williams & Wilkins: Philadelphia 2001:p.2923-69.

34. de Man RA, et al. Hepatology 2001;34(3):578-82.

2. Suzuki H, Woodfield G. Viral hepatitis in Asia: summary of a plenary session. In: Viral hepatitis and Liver Disease. Nishioka K, Suzuki H, Mishiro S, Oda T (Eds.), Springer Verlag: Tokyo 1994:p.385-6. 3. Agarwal R, et al. Natl Med J India 1994;7(5):216-20. 4. Andre FE. Vaccine 1990;8(Suppl):S74-8; discussion S79-80. 5. Irshad M, et al. Natl Med J India 1994;7(5):210-2. 6. Singhvi A, et al. J Trop Med Hyg 1990;93(3):178-82. 7. Prasad SR, et al. Indian J Med Res 1983;78:300-6. 8. Joshi SH, et al. Indian J Med Res 1990;91:340-3.

35. Cooksley WG, et al. J Viral Hepat 2003;10(4):298-305. 36. Beasley RP. Cancer 1988;61(10):1942-56. 37. Jacobson IM. Am J Gastroenterol 2006;101 Suppl 1:S13-S18. 38. Yuen MF, et al. J Antimicrob Chemother 2003;51(3):481-5. 39. Anonymous. The Ayurvedic Pharmacopoeia of India. Part-I. Vol III. Ministry of Health & FW. Govt of India. Department of ISM & H. Govt of India. New Delhi, p.29-131. 40. Khare CP. Indian Medical Plants: An illustrative dictionary. Springer 2007:p.195-6. 41. Jigna P, et al. African J Biomed Res 2006;9:89-93. 42. Kar P, et al. Antiviral Res 2009;84(3):249-53. 43. Nagulendran KR, et al. E-Journal of Chemistry 2007;4(3):440-9.

9. Coopstead, Lee-Ellen C. Pathophysiology. Saunders: Missouri 2010:p.886-7.

44. Gilani AU, et al. Gen Pharmacol 1995;26(3):627-31.

10. Lok AS. N Engl J Med 2002;346(22):1682-3.

45. Rai MG, et al. Gastroenterology Today 2006;X(4):156-9.

11. Gust ID. Gut 1996;38(Suppl 2):S18-23.

46. Rajkumar JS, et al. World J Gastroenterol 2007;13(30):4103-7.

12. Chen CJ, et al. J Gastroenterol Hepatol 2000;15 Suppl:E3-6.

47. Bhattacharya AK, et al. J Herb Med Toxicol 2009;3(2):137-41.

13. World Health Organization, Hepatitis B, Fact sheet No. 204. Available at: http://www.who.int/mediacentre/ factsheets/fs204/en/

48. Jeevan M, et al. J Pharm Res 2012;5(8):4348-52. 49. Varma SR, et al. Hepat Res Treat 2013;2013:125398.

14. Sleisenger MH, et al. In: Fordtranâ&#x20AC;&#x2122;s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 8th edition, Saunders: Philadelphia 2006.

51. Janardan S, et al. Indian J Clin Pract 2006;17(5):39-43.

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50. Arun Kumar M, et al. Indian J Clin Pract 2010;21(5):247-51. 52. Kulkarni KS, et al. Med Update 2002;7:61-3.


Internal Medicine

Probiotics: The Friendly Microbes Manoj Goyal*, Monika Bansal**, Shailesh Yadav†, kriti Malhotra‡

Abstract We tend to think of bacteria as harmful ‘germs’, but, many bacteria actually help the body functions work properly. These bacteria are known as probiotics. The scientific evidence of beneficial effects of probiotics in health and disease is growing. This article highlights various such beneficial and potentially beneficial effects of probiotics.

Keywords: Bacteria, beneficial effects, Lactobacillus, Bifidobacterium

A

lthough we tend to think of bacteria as harmful ‘germs’, many bacteria actually help the body functions work properly. The belief that the bacteria can influence health, has increased the demand for new knowledge in the art and science of medicine. One such novel strategy, which gained interest over recent years is ‘probiotics’. Probiotics are live microorganisms (e.g. bacteria) that are either the same as or similar to microorganisms found naturally in the human body and may be beneficial to health.1 The term was first used by Lilly and Stillwell in 1965 to describe “substances secreted by one microorganism, which stimulates the growth of another” and thus was contrasted with the term antibiotic.2 The first recorded probiotic was ‘fermented milk’ and its role in human diet was known even in Vedic times. But, the scientific interest in this area boosted after the publication of the book entitled ‘The Prolongation of Life’ by Elie Metchnikoff in 1908. He suggested that people should consume fermented milk containing lactobacilli to prolong their lives. Accelerated aging is because of autointoxication (chronic toxemia), which is due to the toxins produced by gut microflora. Bulgarian peasants who were subjected to experiments on longevity had consumed large quantities of sour milk. The pathological reaction might be removed and life expectancy could

*Associate Professor, Dept. of Pharmacology **Assistant Professor, Dept. of Physiology †Professor ‡Junior Resident Dept. of Pharmacology Maharishi Markandeshwar Institute of Medical Sciences and Research Mullana, Ambala, Haryana Address for correspondence Dr Manoj Goyal E-mail: dr_manojgoyal@yahoo.co.in

be enhanced by implanting lactic acid bacteria from Bulgarian yogurt. Since then, researchers started investigations relating to the role of lactic acid bacteria in human and animal health and the term ‘probiotics’ - meaning ‘for life’; eventually came into use.3 After 1965, the definition of probiotics was revised, in the year 2001, by the Food and Agriculture Organization (FAO) and the World Health Organization (WHO), as “live microorganisms which when administered in adequate amounts confer health benefits on the host”. Gradually, as the body of evidence of probiotic effectiveness accumulated, new features to the definition were appended broadening their implications. Probiotics can be bacteria, moulds or yeast. But most probiotics are bacteria.4 Commonly, most of the species ascribed as having probiotic properties belong to the genera Lactobacillus and Bifidobacterium. Among bacteria, lactic acid bacteria are more popular. Lactobacillus acidophilus, L. casei, L. lactis, L. helveticus, L. salivarius, L. plantarum, L. bulgaricus, L. rhamnosus, L. johnsonii, L. reuteri, L. fermentum, L. delbrueckii, Streptococcus thermophilus, Enterococcus faecium, E. faecalis, Bifidobacterium bifidum, B. breve, B. longum are commonly used bacterial probiotics. Saccharomyces boulardii is a yeast that was isolated from litchi fruit in Indonesia, which too had probiotic properties.5 These bacteria are ‘generally regarded as safe’ (GRAS) because they can reside in the human body causing no harm. On the other hand, they are key microorganisms in milk fermentation and food preservation and are used as dietary supplements and in yogurts from the dawn of mankind.4 Recently, there has been an explosion of consumer interest in the active role of functional food such as ‘probiotics’ - food considered

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Internal Medicine in the well-being and life prolongation, as well as in the prevention of initiation, promotion and development of non-transmissible chronic diseases. Nowadays other than just in food supplements, probiotics are also available to consumers as other products such as ‘probiotic suppositories and creams’.6 Criteria for microorganisms to be included in the probiotic group are: ÂÂ

Survival on passing through gastrointestinal tract at low pH and in contact with bile

ÂÂ

Adhesion to intestinal epithelial cells

ÂÂ

Stabilization of the intestinal microflora

ÂÂ

Nonpathogenicity

ÂÂ

Survival in foodstuff and possibly for production of lyophilized preparations

ÂÂ

Fast multiplication, with either permanent or temporary colonization of the gastrointestinal tract

ÂÂ

Another term prebiotic was introduced by Gibson and Roberfroid who exchanged ‘pro’ for ‘pre’, which means ‘before’ or ‘for’. They defined prebiotics as “a nondigestible food ingredient that beneficially affects the host by selectively stimulating the growth and/ or activity of one or a limited number of bacteria in the colon”.2 When prebiotics are found to be effective, the purpose they serve is that of a catalyst to promote the growth of the host’s indigenous colonies of helpful bacteria. A simple way to remember this is, that a prebiotic prepares the way for a probiotic. Prebiotics do not act in isolation, they do not introduce new bacteria, and they typically do not contain an entire culture of bacteria. For a food ingredient to be classified as a prebiotic, it must: ÂÂ

Neither be hydrolyzed nor absorbed in the upper part of the gastrointestinal tract

ÂÂ

Be a selective substrate for one or a limited number of potentially beneficial commensal bacteria in the colon, thus stimulating the bacteria to grow, become metabolically activated or both

ÂÂ

Be able as a consequence to alter the colonic microflora toward a healthier composition.9

Generic specificity of probiotics.5

Just because it says ‘probiotic’, doesn’t mean it is a probiotic. Probiotics are measured in ‘CFU’. CFU stands for colony forming unit, which is the measure of live microbes in a probiotic. CFU amount should be the same as that shown to be effective in clinical studies. More CFUs does not necessarily mean better. Different probiotics have been shown to be effective at different levels. It is not possible to provide one count for all ‘probiotics’. Scientific literature has documented health benefits for products ranging from 50 millions to >1 trillion CFU/day.7 Mechanisms of probiotic action Several mechanisms have been suggested to contribute to the probiotic action. Probiotics improve colonization resistance to gut pathogens by reinforcing the mucosal barrier and restoring normal gut microecology after diarrhea. If the intestinal microflora is deficient, antigen transport is increased. Probiotics have been shown to normalize an increased permeability. Binding is considered to be the first step in pathogenesis, and binding of bacteria to the intestinal mucosa or mucus may allow the colonization. Probiotics compete with pathogens for binding sites and available substrates. However, adhesion to the intestinal mucosa is considered important for the beneficial health effect. Probiotics also seem to diminish the rate of progression from inflammation through dysplasia to colon cancer in experimental animals.8

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Modification by prebiotics of the composition of the colonic microflora leads to the predominance of a few of the potentially health-promoting bacteria, especially, but not exclusively, lactobacilli and bifidobacteria. The only prebiotics for which sufficient data have been generated to allow an evaluation of their possible classification as functional food ingredients are the inulin-type fructans, which include native inulin, enzymatically hydrolyzed inulin or oligofructose and synthetic fructo-oligosaccharides. Inulin-type fructans are used as sugar substitutes, as fat replacers (inulin only), and as a means of providing texture, stabilizing foam or improving mouth feel in miscellaneous products such as fermented dairy products; desserts such as jellies and ice creams; bakery products such as cookies, breads and pastries; spreads and infant formulas. In a recent consensus paper, inulin-type fructans were classified as nondigestible oligosaccharides.10 Fructooligosaccharides are the only products presently recognized and used as food ingredients that meet these criteria to be said as a prebiotic. Experimental evidence suggests that certain other carbohydrate based components such as transgalactosylated disaccharides and soybean oligosaccharides may also fit in mentioned


Internal Medicine classification. At present, most searches for prebiotics are directed towards the growth of lactic acid producing microorganisms.9 Prebiotics are predominantly a type of dietary fiber that help probiotics to grow and thrive in the digestive tract. Onions, garlic, spinach, apples, banana, berries, beans, oats are a few of the examples that provide prebiotics.11 Synbiotic The term synbiotic is used when a product contains both probiotics and prebiotics. Because the word alludes to synergism, this term should be reserved for products in which the prebiotic compound selectively favors the probiotic compound. In this strict sense, a product containing oligofructose and probiotic bifidobacteria would fulfil the definition, whereas a product containing oligofructose and a probiotic L. casei strain would not. However, one might argue that synergism is attained in vivo by ingestion of lactobacilli on the one hand and promotion of indigenous bifidobacteria on the other hand.2 Evidence of Probiotic Effectiveness The comprehensive review of the literature by the expert panel of FAO and WHO demonstrated a number of areas in which probiotics have proven their antidisease effects. Following are the various examples.12

Oral Health The interest in oral probiotics has been growing during the last decades. Some of the probiotic bacteria used in various probiotic products may colonize the oral cavity during the time they are in use; thus, the effects of probiotic bacteria in the oral cavity are important to understand.13 Molecular analyses of the oral microbiota in preschool children have shown that Streptococcus mutans is significantly associated with early childhood dental caries. Several studies suggest that consumption of products containing probiotic lactobacilli or bifidobacteria could reduce the number of Mutans Streptococci in saliva responsible for dental caries. Mutans streptococci are gram-positive bacteria commonly found in the oral cavity of humans and are the most cariogenic for the tooth enamel. It promotes the sticking of bacteria to tooth enamel forming a plaque biofilm and contributes to cariogenicity. The beneficial effects of use of these ‘live organisms’ cannot be limited to caries but may be extended to in the use of periodontal diseases, oral candidiasis and in halitosis

as well. Potential mechanism by which probiotic bacteria affects oral health is by competing for adhesion sites and enhancing clearance of the pathogenic bacteria. They also produce antimicrobial compounds including acids and check the growth of offending organisms. They also have an influence on the local and systemic immune responses by enhancing the production of salivary immunoglobulin A (IgA), defensins and proinflammatory cytokines. All these actions play an antagonistic role against pathogenic bacteria and finally reduce inflammation and tissue destruction.14

Diarrhea There is a recent resurgence of interest in probiotics due to consumer demand for better therapies and problems like drug resistance and opportunistic infections due to inadvertent use of antimicrobial therapy. Diarrhea is a common gastrointestinal problem especially in the developing world. Decrease in shortchain fatty acid important for absorption of water and electrolytes, loss of carbohydrate digesting gut bacteria leading to osmotic diarrhea or use of drugs such as erythromycin (motilin agonist), which is a direct stimulator of gut motility, are all responsible for the pathogenesis of preventable diarrhea. The problem of infectious diarrheas can be best addressed by improving sanitation and nutrition, but an inexpensive and effective probiotic are shown to reduce the incidence of diarrheal episodes when used as adjunct to oral rehydration therapy.15 The pathogen, Helicobacter pylori is responsible for type B gastritis and peptic ulcers. There is some in vitro and animal data to indicate that lactic acid bacteria can inhibit the pathogen’s growth and decrease the urease enzyme activity necessary for it to survive in the acidic environment of the stomach. In humans, there is also evidence that probiotic strains can suppress infection and lower the risk of recurrences. Similar benefits of probiotics are seen to be associated with inflammatory disease and bowel syndromes (Crohn’s disease and ulcerative colitis, polyps, diverticulosis, diverticulitis, etc.) Diarrheas in newborn and children Intestinal infections in newborn children are common, and in developing countries diarrhea is a prime cause of morbidity and mortality. Necrotizing enterocolitis is a devastating intestinal disorder, which is characterized by an inflammatory cascade with septic shock and intestinal necrosis. Bacterial colonization or infection of the intestine by pathogens such as Clostridium, Escherichia, Klebsiella, Salmonella,

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Internal Medicine Shigella, Campylobacter, Pseudomonas, Streptococcus, Enterococcus, Staphylococcus aureus and coagulasenegative staphylococci increases the risk of necrotizing enterocolitis. If nonpathogens, such as lactobacilli and bifidobacteria, colonize the intestine or if breast milk rather than formula is used, the incidence of necrotizing enterocolitis has been reported to decrease. Several potential mechanisms have been proposed for how lactobacilli reduce the duration of rotavirus diarrhea. One is competitive blockage of receptor sites in which lactobacilli bind to receptors, thereby preventing adhesion and invasion of the virus. The second potential mechanism may be the enhanced immune response by lactobacilli, by inducing local IgA antibodies against the virus. Alternatively, stimulation of T cells to produce g-interferon, leading to potential inhibition of chloride secretion, might also inhibit diarrhea. A final theory is that lactobacilli produce substances that inactivate the viral particles. This has been shown in vitro. Whether or not the viral killing activity can inhibit diarrhea remains to be determined.12 The mechanism of action of these probiotics as antidiarrheal more or less remains the same in all types of diarrheas on a broad aspect.

Lactose Intolerance Probiotic strains are also beneficial in the lactose intolerance, a physiological state in human beings where they lack the ability to produce an enzyme named lactase or β-glycosidase, which is essential to assimilate the disaccharide present in milk and needs to be split into glucose and galactose. Individuals lacking lactase will not be able to digest milk and it often poses a problem in newborn infants. The resident bacteria in the colon ferment undigested lactose, producing acid and gas, causing symptoms such as abdominal pain, bloating and diarrhea. Yogurt contains less lactose than milk and delays gastric emptying, which partly explains why lactose-intolerant individuals tolerate yogurt. However, yogurt tolerance is mainly due to the supply of lactase activity from the lactic acid bacteria present in the yogurt itself. Evidence shows that bacteria must be live and present in sufficient quantity to be of benefit. Yogurts containing 108 bacteria/ml are required to produce beneficial effects. Another problem associated with lactose intolerance is calcium deficiency. A person consuming non-milk diet will naturally develop calcium deficiency, leading to osteoporosis. Birge et al confirmed that lactose deficiency leads to calcium malabsorption and thereby to osteoporosis. Calcium absorption is better and more in acidic conditions; hence, if lactose is converted to lactic acid, pH of the

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gut decreases, i.e. it becomes acidic favoring enhanced absorption of calcium. So, if probiotics are fed to lactose intolerance patients, then milk lactose is hydrolyzed by probiotic strains and lactose is assimilated and calcium absorption is also favored.3

Cholesterol Assimilation Probiotic strains, especially lactic acid bacteria have a major role to play in the cholesterol lowering mechanism. The cholesterol levels can be brought down using probiotics. The mechanisms can be direct or indirect. Direct mechanism is by either inhibiting the de novo synthesis or decreasing the intestinal absorption of dietary cholesterol. The dietary cholesterol absorption is reduced by three ways - assimilation, binding or by degradation. Probiotic strains assimilate the cholesterol for their own metabolism. Probiotic strains can bind to the cholesterol molecule, and they are capable of degrading cholesterol to its catabolic products. The cholesterol level can be reduced indirectly by deconjugating the cholesterol to bile acids, thereby reducing the total body pool. Deconjugation by different lactic acid bacterial cultures was also tried using two forms of bile salts, viz. taurocholates and glycocholates. Though, the results were nonsignificant, there was a drastic reduction in serum cholesterol of fermented milk-fed rats, indicating that cholesterol levels in serum can be reduced by consumption of probiotics.5

Allergy A change in the proper functioning of the immune system can present itself as an allergy. Large-scale studies have indicated an alteration in the composition of the gut microflora, such as decrease in the numbers of lactobacilli, preceding the development of an allergy. Probiotics have also been shown to reduce the incidence of childhood eczema. A follow-up study demonstrated a two-fold increase in transforming growth factor β2, an anti-inflammatory cytokine, in the breast milk of mothers receiving probiotics compared to placebo. Probiotics may exert a beneficial effect on allergic reaction by improving mucosal barrier function. In addition, probiotics consumption by young children may beneficially affect immune system development. Probiotics such as Lactobacillus GG may be helpful in alleviating some of the symptoms of food allergies such as those associated with milk protein. Probiotics consumption may thus be a means for primary prevention of allergy in susceptible individuals.


Internal Medicine This could play a key role in minimizing allergy at a time when the prevalence of allergic disease in Western societies has increased dramatically over the past 40 years.

Anticancer Effects The anticancer benefits of fermented foods were regarded as folklore, with no scientific backing. But, now there is a strong attestation to the importance of Lactobacilli in human nutrition and health, as well as the inter-relationship between many dietary factors and cancer. Diets high in animal protein and fat appear to increase the susceptibility to colon cancer, apparently through conversion of pro-carcinogens to carcinogens by the intestinal microflora. Fats and fried foods also have been implicated in cancers of breast, prostate and pancreas. There is some evidence that probiotics can interfere at various stages of the cancer process. The changes in gut bacterial enzymes that generate carcinogens and tumor promoters such as ammonia (NH3) and secondary bile acids, stimulation of immune surveillance, suppression of inflammatory processes, binding of carcinogens in the gut will have various levels of scientific support.3

Other Effects It is believed that most probiotics do not permanently adhere in the intestine, but exert their effects as they metabolize and grow during their passage through the intestine (colonization). Thus, daily consumption of these bacteria is probably the best way to maintain their effectiveness. Other beneficial effects which these wonder live microorganisms produce are reduction of blood pressure in hypertensives, synthesize nutrients (folic acid, niacin, riboflavin, vitamins B6 and B12). Increase nutrient bioavailability, improve urogenital health and optimize effects of vaccines (e.g. rotavirus vaccine, typhoid fever vaccine).16 Future Implications Modern consumers are increasingly interested in their personal health, and expect the food that they eat to be healthy or even capable of preventing illness. Producers and marketers of cultured milks are making every effort to keep them growing through product development and packaging innovations while delivering a â&#x20AC;&#x2DC;good for youâ&#x20AC;&#x2122; flavorful products suited for all occasions of gastronomic indulgence. Over the past century, voluminous scientific knowledge has been well-established regarding the technological aspects of fermented milks, including the physiology of starter cultures and related probiotic microflora.

There is considerable potential for the benefits of probiotics consumption over a wide range of clinical conditions. Ongoing research will continue to identify and characterize existing strains of probiotics, identify strain-specific outcomes and determine optimal doses needed for certain results. Conclusion Probiotics seem to have quite a number of beneficial effects in the different organ systems of the body. The full potential of probiotics can only be realized when their benefits can be established scientifically. It is highly likely that benefits from current and future probiotics have gone undetected and, therefore, full utilization of these organisms has not been achieved. At best, the intestinal health is greatly improved and the immune system is strengthened. At worst, there are no adverse effects and you get some nutrients in the bargain. With the current focus on disease prevention and the quest for optimal health at all ages, the probiotic market potential is enormous. Health professionals are in an ideal position to help guide their clients toward appropriate prophylactic and therapeutic uses of probiotics that deliver the desired beneficial health effects. References 1. Oral probiotics: An introduction. Get the facts. National Centre for Complementary and Alternative Medicine. Retrieved from http://nccam.nih.gov/health/probiotics/ introduction.htm. 2. Schrezenmeir J, de Vrese M. Probiotics, prebiotics, and synbiotics - approaching a definition. Am J Clin Nutr 2001;73(2 Suppl):361S-364S. 3. Suvarna VC, Boby VU. Probiotics in human health: a current assessment. Curr Sci 2005;88(11):1744-8. 4. Stamatova I, Meurman JH. Probiotics: health benefits in the mouth. Am J Dent 2009;22(6):329-38. 5. Tomasik PJ, Tomasik P. Probiotics and prebiotics - review. 2003;80(2):113-7. 6. Granato D, Branco GF, Nazzaro F, Cruz AG, Faria JA. Functional foods and nondairy probiotic food development: trends, concepts, and products. Comprehensive Reviews in Food Science and Food Safety 2010;9:292-302. 7. Probiotics: A Consumer Guide for Making Smart Choices. Developed by the International Scientific Association for Probiotics and Prebiotics. March 11, 2009. Retrieved from (www.isapp.net). 8. Meurman JH. Probiotics: do they have a role in oral medicine and dentistry? Eur J Oral Sci 2005;113(3):188-96.

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Internal Medicine 9. Khurana HK, Kanawjia SK. Recent trends in development of fermented milks. Curr Nutr Food Sci 2007;3(1):91-108.

13. Haukioja A. Probiotics and oral health. Eur J Dent 2010;4(3):348-55.

10. Roberfroid MB. Prebiotics and probiotics: are they functional foods? Am J Clin Nutr 2000;71(6 Suppl): 1682S-7S; discussion 1688S-90S.

14. Hasslöf P, Hedberg M, Twetman S, Stecksén-Blicks C. Growth inhibition of oral mutans streptococci and candida by commercial probiotic lactobacilli - a in vitro study. BMC Oral Health 2010;10:18.

11. The Excell Express. Saturday Nov. 26, 2011. Jammu. Empower your palate with probiotics. Health and Entertainment. Pg.4. (col. 3).

15. Sharma AK, Mohan P, Nayak BB. Probiotics: making a comeback. Indian J Pharmacol 2005;37(8):358-65.

12. Reid G, Jass J, Sebulsky MT, McCormick JK. Potential uses of probiotics in clinical practice. Clin Microbiol Rev 2003;16(4):658-72.

16. Probiotics – Friendly bacteria with a host of benefits. Dairy Council of California. 2000. Available from: www. dairycouncilofca.org.

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Medical Interns Spend Very Little Time at Patient Bedsides Medical interns spend only 12% of their time examining and talking with patients, and more than 40% of their time on computer tasks, according to a time-motion study published online April 18 in the Journal of General Internal Medicine. (Source: Medscape)

Better Heart Health brings Lower Stroke Risk Meeting American Heart Association/American Stroke Association criteria for at least average cardiovascular health may lower the risk of stroke, researchers found. (Source: Medpage Today)

JCV Test ‘Useful but not Sufficient’ to Gauge PML Risk A new report raises questions about the reliability of the test for JC virus (Stratify, Biogen Idec) to help determine risk for progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) treated with natalizumab (Tysabri, Biogen Idec). (Source: Medscape)

Tumor Features Predict Colon Blockage The likelihood of bowel obstruction among older patients with stage IV colon cancer depended on the site, grade, and histology of the tumor, a large retrospective analysis found. (Source: Medpage Today)

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Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013


Neurology

False Localizing Signs in Neurology Jobin v joseph

Abstract False localizing neurological signs reflect dysfunction distant from the site of the pathology. They pose considerable difficulties to the treating neurologist as they are unreliable when attempting to localize the lesion, which challenges the traditional clinicoanatomical correlation. It is important to be aware of false localizing signs and the situations in which they occur as they may be indicative of a serious, even life-threatening, pathology for appropriate and timely investigations and management.

Keywords: False localizing signs, raised ICP, intracranial pathology

N

eurological signs have been described as â&#x20AC;&#x2DC;false localizingâ&#x20AC;&#x2122; if they reflect dysfunction distant or remote from the expected anatomical locus of pathology and hence challenging the traditional clinicoanatomical correlation paradigm on which neurological examination is based.1

History The notion false localizing signs was first elucidated by James Collier in 1904 on the basis of clinical examination during life and subsequent postmortem studies.2 Gassel noted false localizing signs to be more common in patients with raised intracranial pressure (ICP).3 Structural imaging, particularly magnetic resonance imaging (MRI), which gives an opportunity to study pathological anatomy contemporaneous with clinical examination, has provided some new insight into the causes of these signs. Pathogenesis The pathogenesis of false localizing signs remain uncertain. False localizing signs occur in two contexts: As a consequence of raised ICP, which is symptomatic of intracranial pathology (tumor, hematoma, abscess)

or idiopathic (idiopathic intracranial hypertension [IIH]) and with spinal cord lesions. Associated lesions may be intra- or extraparenchymal. The course of the associated disease may be acute (cerebral hemorrhage) or chronic (IIH, tumor). Disturbance of higher mental functions, cranial nerve palsies, hemiparesis, sensory features and muscular atrophy, may all occur as false localizing signs. False localizing signs

Cortical Functions Signs traditionally thought to be of cortical origin, such as aphasia and inattention, may some times occur with exclusively subcortical pathology; conversely exclusively cortical lesions may results in dysarthria. Hemineglect is much commoner with right rather than left parietal lobe lesions. False localizing ipsilateral hemineglect has been reported in patients with posterior fossa tumors like meningioma causing left pontine compression, despite normal imaging of cerebral hemispheres.

Cranial Nerves Oculomotor Nerve

Assistant Professor Dept. of Medicine SSIMS&RC, Davangere, Karnataka Address for correspondence Dr Jobin V Joseph Assistant Professor, Vallipparambil (h) Dep. of General Medicine Manjoor, SSIMS&RC, Bypass Road, Kottayam Davangere 4, Kerala - 686 603 E-mail: drjobinvj@yahoo.com

Unilateral fixed dilated pupil (Hutchinsonâ&#x20AC;&#x2122;s pupil) may occur with an ipsilateral lesion such as an intracerebral hemorrhage, due to transtentorial herniation of the brain compressing the oculomotor nerve against the free edge of the tentorium. Because of the fascicular organization of the fibers within the oculomotor nerve, the externally placed pupillomotor fibers are most vulnerable. Very occasionally, fixed pupil may occur contralateral, and hence false localizing, to cranial

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Neurology pathology.4 The exact mechanism for this clinical observation is not known. The mechanism for this third nerve palsy has traditionally been ascribed to extrinsic compression of the third nerve on the margin of the tentorium. An alternative explanation, possibly relevant to false localizing third nerve palsy, is that raised ICP causes kinking of the nerve over the clivus, just posterior to the clinoid.17 Another suggestion is that a central mechanism might be responsible, supratentorial pressure causing the brainstem to buckle as it descends because of caudal tethering of the neuraxis at the first dentate ligament (“dynamic axial brainstem distortion”). Divisional third nerve palsy is usually associated with lesions at the superior orbital fissure or anterior cavernous sinus, where the superior division of the oculomotor nerve passes to the superior rectus and levator palpabrae, and the inferior division to the medial and inferior recti and inferior oblique muscles. Divisional third nerve palsies may sometimes occur with more proximal lesions, presumably as a consequence of the topographic arrangement of the fascicles within the nerve, for example with intrinsic brainstem disease (e.g. stroke)5 or with pathology in the subarachnoid space where the nerve rootlets emerge from the brainstem (e.g. malignant infiltration).6 Trochlear Nerve False localizing fourth nerve palsies, causing diplopia on downward and inward gaze, have occasionally been described in the context of IIH.7,8 Trochlear nerve palsy might be overlooked in cases in which other cranial nerves are affected (sixth, third) because the signs are subtle. Trigeminal Nerve Trigeminal nerve hypofunction (trigeminal sensory neuropathy) or hyperfunction (trigeminal neuralgia) may on occasion be false-localizing, for example in association with IIH9 or with contralateral pathology, often a tumor.10 For example, trigeminal neuralgia has been associated with a contralateral chronic calcified subdural hematoma, which caused rotational displacement of the pons, with resolution after removal of the hematoma.11 This dysfunction may be hypoactive or hyperactive, manifesting with negative or positive Jacksonian symptoms, respectively; hence there may be trigeminal neuropathy2,12–14 or trigeminal neuralgia,15,16 Gassel found motor involvement in only two of eight patients with false localizing fifth nerve involvement.3

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Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

Arsava et al reported both clinical and electrophysiological evidence of left trigeminal neuropathy in a patient with IIH: Examining the blink reflex, no response was elicited either ipsi- or contralaterally when stimulating the left supraorbital nerve, and although trigeminal motor function was clinically intact, no response was elicited from the left masseter muscle when measuring the latency of the jaw reflex.9 As with the idiopathic condition, there has been debate about the pathophysiology of trigeminal neuralgia associated with contralateral tumors. Some favor vascular compression of the nerve root as the proximate cause of paroxysmal ephaptic transmission,15 whereas others implicate angulations and distortion of the nerve root entry/exit zone as a consequence of displacement of brain tissue caused by an expanding mass lesion in the posterior fossa.10,16 In favour of the latter explanation, two cases have been reported in which trigeminal neuropathy was ‘converted’ to trigeminal neuralgia (hence, a lesser degree of dysfunction) following removal of a contralateral posterior fossa tumor.10,16 However, other cases have been presented in which trigeminal neuralgia did not resolve after tumor removal alone.16 Matsuura and Kondo implicate adherence of arachnoid membrane to the nerve as a contributing factor and advocate its resection in order to straighten the nerve axis.10 Abducens Nerve Sixth nerve palsies are the most common false-localizing sign of raised ICP. In one series of 101 cases of IIH, 14 cases were noted, 11 unilateral and three bilateral.17 Stretching of the nerve in its long intracranial course or compression against the petrous ligament or ridge of the petrous temporal bone have been suggested as the mechanism for false-localizing sixth nerve palsy.18 Facial Nerve Lower motor neurone type facial weakness has been described in the context of IIH,19 sometimes occurring bilaterally to cause facial diplegia,20 usually with concurrent sixth nerve palsy or palsies. Hemifacial spasm has rarely been described with contralateral posterior fossa lesions.10 Vestibulo Cochlear Nerve Hearing loss has on occasion been reported as a complication of IIH.21 Multiple Lower Cranial Nerve involvement Concurrent false-localizing involvement of multiple cranial nerves has been noted on occasion, for


Neurology example, trigeminal, abducens and facial nerves with a contralateral acoustic neuroma,14 and trigeminal, glossopharyngeal and vagus nerves with a contralateral laterally-placed posterior fossa meningioma.12

mimic Guillain-Barré syndrome (flaccid-areflexic quadriplegia).30 The postulated mechanism for such radiculopathy is mechanical root compression due to elevated cerebrospinal fluid (CSF) pressure.

Motor System

Cerebellar Syndrome

Kernohan’s Notch Syndrome: False-localizing Hemiparesis A supratentorial lesion, such as acute subdural hematoma, may cause transtentorial herniation of the temporal lobe, with compression of the ipsilateral cerebral peduncle against the tentorial edge; since this is above the pyramidal decussation, a contralateral hemiparesis results. Occasionally, however, the hemiparesis may be ipsilateral to the lesion, and hence false-localizing; this occurs when the contralateral cerebral peduncle is compressed by the free edge of the tentorium. This is the Kernohan-Woltman notch phenomenon, or Kernohan’s notch syndrome.22 There may be concurrent homolateral third nerve palsy, ipsilateral to the causative lesion.23 Brainstem Compression: False-localizing Diaphragm Paralysis

Frontocerebellar pathway damage, for example, as a result of infarction in the territory of the anterior cerebral artery, may result in incoordination of the contralateral limbs, mimicking cerebellar dysfunction. Suboccipital exploration to search for cerebellar tumors based on these clinical findings was known to occur before the advent of brain imaging.31 Pseudo-internuclear Ophthalmoplegia To describe internuclear ophthalmoplegia, usually indicative of medial longitudinal fasciculus dysfunction, in patients with myasthenia gravis;32 this ‘pseudointernuclear ophthalmoplegia’ has also been observed in dermatomyositis. Pseudoathetosis

Hemidiaphragmatic paralysis with ipsilateral brainstem (medullary) compression by an aberrant vertebral artery has been described, in the absence of pathology localized to the C3-C5 segments of the spinal cord where phrenic motor neurones originate, hence it a false-localizing sign.24

Pseudoathetosis or abnormal writhing movements, usually of the fingers, caused by a failure of joint position sense (propioception). They indicate disruption of the proprioceptive pathway, from peripheral nerve to parietal cortex. It may be mistaken for choreoathetosis. However, these abnormal movements are relatively constant irrespective of whether the eyes are open or closed and occur in the absence of propioceptive loss.

Foramen Magnum/Upper Cervical Cord

Pseudosyringomyelia

Paresthesia in the hands with intrinsic hand muscle wasting and distal upper limb areflexia, with or without long tract signs, suggestive of a lower cervical myelopathy may occur with lesions at the foramen magnum or upper cervical cord (‘remote atrophy’).25

Pseudosyringomyelia” has been used to describe a selective loss of pain and temperature sensation with relative preservation of vibration and position sense seen in amyloid polyneuropathy and Tangier disease, (a small fibre sensory neuropathy), in the absence of any spinal cord pathology, and hence false localizing.

Lower Cervical/Upper Thoracic Cord Compressive lower cervical or upper thoracic myelopathy may produce spastic paraplegia with a mid-thoracic sensory level (or ‘girdle sensation’).26,27 For example, in one case a spastic paraplegia with a sensory level at T10 was associated with cervical compression from a herniated disc at C5/C6.28

Discussion

Radiculopathy

For the practicing neurologist, an awareness of the possibility of false localizing signs, and knowledge of the situations in which they are most likely to occur, is necessary to heighten the index of clinical suspicion, so that the possible pathological import of false localizing signs is not missed. The pathophysiology of many false

False-localizing radiculopathy may occur in the context of IIH and cerebral venous sinus thrombosis, manifesting as acral paresthesias, backache and radicular pain, and less often with motor deficits,29 which on occasion may be sufficiently extensive to

False localizing neurological signs have presented significant challenges to clinical neurologists. In the era before neuroimaging, operations were sometimes performed on, and treatments administered to, the wrong side based on these signs.2

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Neurology localizing signs is still poorly, if at all, understood.4,33 The preponderant association with extrinsic mass lesions, such as intracranial tumors (especially meningioma), subdural hematoma, and intervertebral disc prolapse, has long been noted, although intrinsic lesions may certainly be responsible on occasion.10,14 Some of these pathologies exert their effects acutely, whereas for others (for example, meningiomas) it is their slow growth which is implicated. The possibility of multifactorial pathophysiology therefore seems likely. Most importantly, since false localizing signs may be indicative of serious, even life threatening, pathology within neural pathways, awareness of them and the situations in which they occur, will facilitate appropriate and timely investigation and management. References 1. Larner AJ. A dictionary of neurological signs: Clinical Neurosemiology. Kluwer Academic Publishers, October 2001. 2. Collier J. The false localising signs of intracranial tumour. Brain1904;27(4):490â&#x20AC;&#x201C;508. 3. Gassel MM. False localizing signs. A review of the concept and analysis of the occurrence in 250 cases of intracranial meningioma. Arch Neurol 1961;4:526-54. 4. Marshman LA, Polkey CE, Penney CC. Unilateral fixed dilation of the pupil as a false-localizing sign with intracranial hemorrhage: case report and literature review. Neurosurgery 2001;49(5):1251-5; discussion 1255-6. 5. Ksiazek SM, Repka MX, Maguire A, Harbour RC, Savino PJ, Miller NR, et al. Divisional oculomotor nerve paresis caused by intrinsic brainstem disease. Ann Neurol 1989; 26(6):714-8.

11. Kondoh T, Tamaki N, Takeda N, Shirataki K, Mastumoto S. Contralateral trigeminal neuralgia as a false localizing sign in calcified chronic subdural hematoma: a case report. Surg Neurol 1989;32(6):471-5. 12. Maurice-Williams RS. Multiple crossed false localizing signs in a posterior fossa tumour. J Neurol Neurosurg Psychiatry 1975;38(12):1232-4. 13. Davenport RJ, Will RG, Galloway PJ. Isolated intracranial hypertension presenting with trigeminal neuropathy. J Neurol Neurosurg Psychiatry 1994;57(3):381. 14. Ro LS, Chen ST, Tang LM, Wei KC. Concurrent trigeminal, abducens, and facial nerve palsies presenting as false localizing signs: case report. Neurosurgery 1995;37(2):3224; discussion 324-5. 15. Michelucci R, Tassinari CA, Plasmati R, Rubboli G, Forti A, Tognetti F, et al. Trigeminal neuralgia associated with contralateral intracranial tumour: a false localising sign caused by vascular compression? Report of two cases. J Neurol Neurosurg Psychiatry 1989;52(10):1202-3. 16. Grigoryan YA, Onopchenko CV. Persistent trigeminal neuralgia after removal of contralateral posterior cranial fossa tumor. Report of two cases. Surg Neurol 1999;52(1):56-60; discussion 60-1. 17. Round R, Keane JR. The minor symptoms of increased intracranial pressure: 101 patients with benign intracranial hypertension. Neurology 1988;38(9):1461-4. 18. Larner AJ. False localising signs. J Neurol Neurosurg Psychiatry 2003;74(4):415-8. 19. Davie C, Kennedy P, Katifi HA. Seventh nerve palsy as a false localising sign. J Neurol Neurosurg Psychiatry 1992;55(6):510-1. 20. Kiwak KJ, Levine SE. Benign intracranial hypertension and facial diplegia. Arch Neurol 1984;41(7):787-8. 21. Dorman PJ, Campbell MJ, Maw AR. Hearing loss as a false localising sign in raised intracranial pressure. J Neurol Neurosurg Psychiatry 1995;58(4):51.

6. Larner AJ. Proximal superior division oculomotor nerve palsy from metastatic subarachnoid infiltration. J Neurol 2002;249(3):343-4.

22. Kernohan JW, Woltman HW. Incisura of the crus due to contralateral brain tumor. Arch Neurol Psychiatry 1929;21:274-287.

7. Lee AG. Fourth nerve palsy in pseudotumor cerebri. Strabismus 1995;3(2):57-9.

23. Cohen AR, Wilson J. Magnetic resonance imaging of Kernohanâ&#x20AC;&#x2122;s notch. Neurosurgery 1990;27(2):205-7.

8. Speer C, Pearlman J, Phillips PH, Cooney M, Repka MX. Fourth cranial nerve palsy in pediatric patients with pseudotumor cerebri. Am J Ophthalmol 1999;127(2): 236-7.

24. Schulz R, Fegbeutel C, Althoff A, Traupe H, Grimminger F, Seeger W. Central sleep apnoea and unilateral diaphragmatic paralysis associated with vertebral artery compression of the medulla oblongata. J Neurol 2003;250(4):503-5.

9. Arsava EM, Uluc K, Nurlu G, Kansu T. Electrophysiological evidence of trigeminal neuropathy in pseudotumor cerebri. J Neurol 2002;249(11):1601-2. 10. Matsuura N, Kondo A. Trigeminal neuralgia and hemifacial spasm as false localizing signs in patients with a contralateral mass of the posterior cranial fossa. Report of three cases. J Neurosurg 1996;84(6):1067-71.

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25. Sonstein WJ, LaSala PA, Michelsen WJ, Onesti ST. False localizing signs in upper cervical spinal cord compression. Neurosurgery 1996;38(3):445-8; discussion 448-9. 26. Adams KK, Jackson CE, Rauch RA, Hart SF, Kleinguenther RS, Barohn RJ. Cervical myelopathy with false localizing sensory levels. Arch Neurol 1996;53(11):1155-8.


Neurology 27. Ochiai H, Yamakawa Y, Minato S, Nakahara K, Nakano S, Wakisaka S. Clinical features of the localized girdle sensation of mid-trunk (false localizing sign) appeared in cervical compressive myelopathy patients. J Neurol 2002;249(5):549-53. 28. Pego-Reigosa R, Trobajo de las Matas JE, Branas F, Martinez-Vazquez F Cortes-Laino JA. Dorsal sensory level as a false localizing sign in cervical myelopathy. Rev Neurol 1998;27(155):86-8. 29. Moosa A, Joy MA, Kumar A. Extensive radiculopathy: another false localising sign in intracranial hypertension. J Neurol Neurosurg Psychiatry 2004;75(7):1080-1. 30. Obeid T, Awada A, Mousali Y, Nusair M, Muhayawi S,

Memish S. Extensive radiculopathy: a manifestation of intracranial hypertension. Eur J Neurol 2000;7(5):549-53 31. Gado M, Hanaway J, Frank R. Functional anatomy of the cerebral cortex by computed tomography. J Comput Assist Tomogr 1979;3(1):1-19. 32. Bakheit AM, Behan PO, Melville ID. Bilateral internuclear ophthalmoplegia as a false localizing sign. J R Soc Med 1991;84(10):627. 33. Cohen L. Tumors in the region of the foramen magnum. In: Handbook of Clinical Neurology, Volume 17, Tumours of the brain and skull. Part II. Vinken PJ, Bruyn GW (Editors), Amsterdam: North-Holland 1974: p.719-30.

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What Makes People Think and Behave Differently? Clues Provided by Brain Research Differences in the physical connections of the brain are at the root of what make people think and behave differently from one another. Researchers reporting in the Cell Press journal Neuron shed new light on the details of this phenomenon, mapping the exact brain regions where individual differences occur. Their findings reveal that individuals' brain connectivity varies more in areas that relate to integrating information than in areas for initial perception of the world. The researchers discovered that the brain regions devoted to control and attention displayed a greater difference in connectivity across individuals than the regions dedicated to our senses like touch and sight. When they looked at other published studies, the investigators found that brain regions previously shown to relate to individual differences in cognition and behavior overlap with the regions identified in this study to have high variability among individuals. The researchers were therefore able to pinpoint the areas of the brain where variable connectivity causes people to think and behave differently from one another. (Source: Science Daily)

FDA: Alzheimer Drugs must Show Clinical Benefit In a long-awaited draft guidance document, the FDA said it would not accept biomarker or imaging-based outcomes as a primary endpoint in pivotal trials for Alzheimer's disease drugs . The primary efficacy measure for proposed disease-modifying therapies must reflect a benefit in patients' cognition and/or ability to function, the agency indicated. In fact, the FDA would prefer that sponsors of Alzheimer's disease therapies include both types of clinical outcomes in their primary endpoints. "Clinical trials in the dementia stage of AD (Alzheimer's disease) should use a coprimary outcome measure approach in which a drug demonstrates efficacy on both a cognitive and a functional or global assessment scale," the draft guidance said. (Source: MedPage Today)

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Obstetrics and Gynecology

A Study of Hyperinsulinemia and Waist-hip Ratio in Patients with Chronic Anovulation Aruna Verma*, Abhilasha Gupta**, A Sarup†

Abstract Introduction: Anovulation presents a variety of clinical problems like amenorrhea, irregular menses and hirsutism. When anovulation and android obesity are present, hyperinsulinemia may be an underlying disorder in most of cases. Aims and objectives: To study the markers of insulin resistance (IR) in women with chronic anovulation, which are waist-hip ratio (WHR), fasting plasma insulin (FPI) and fasting plasma glucose/fasting plasma insulin (FPG/FPI). Material and methods: The present study was conducted in Dept. of Obstetrics and Gynecology, LLRM Medical College, Meerut from November 2003 to October 2004. Total 37 cases of anovulatory bleeding on the basis of history and clinical examination were included in the study and they were examined for following parameters: Body mass index (BMI) (kg/m2), waist circumference (WC), WHR, FPG/FPI (>4.8 = IR). The tests applied to see the distribution and significance were binomial, Chi-square, Fisher’s exact test. Observations and results: Out of 37 patients with chronic anovulation, 28 (75.5%) had WHR >0.85 (android obesity), 23 (62.2%) had fasting hyperinsulinemia and only 11 (29.11%) patients had IR. All the patients of IR, had android obesity; 90.9% of patients with IR had fasting hyperinsulinemia. Conclusion: There is strong association of android obesity and chronic anovulation and these patients are at risk of type 2 diabetes mellitus.

Keywords: Chronic anovulation, hyperinsulinemia, waist circumference, hip circumference, waist-hip ratio

I

n the present scenario, anovulation is a very common problem. It presents with a variety of clinical manifestation including amenorrhea, irregular menses and hirsutism. Normal ovulation requires coordination of the menstrual system at all levels:

ÂÂ

The central hypothalamopituitary axis

ÂÂ

The feedback signals

ÂÂ

Focal response within ovary.

Obese anovulatory women have a characteristic distribution of body fat known as android obesity, which refers to fat located in the abdominal wall and visceral mesentric location. This fat distribution is associated with hyperinsulinemia, impaired glucose tolerance (IGT), diabetes mellitus and increased androgen production rates, decrease sex hormonebinding globulin (SHBG), increased free testosterone and estradiol levels. Waist-hip ratio (WHR) is a means

*Lecturer **Professor and Head †Ex-Resident Dept. of Obstetrics and Gynecology LLRM Medical College, Meerut, UP Address for correspondence Dr Aruna Verma C/o.: Dr Gyaneshwar Tonk R-18, Campus, LLRM Medical College, Meerut - 250 004 (UP) E-mail: arunatonk@yahoo.co.in

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Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

to estimate the degree of upper and lower abdominal fat, which is increased in android obesity. Since, polycystic ovary syndrome (PCOS) is a state of chronic anovulation, it is reasonable to study the presence of insulin resistance (IR), body mass index (BMI) and WHR in patients with anovulatory dysfunctional uterine bleeding (DUB). AIMS and OBJECTIVES The aims and objectives of the study were to investigate markers of IR in women with chronic anovulation without features of PCOS. The markers studied were: ÂÂ

WHR

ÂÂ

Fasting plasma insulin (FPI) levels

ÂÂ

Ratio of fasting plasma glucose to fasting plasma insulin (FPG:FPI).

MATERIAL and METHODS This study was conducted in the Dept. of Obstetrics and Gynecology, SVBP Hospital, LLRM Medical College, Meerut, for period of one year (November 2003 to October 2004). Thirty-seven outdoor attending patients who were diagnosed as a case of anovulatory bleeding on the basis of history and clinical examination formed the subject of this study.


Obstetrics and Gynecology Inclusion Criteria ÂÂ

Postmenarchal adolescent two years after menarche.

ÂÂ

Perimenopausal women with anovulation as determined by clinical presentation of menstrual dysfunction ranging from irregular cycle to amenorrhea.

Every eugonadotrophic, amenorrhea were included.

nonhyperprolactenemic

Women were examined for the following parameters

ÂÂ

BMI =

Wt. in Kg. Ht. in m2

Table 1. Baseline Data Distribution of Subjects according to Age, BMI, WHR, FPI, IR Characteristics

Frequency

%

15-20

10

27.0

21-25

10

27.0

26-30

12

32.4

31-35

05

13.5

≤27 kg/m2

13

35.1

kg/m2

24

64.9

Normal <0.85

09

24.3

High ≥0.85

28

75.5

BMI (kg/m2) >27

(if >27 = obesity)

P value

Age groups (years)

WHR

ÂÂ

Waist circumference (WC) (if >90 cm = obesity)

ÂÂ

WHR (if >0.85 = android obesity)

ÂÂ

FPG and FPI ratio (if <4.5 = IR)

p = 0.0012 (S)

FPI

zz

WC was the smallest circumference between rib cage and iliac crest.

Normal <0.85

14

37.8

High ≥0.85

23

62.2

zz

Hip circumference was the circumference over the buttocks.

IR (FPG/FPI) Normal (absent) (>4.5)

26

70.3

IR (present) (<4.5)

11

29.7

zz

p = 0.0495 (S)

maximal

The statistical tests applied on the data determining the frequency distribution of obesity, WHR, FPG/FPI, hyperinsulinemia in general population is binomial test.

The statistical tests applied to determine the significant association between markers of IR and clinical features of anovulatory DUB were Chi-square test/Fisher exact test. A p value <0.05 was taken as statistically significant. OBSERVATIONS and RESULTS In the present study, the mean age of patient was 24.7 years. But, maximum number of patients belonged to 26-30 years of age. Out of total 37 cases, 64.9% had BMI >27, which is statistically significant. Among total cases, 75.7% had WHR >0.85, 62.2% had hyperinsulinemia and 29.1% had insulin resistance, which was statistically significant (Table 1). Out of 11 IR patients, 90.9% were obese and 9.1% were nonobese but this association was found insignificant (p = 0.33) (Table 2). All patients of IR had WHR >0.85 and this association was found statistically significant (p = 0.025) (Table 3). Among 11 IR patients, 90.9% had hyperinsulinemia and 9.1% had normal insulin level, which was statistically significant (p = 0.020) (Table 4).

p = 0.043 (S)

p = 0.01003 (S)

Table 2. Association between Obesity and IR Obesity

FPG to FPI Ratio IR (<4.5) (n = 11)

Normal (≥ 4.5) (n = 26)

Total

No.

%

No.

%

No.

%

Absent (≤ 27 kg/m2)

01

9.1

12

46.2

13

35.1

Present (>27 kg/m2)

10

90.9

14

53.8

24

64.9

Total

11

100.0

26

100.0

37

100.0

Table 3. Association between WHR and IR WHR

FPG to FPI ratio IR (<4.5) (n = 11)

Normal (≥ 0.5) (n = 26)

Total

No.

%

No.

%

No.

%

Normal (<0.85)

0

0.0

9

34.6

9

24.3

High (>0.85)

11

100.0

17

65.4

28

75.7

Total

11

100.0

26

100.0

37

100.0

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Obstetrics and Gynecology Table 4. Association between Hyperinsulinemia and Obesity Obesity (Count % within hyperinsulinemia)

Hyperinsulinemia Normal insulin level (≤10 MIU/ml (n = 14)

Increased insulin level (>10 MIU/ml) (n = 23)

Total

No.

%

No.

%

No.

%

Normal (≤27 kg/m2)

5

35.7

8

34.8

13

35.1

Present (>27 kg/m2)

9

64.3

15

65.2

24

64.9

Total

14

100.0

23

100.0

37

100.0

Table 5. Association between Fasting Hyperinsulinemia and WHR WHR (count % within hyperinsulinemia)

Hyperinsulinemia Normal (≤10 IU/ml) (n = 14)

Hyper insulinemia

Total

No.

%

No.

%

No.

%

Normal (<0.85)

6

42.9

3

13.0

9

24.3

High (≥ 0.85)

8

57.1

20

87.0

28

75.7

Total

14

100.0

23

100.0

37

100.0

association with chronic anovulation shows that IR is a feature not specific to PCOS but associated with anovulation. Among 11 IR subjects 90.9% were obese and only 9.1% were nonobese. This observation was consistent with the previous observation on patient with chronic anovulation who concluded from their study that association between percentage body fat and FPG/FPI was not significant.6 WHR >0.85 i.e. android obesity was found in 75.5% of chronic anovulatory patients. All cases with increased WHR (>0.85) (75.5% of total), were found with IR. This is consistent with the previous studies, which show that it is the intra-abdominal fat accumulation, which is associated with metabolic abnormalities.1,7-9 Of 23 patients with fasting hyperinsulinemia, 65.2% were obese and 34.8% were nonobese. Previous study by McAuley, et al, showed plasma insulin concentration as a useful surrogate marker of IR.10 Out of 23 patients with fasting hyperinsulinemia, 87% had android obesity, thereby showing that derangement of insulin levels are associated with accumulation of intra-abdominal fat. This finding is consistent with the observation in which WHR was found to be a significant predictor of insulin concentration.3-5 CONCLUSION

Out of 23 patients with fasting hyperinsulinemia, 65.2% were obese and 34.8% were nonobese. Association between these entities was statistically insignificant (p = 0.613) (Table 5). Among all patients with fasting hyperinsulinemia 87% had android obesity (WHR >0.85) and 13% had WHR <0.85. This association between hyperinsulinemia and android obesity was statistically significant. DISCUSSION In the present prospective study, 37 patients with chronic anovulation without any clinical features of hyperandrogenism were evaluated. In terms of distribution of body fat, WHR >0.85 (i.e. android obesity), was found in 28 patients (75.5%). This observation was consistent with various studies, which showed that android obesity was related with metabolic disturbances.1-5 Intra-abdominal fat accumulation causes metabolic derangement, which results in altered physiology. The presence of IR was observed in 11 (29.7%) subjects from study group of 37 subject. Evidence of IR in PCOD subjects is available in literature. But, this significant

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Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

In chronic anovulatory patients, the carbohydrate metabolism is deranged, which may lead to development of type 2 diabetes mellitus in these patients. Although, percentage of patients with IR were less, it had the best association with other markers of IR. While presence of IR and markers of IR are hallmark of PCOS, the present study though involving small number of patients does indicate a similar biochemical derangement in non PCOS chronic anovulators. REFERENCES 1. Fujioka S, Matsuzawa Y, Tokunaga K, Tarui S. Contribution of intra-abdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity. Metabolism 1987;36(1):54-9. 2. Vague J. La differentiation sexuelle hymanic: ses ioncidences en pathologic. Paris Masson, 1953. 3. Kissebah AH, Vydelingum N, Murray R, Evans DJ, Hartz AJ, Kalkhoff RK, et al. Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab 1982;54(2):254-60. 4. Kalkhoff RK, Hartz AH, Rupley D, Kissebah AH, Kelber S. Relationship of body fat distribution to blood pressure, carbohydrate tolerance, and plasma lipids


Obstetrics and Gynecology in healthy obese women. J Lab Clin Med 1983;102(4): 621-7.

theophylline, prostaglandin E1 and age. Acta Chir Scand 1969;135(8):663-70.

5. Evans DJ, Hoffmann RG, Kalkhoff RK, Kissebah AH. Relationship of body fat topography to insulin sensitivity and metabolic profiles in premenopausal women. Metabolism 1984;33(1):68-75.

8. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963;1(7285):785-9.

6. Vital Reyes VS, Mc Enriquez Miranda, Hartines E, et al. Relacion insulina-glucosa y composicion corporal grasa en paciewntes con enovulacion cronica y esteriudad. Ginecol obstet Mex., Feb 2002; Vol 70, No. 2. ISSN 0300-9041.

9. Cusin I, Rohner-Jeanrenaud F, Terrettaz J, Jeanrenaud B. Hyperinsulinemia and its impact on obesity and insulin resistance. Int J Obes Relat Metab Disord 1992;16 Suppl 4:S1-11.

7. Micheli H, Carlson LA, Hallberg D. Comparison of lipolysis in human subcutaneous and omental adipose tissue with regard to effects of noradrenaline,

10. McAuley KA, Williams SM, Mann JI, Walker RJ, LewisBarned NJ, Temple LA, et al. Diagnosing insulin resistance in the general population. Diabetes Care 2001;24(3):460-4.

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Time Limit of Abortions Raised to Nine Weeks The time limit for abortions has been increased from 7 to 9 weeks to facilitate family planning, the Drug Controller General of India has said. Nozer Sherian, secretary general of the Federation of Obstetric and Gynaecological Societies (FOGSI), said here Friday: "The Drug Controller General has increased the time limit of abortions to 63 days, that is nine weeks." In the last two years, 3,32,000 medical abortions were carried out, which show that if given a choice, women want to limit their families. "This is very important as around eight percent of maternal deaths take place due to unsafe abortions," he said. FOGSI is promoting medical abortions along with Intrauterine Medical Devices (IUD) to help people plan their families. Hema Diwakar, president of FOGSI, said that women are now given a choice of post-placental IUD as soon as they give birth. The family planning initiative taken up by the FOGSI and the Population Services International (PSI) is called 'Pehel'. It is run mostly in urban slums. It covers 30 districts in Rajasthan, Uttar Pradesh and Delhi. Ten additional districts in these three states would be covered in the next phase. "Pehel Phase 3 will continue to complement the government's efforts to reduce maternal mortality and increase the contraceptive prevalence rate," said Pritpal Marjara, director of PSI. According to government data, every year about 78,000 women die during pregnancy, child birth or within 43 days of delivery in India. (Source: The Pioneer, 26 April 2013).

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Ophthalmology

Evaluation of a Case of Penetrating Ocular Injury Jitender Phogat*, Vivek Gagneja**, Sumit Sachdeva*, Mukesh Rathi†

Abstract Ocular trauma is an important cause of visual loss and disability. It can be categorized as penetrating and nonpenetrating. Penetrating ocular injury may result in ocular damage of various degrees. With modern diagnostic techniques, surgical approaches and rehabilitation, many eyes can be salvaged with retention of vision. But penetrating ocular trauma is a complicated and challenging condition.

Keywords: Globe rupture, intraocular foreign body, endophthalmitis

O

cular injuries are a frequent cause of unilateral visual loss. Children account for between 20% and 50% of all ocular injuries.1-3 It has been estimated that 90% of all ocular injuries are preventable.4 Strategies for prevention require a knowledge of the cause of injury and hence may enable more appropriate targeting of resources towards prevention of such injuries. The etiology of pediatric ocular injuries is likely to differ from that of adult. Injury was classified as penetrating injury in accordance with the Birmingham Eye Trauma Terminology (BETT) (Table 1).5 Ocular trauma severity is calculated by ocular trauma score (OTS) (Table 2).6

The National Academy of Sciences has called trauma the ‘neglected epidemic of modern society,’7 Ocular trauma in children can result in catastrophic visual and psychological outcomes both for the child and his/her family. According to the World Health Organization (WHO), childhood blindness is one of the major causes of avoidable blindness and so target of the Vision 2020 Program. According to a rough estimate, 5-10% of cases of childhood blindness are due to trauma.8

*Assistant Professor **Senior Resident †Ex-Senior Resident Regional Institute of Ophthalmology, Pt. BD Sharma Postgraduate Institute of Medical Sciences (PGIMS), Rohtak, Haryana Address for correspondence Dr Jitender Kumar Phogat Assistant Professor, Regional Institute of Ophthalmology Postgraduate Institute of Medical Sciences (PGIMS), Rohtak -124 001, Haryana E-mail: drjitenderphogat@gmail.com

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Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2012

Despite the strong anatomical barrier and vigilant physiological protection provided by nature to the eye, the incidence of ocular injuries remains high. The fate of the traumatized eye depends upon the treatment adopted. Timely reporting of cases and early surgical management reduces the visual loss. Promptness in decision of action in emergency is the best test of the powers and resources of any man, especially medical men. Annually, more than two million cases of eye trauma are reported, out of which more than 40,000 cases end up with severe visual impairment accounting for socioeconomic burden. Most of the cases are less than 40 years of age and 90% blindness due to trauma is preventable. Management of Penetrating Ocular Injury Management varies widely according to severity, extent and location of the injury. Some general principles which apply are: ÂÂ

Primary closure of the penetrating wound

ÂÂ

Removal of any foreign body material

ÂÂ

Penetrating of further or secondary injury to eye (infection)

ÂÂ

Anatomic and visual rehabilitation of the eye

ÂÂ

Protection of the fellow uninvolved eye (protective eye wear)

ÂÂ

General rehabilitation of the patient.

CASE REPORT A 12-year-old male child presented to the OPD in our Institute with a history of injury in his left eye with an iron nail while playing. After the injury, the patient had diminution of vision, mild pain, irritation and


Ophthalmology Table 1. The Birmingham Eye Trauma Terminology5 Glossary of terms

Definition and explanation

Eyewall

Sclera and cornea

Closed globe injury

No full-thickness wound of eyewall

Open globe injury

Full-thickness wound of the eyewall

Contusion

There is no (full-thickness) wound (Due to direct energy delivery by the object e.g., choroidal rupture or to the changes in the shape of the globe e.g., angle recession)

Lamellar laceration

Partial thickness wound of the eyewall

Rupture

Full-thickness wound of the eyewall, caused by a blunt object (Inside - out mechanism).

Laceration

Full-thickness wound of the eyewall, caused by a sharp object (By an outside - in mechanism).

Penetrating injury

Entrance wound (If more than one wound is present, each must have been caused by a different agent. Retained foreign object/s are technically a penetrating injury, but grouped separately because of different clinical implications).

Perforating injury

Entrance and exit wounds (Both wounds caused by the same agent).

Table 2. The Ocular Trauma Score (Version 11.1) Computational Method for Deriving the OTS6 Initial visual factor Initial visual acuity category

Raw point NLP

60

LP/HM

70

1/200-19/200

80

20/200-20/50

90

≥20/40

100

Globe rupture

–23

Endophthalmitis

–17

Perforating injury

–14

Retinal detachment

–11

Afferent pupillary defect (Marcus Gunn pupil)

–10

Raw score sum = sum of raw points HM: Hand movements; LP: Light perception; NLP: No light perception.

watering from the affected eye. He did not seek any medical help for two days, but when the symptoms did not subside, the patient presented to us, where on examination patient had a visual acuity of 6/6 in right eye (R/E) and 6/36 in left eye (L/E). On slit-lamp examination, his R/E was within normal limits (WNL) and the left eye had mild superficial and deep congestion. A scleral tear with iris prolapse of 4 mm was present from 8 O’clock to 10 O’clock. The adjacent 2-3 mm of cornea had stromal edema. Anterior chamber had cells and flare of Grade 2 and fundal glow was present. After prescribing injection tetanus toxoid (TT) 0.5 mg IM, he was put on one hourly preservative-free moxifloxacin and injection ciprofloxacin 75 ml b.i.d. After taking consent and proper anesthetic check-up, the patient was operated upon under general anesthesia. During the

operation, the iris was abscised and the scleral tear was repaired with 9-0 monofilament polyamide. Intravitreal injection, vancomycin and ceftazidime were given in recommended therapeutic dosage. Postoperatively, the patient was put on injection ciprofloxacin 75 ml b.i.d., tablet prednisolone 30 mg after breakfast and capsule lansoprazole 30 mg BBF and pad and bandage was applied for 24 hours. On the first postoperative day, his vision was 6/18 and patient was put on fortified vancomycin, fortified ceftazidime, preservative-free moxifloxacin eye drops 0.3% one hourly, bromfenac eye drops 0.09% b.i.d., atropine eye drops 1% t.i.d. and natamycin 5% eye drops. Postoperatively at two weeks, his vision in L/E was 6/9 and in R/E, the vision was 6/6 with refraction (Figs. 1 and 2).

Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2012

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Ophthalmology

Figure 1. Preoperative case of penetrating injury to eye.

Figure 2. Postoperative picture of the same patient.

DISCUSSION

REFERENCES

Prognosis for vision depends upon severity of initial penetrating injury. The most important factors on which final visual outcome depends include initial visual acuity, presence of an afferent pupillary defect and presence of infection. The presence of massive choroidal detachment and posterior exit wounds, retinal detachment, or subretinal hemorrhage, large corneoscleral laceration are associated with worse visual outcome.

1. Punnonen E. Epidemiological and social aspects of perforating eye injuries. Acta Ophthalmol (Copenh) 1989;67(5):492-8.

X-ray is an easy tool to look for any metallic foreign body. Diagnostic ultrasound may provide useful information. Computed tomography (CT) and magnetic resonance imaging (MRI) are also very helpful for assessment of injury. Proper surgical repair, prevention of infection and sympathetic ophthalmitis in normal eye are key for optimal outcome. CONCLUSION Penetrating ocular injuries present a challenge to salvage useful vision in injured eye. Prevention, early presentation and proper management help to save vision and early rehabilitation of the patient.

2. Blomdahl S, Norell S. Perforating eye injury in the Stockholm population. An epidemiological study. Acta Ophthalmol (Copenh) 1984;62(3):378-90. 3. Moreira CA Jr, Debert-Ribeiro M, Belfort R Jr. Epidemiological study of eye injuries in Brazilian children. Arch Ophthalmol 1988;106(6):781-4. 4. National Society to Prevent Blindness: Fact sheet. National Society to Prevent Blindness: New York, 1980. 5. Kuhn F, Morris R, Witherspoon CD, Heimann K, Jeffers JB, Treister G. A standardized classification of ocular trauma. Ophthalmology 1996;103(2):240-3. 6. Kuhn F, Maisiak R, Mann L, Mester V, Morris R, Witherspoon CD. The Ocular Trauma Score (OTS). Ophthalmol Clin North Am 2002;15(2):163-5, vi. 7. Committee on Trauma and Committee on Shock. Accidental death and disability: the neglected disease of modern society. National Academy Press: Washington 1966:p.5. Available at: http://http://www.nap.edu/catalog. php?record_id=9978. Accessed April 17, 2006. 8. Shukla B, Natarajan S. Management of ocular trauma. 2005:288.

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Poor Vision Tied to Poor Balance Visual impairment - correctable or not - is associated with poor balance, researchers reported. (Source: Medpage Today)

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Orthopedics and Rheumatology

An Unusual Swelling at Ankle: An Osteochondroma in Adult? Vivek AN

Abstract Osteochondroma is the most common benign tumor of bone commonly seen in children and young adults, arising in the metaphyseal region of a long bone, though it is occasionally seen affecting flat bones. It affects the small bones, of the hand and feet in approximately 10% of cases and the growth of the lesion usually ceases with fusion of the adjacent growth plate. We present a rare case of osteochondroma in a 60-year-old patient who had a swelling arising from the talus, which was treated by excisional biopsy and histologically confirmed to be osteochondroma.

Keywords: Osteochondroma, benign tumor, talus

O

steochondroma is the most common benign tumor of bone commonly seen in children and young adults. In most cases, the osteochondroma ceases to grow at skeletal maturity. To our knowledge, a case developing such lesions after 30 years of age has not been reported in the literature. We report a 60-year-old patient presenting with swelling arising from the talus, which was treated by excisional biopsy and histologically confirmed to be osteochondroma.

Case Report A 60-year-old male presented with a hard swelling at the right ankle of 8-month duration. He gave a history of trauma to the ankle due to fall and development of swelling and pain, which subsided without any specific treatment. He noticed a small painless swelling developing at the same area after a month, which was not associated with pain. When the patient presented to us, the swelling was 8 Ă&#x2014; 6 cm anterior to the ankle. The swelling was nontender, bony hard and was immobile. Ankle movements were restricted with 100 and 200 of dorsiflexion and plantar flexion, respectively. An excisional biopsy was performed by anterior approach

Consultant Orthopedic and Arthroscopic Surgeon Lifeline Hospitals Perugudi, Chennai

and the swelling was excised in toto. Peroperatively the swelling was attached to the neck of talus by a narrow stalk, which was osteotomized along with a flake of normal bone. Grossly, the tumor was glistening white and was entirely covered by cartilage except at its attachment to talus. On sectioning, the tumor was bony hard and revealed a uniformly thick cartilage cap. Histologically, there was normal trabecular pattern of mature bone tissue with uniform layer of cartilage cap. There were areas of marrow fat within the tumor. There were no features suggesting malignancy. Multiple sections were made at regular intervals along the length of the tumor to rule out malignancy and other likely lesions.

Figure 1. Preoperative radiograph.

Figure 2. Postoperative radiograph.

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Orthopedics and Rheumatology

Figure 3. Photograph of the excised specimen.

Figure 4. Histopathological picture.

Discussion

woven bone, cartilage or a mix of chondroid, osteoid and myxoid elements. There may be zonal maturation of the tissues as is seen in myositis ossificans.

Differential diagnosis of a bony swelling which clinically and radiologically appears benign arising from an atypical location in an elderly patient includes heterotrophic ossification, florid reactive periostitis, Nora’s lesion, turret exostoses and osteochondroma.1-3 Heterotrophic ossification or post-traumatic ossification is a rare cause of joint stiffness. It occurs in cases of severe injury to a joint, and especially when the capsule and periosteum have been stripped from the bone. In general, the degree of ossification is inversely proportional to the age of the subject, so that the most exuberant ossifications are observed in children and young adults. Florid reactive periostitis was first described by Spjut and Dorfman in 1981.4 It is a rare benign bone lesion that affects the fingers or toes of adolescents and young adults (range 5-70 years). The lesion appears to be a reactive process rather than a true neoplasm. The cause is unknown, but about one-half of patients with this lesion give a history of trauma to the area. Clinically, there is a history of gradually progressive swelling, erythema and pain or a painful mass in the affected part. Approximately 50% of patients have a history of trauma. Plain radiographs show the tumor is adjacent to the bone rather than arising from it. Soft tissue swelling is accompanied by marked periosteal reaction. There may be new bone formation in the soft tissues and subtle cortical thinning. While the lesion is benign, the findings overlap with that of osteosarcoma, infection and other aggressive lesions. Histologically, the predominant cells are large spindle shaped fibroblasts with prominent nuclei. There is no pleomorphism. Mitoses are present, which may be frequent but not abnormal. Multinucleated giant cells are frequently seen. There is mature and immature osteoid and

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Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

Bizarre parosteal osteochondromatous proliferation (BPOP) or Nora’s lesion was described by Nora et al in 1983.5 It is a rare lesion commonly affecting the hands and feet of young adults in their 20s and 30s. Males and females are equally affected. It most commonly occurs in the proximal and middle phalanges, metacarpal and metatarsal bones.3 BPOP typically presents with a painless or mildly painful mass that grows over a period of weeks to months.5 In contrast to malignant lesions, BPOP exhibits no periosteal reaction and has normal underlying bone and adjacent soft tissue radiologically. On gross examination, BPOP appears as a lesion with a nodular surface covered by glistening cartilage and a distinct blue tint of the bone within.3 It contains disorganized and irregular cartilage with patchy ossification. The periphery of the lesion contains lobulated hypercellular cartilage and fibrous tissue with occasional large chondrocytes. There are uniform osteoblasts on the bony trabeculae. Chondrocytes may be binucleated5 and proliferation of bizarre (even spindle-shaped) fibroblast in the intertrabecular spaces of disorganized bone has been reported.6 Typically, the cartilage lobules show mild atypia and moderate mitotic activity is seen in the spindle cells. This often confuses the diagnosis and the lesion needs to be distinguished from conventional osteosarcoma, low-grade parosteal osteosarcoma and chondrosarcoma. Osteochondromas on the other hand, contains a few-millimeters thick chondral cap resembling normal cartilage, beneath which is cancellous bone that is in direct continuity with the underlying bone.7 The cap however, may be entirely absent in adults, and binucleated chondrocytes may be found in young patients.7 In contrast to BPOP, osteochondromas have normal ‘columnation’ of the cartilage.5


2013


Orthopedics and Rheumatology Turret exostosis or acquired osteochondroma is an uncommon lesion that mainly affects phalanges of the upper extremity and rarely phalanges of the foot. Turret exostosis was proposed by Wissinger et al in 1966.2 Radiologically, there is a well-defined osseous mass fused to the underling bony cortex without communication to the medullary canal, which is typical of osteochondromas. The lesion is covered by a thin cartilage shell, which demonstrates less cytologic atypia. Subungual exostosis is a clinical entity similar to turret exostosis. This type of exostosis more often affects the distal phalanx of the big toe.

References

The osteochondroma or osteocartilaginous exostosis is the most common tumor of bone. Seventy to 80% of solitary osteochondromas occur in children or adolescents younger than 20 years of age, arising in the metaphyseal region of a long bone, though it is occasionally seen affecting flat bones (pelvis and scapula). It affects the small bones of the hand and feet in approximately 10% of cases and the growth of the lesion usually ceases with fusion of the adjacent growth plate.7 Since, these tumors are active during the period of normal skeletal growth and cease to grow at the time of skeletal maturation, it may be argued that they are not true tumors but simply aberrations of bone growth. Essentially, they are cylinders or pedicles of adult bone capped by an epiphyseal disk of cartilage.

4. Spjut HJ, Dorfman HD. Florid reactive periostitis of the tubular bones of the hands and feet. A benign lesion which may simulate osteosarcoma. Am J Surg Pathol 1981;5(5):423-33.

1. Abramovici L, Steiner GC. Bizarre parosteal osteochondromatous proliferation (Nora’s lesion): a retrospective study of 12 cases, 2 arising in long bones. Hum Pathol 2002;33(12):1205-10. 2. Wissinger HA, McClain EJ, Boyes JH. Turret exostosis. Ossifying hematoma of the phalanges. J Bone Joint Surg Am 1966;48(1):105-10. 3. Meneses MF, Unni KK, Swee RG. Bizarre parosteal osteochondromatous proliferation of bone (Nora’s lesion). Am J Surg Pathol 1993;17(7):691-7.

5. Nora FE, Dahlin DC, Beabout JW. Bizarre parosteal osteochondromatous proliferation of the hands and feet. Am J Surg Pathol 1983;7(3):245-50. 6. Smith NC, Ellis AM, McCarthy S, et al. Bizarre parosteal osteochondromatous proliferation: a review of seven cases. Aust NZ J Surg 1996;66(10):694-7. 7. Resnick D, Kyriakos M, Greenway GD. Tumors and tumorlike lesions of bone: imaging and pathology of specific lesions. In: Diagnosis of Bone and Joint Disorders. 3rd edition, Resnick D (Eds.), WB Saunders, Co.:Philadelphia 1995;p.3725-66, 3978-9.

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Adolescents with Joint Hypermobility at Increased Risk for Joint Pain A prospective study by UK researchers found that adolescents who are double-jointed - medically termed joint hypermobility - are at greater risk for developing musculoskeletal pain as they get older, particularly in the shoulders, knees, ankles and feet. Findings published in Arthritis & Rheumatism, a journal of the American College of Rheumatology (ACR), indicate that children with joint hypermobility are approximately twice as likely to develop pain at these joints.

Vitamin D and Calcium may not Prevent Fractures Vitamin D and calcium supplements do not prevent fractures in adult men or women, according to a report published in the journal Annals of Internal Medicine. After discovering that there was not sufficient scientific proof to demonstrate that vitamin D and calcium supplements help protect bones from breaking in men or the majority of postmenopausal women, the US Preventive Services Task Force (Task Force) made their final recommendation.

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Pediatrics

Clinico-etiological and EEG Profile of Neonatal Seizures Shwetal Bhatt*, Nita Raju**, Supriya Phanse**, Sangita V Patel†, Geetika Madan‡, Sanjeev Mehta¶, Chetan Trivedi#

Abstract Background: Incidence of seizures is highest during the neonatal period, but clinical diagnosis is often difficult, thereby making it difficult to estimate the true incidence of neonatal seizures. Electroencephalography (EEG) provides a useful noninvasive test to diagnose neonatal seizures and evaluate degree of perinatal damage to brain and long-term prognosis. Aim: To evaluate the clinical, etiological and EEG profile of neonatal seizures. Material and methods: An observational study was carried out at tertiary care level neonatal intensive care units (NICUs) of SSG Hospital, Vadodara. A total of 172 newborns having seizures within first 28 days of life were enrolled. Baseline data was collected including antenatal history, perinatal history and evidence of HIE (hypoxic ischemic encephalopathy). Description of seizures, a complete examination and investigations including blood sugar, serum calcium, magnesium, electrolytes and treatment were also recorded. Due to financial constraints as well as general condition of the patients, it was possible to record EEGs in 50 newborns using neonatal montages as per guidelines of American EEG Society. Results: The incidence of seizures was 0.77% among term newborns and 1.1% among preterm newborns. HIE was the most common etiology (77%), while multifocal seizures (51%) were the most common presentation; 65.9% had easy to control seizures while 34% had difficult-to-control seizures requiring more than one drug. Of the total 50 EEGs done, 14 were abnormal; maximum being in HIE (57%) followed by mixed etiology (28.57%), hypocalcemia (7.14%) and pyogenic meningitis (7.14%). Conclusion: The overall incidence of neonatal seizures was found to be 0.77%, majority being preterm, low birth weight infants and within first 48 hours of life. EEG abnormalities were found in 28% of the recorded EEGs. HIE (77%) was the most common cause of neonatal seizures with EEG abnormalities.

Keywords: Neonatal seizures, electroencephalography

C

linical seizures are defined as paroxysmal alteration in the neurological function i.e., behavioral, motor and/or autonomic function. The incidence of seizures is highest during the neonatal period, but clinical diagnosis is often difficult, thereby making it difficult to estimate the true incidence of neonatal seizures. Seizures are often the first sign of neurological dysfunction in the newborn, but their clinical presentation is quite variable often presenting only as subtle seizures in the form of chewing, lip smacking, fluttering of eyelids, staring look, etc. Volpe1 has classified seizures into five clinical types, viz. subtle, multifocal clonic, focal clonic, generalized tonic and

myoclonic. Moreover, neonatal seizures are difficult to investigate and consequently determination of etiology and initiation of therapy may be delayed resulting in poor neurological outcome. Neonatal seizures can be due to various causes such as hypoxic-ischemic encephalopathy, intracranial hemorrhage (ICH), meningitis, hypoglycemia, hypocalcemia, congenital malformation, etc. Though electroencephalography (EEG) provides a useful noninvasive test to diagnose neonatal seizures and evaluate degree of perinatal damage to brain and long-term prognosis, yet its interpretation is influenced by variations in normal maturation process of brain. Aim

*Associate Professor **Senior Resident, Dept. of Pediatrics †Associate Professor ‡Tutor (PG Student), Dept. of PSM ¶Pediatric Neurologist #Neurophysician Medical College and SSG Hospital, Vadodara Address for correspondence Dr Shwetal Bhatt 12, Samruddhi Society, Bh. Avishkar Complex, Akota, Vadodara E-mail: dr_shwetal@yahoo.co.in

To evaluate the correlation of EEG with clinical and etiological profile of neonatal seizures. MATERIAL AND METHODS The study was conducted at the tertiary care level neonatal intensive care units (NICUs) of the Dept. of Pediatrics, SSG Hospital, Vadodara. Prior to beginning

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Pediatrics

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11.30%

12 10 8

Term Preterm

6 4 2

0.70%

0

1.10%

Intramural

0.70% Extramural

Figure 1. Distribution of incidence of seizures.

H

IE al ce H m yp ia Py og og ly ce en m ic ia m en in Bi gi lir tis ub in en IC ce El H ph ec a tro lo pa ly te th y im ba l an M ix ce ed ca us es

90 80 70 60 50 40 30 20 10 0

yp oc

Once the neonate was hemodynamically stable and off intravenous fluids, he/she was sent for the EEG recording at the earliest. EEG was obtained on RMS EEG machine having 25 leads. EEG was done at a Neurophysianâ&#x20AC;&#x2122;s clinic and was read by a Pediatric neurophysician. The techniques used were as per guidelines of the American EEG Society for recording EEG in neonates. Neonatal montages were used and 16 leads were used as against the standard of 25 leads in the adult. Triclofos was used in the dose of 50 mg/kg/dose to induce sleep when required. Babies were also subjected to photic stimulation to provoke any abnormalities in brain activity. Each EEG recording was made for 30-40 minutes in order to bring out the sleep wake cycles in each neonate and read by a pediatric neurologist.

During the study period a total of 4,412 babies were admitted in the intramural NICU, and 1,900 were admitted in the extramural NICU. One hundred seventy-two newborns satisfying the inclusion criteria were enrolled in the study. The incidence of seizures was found to be 0.77% with 0.7% among term newborns and 1.1% among preterm newborns (Fig. 1). One hundred twenty-one males and 51 females were enrolled in the study and the male:female ratio was found to be 2.37:1. The incidence of seizures was found to be 2.8% among low birth weight and 0.88% among very low birth weight infants. Twenty-two percent of the newborns with neonatal seizures were found to be small for date (SFD). Eighty-one percent of the neonatal seizures were found to be early-onset (<48 hours of life)

H

Investigations done included: Serum C-reactive protein, random blood sugar, packed cell volume, serum calcium, serum magnesium, serum sodium, blood urea, serum creatinine, serum bilirubin, blood culture and sensitivity, cerebrospinal fluid (CSF) examination, USG head, CT scan, MRI (wherever feasible and indicated) and EEG. All babies were treated using standard treatment protocol.

RESULTS

Percentage (%)

Details of each baby with a complete antenatal and perinatal history including Apgar scores for intramural deliveries and history suggestive of birth asphyxia or examination revealing signs of hypoxic ischemic encephalopathy (HIE), were noted. A history of seizures associated with poor feeding, prolonged lethargy, recurrent vomiting, with family history of consanguinity and/or neonatal seizure with early fetal and neonatal death was taken to rule out inborn errors of metabolism. A complete description of the seizure, day of onset, duration and frequency was noted and classified according to Volpe. Vital signs, congenital malformation and cutaneous markers, were examined for and systemic examination was done. Neurological examination was done at the time of onset of seizures. Sarnat and Sarnat score was considered for HIE grading.

Statistical analysis: Data was recorded in a pretested detailed Proforma and entered in Microsoft Excel worksheet. Median and mean were used to analyze data that was distributed in the Gaussian manner.

Percentage (%)

the study, ethical approval was taken from the local IECHR (Institutional Ethics Committee for Human Research), Medical College Baroda. The cohort consisted of neonates admitted in the NICUs (intramural and extramural) from September 2008 to November 2009. It was an observational study. A total of 172 neonates who either had seizures during the NICU stay or had seizures which were noticed by other doctors and referred from outside, were included in the study after written and informed consent of the parents.

Figure 2. Distribution of various etiologies of neonatal seizures.


Pediatrics with 90% of them attributable to HIE. The rest 19% were late-onset (>48 hours of life) with pyogenic meningitis contributing to 31% of them. A total of 352 seizure episodes were noted in the 172 newborns, with a median onset of 38.5 hours for the first episode. Multifocal seizures (51%) were found to be the most common seizure type followed by subtle seizures (43%), tonic seizures (4.6%) and clonic seizures Table 1. Babies with Abnormal EEGs in Various Etiologies Etiology

No. of cases

No. of babies with EEG done

No. of babies with abnormal EEGs

HIE

134

35

10 (28.57%)

Hypocalcemia

15

9

3 (33.33%)

Hypoglycemia

8

5

-

Pyogenic meningitis

14

4

3 (75%)

ICH

6

2

1 (50%)

Bilirubin encephalopathy

3

1

-

Electrolyte imbalance

9

7

2 (28.6%)

Mixed

15

11

4 (36.36%)

74*

23 (31%)

Total

*Though the total number of EEGs done was 50, due to overlapping of some etiologies e.g. hypocalcemia and pyogenic meningitis, the total figure is >50.

(0.65). HIE (77.9%) was found to be the most common etiology of seizures, followed by hypocalcemia (8.7%), pyogenic meningitis (8.1%), mixed causes (8.7%), electrolyte imbalance (5.2%), hypoglycemia (4.65%), ICH (3.5%) and bilirubin encephalopathy (1.74%) (Fig. 2). About 65.9% patients had easy-to-control seizures while 34% had difficult-to-control seizures requiring more than one drug for seizure control. Of the total 50 EEGs done, 36 (72%) were normal, while 14 (28%) were found to be abnormal (Table 1). On elaborating the etiologies found with the abnormal EEGs, 28.57% of EEGs were done in patients with HIE, 33.33% were done in patients with hypocalcemia, 75% were done in pyogenic meningitis, 50% were done in ICH, 28.57% were done in electrolyte imbalance and 36.36% of the EEGs were done in patients with mixed causes were found to be abnormal. On interpreting the data in a different way, out of the total number of abnormal EEGs, HIE showed maximum abnormalities (57%), followed by mixed etiology (28.57%), hypocalcemia (7.14%) and pyogenic meningitis (7.14%). Among the abnormalities found in the EEGs, background abnormalities were found in 22 EEGs, out of which 10 had invariant delta activity, seven had disorganized sleep pattern (Fig. 3) and five were immature for chronological age. One EEG had multifocal sharp wave discharges (Table 2). Of the 22 EEGs with background abnormalities, nine were due to HIE. And the one EEG with multifocal sharp waves was also found to be due

Table 2. EEG Abnormalities in Various Etiologies EEG

HIE

Hypocalcemia Hypoglycemia

ICH

Pyogenic meningitis

Electrolyte imbalance

Bilirubin enceph

Mixed causes

Background abnormalities Low voltage

-

-

-

-

-

-

-

-

Lack of sleep patterns

1

2

-

-

1

1

-

2

Invariant delta activity

5

-

-

1

1

1

-

2

Immature for age

3

1

-

-

1

-

-

-

Discharges a) Area of involvement yy Generalized

-

-

-

-

-

-

-

-

yy Multifocal

1

-

-

-

-

-

-

-

yy Focal

1

-

-

-

-

-

-

-

yy Spikes

2

-

-

-

-

-

-

-

yy Sharp

1

-

-

-

-

-

-

-

yy Both

-

-

-

-

-

-

-

-

b) Types of discharges

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Pediatrics to HIE (Table 2). Cranial ultrasound (CUS) was done in 39 patients, out of which 12 (31%) were found to be abnormal. Seven CUS showed dilatation of ventricles and three showed ICH. CT head could be done in four patients, out of which 2 patients had IVH with hydrocephalus, one had bilateral cerebral infarcts and the other had changes suggestive of HIE.

is an important risk factor, as clinical seizures in low birth weight babies often indicate severe brain injury and are associated with serious morbidity and a high mortality risk.

The male:female ratio among the enrolled newborns was 2.37:1, as compared to 2.46:1 in the hospital admissions. Comparable results were shown by Eghbalian et al3 with a ratio of 3:1, though NNPD 2002-2003 reported a ratio of 1.1:1 for intramural and 2.01:1 for extramural admissions.2 Low birth weight

The risk of neonatal seizures varies inversely with birth weight. In the present study, the incidence of seizures in low birth weight babies was 2.8% as compared to 6% as reported by Eghbalian et al3 and 1.5% reported by Kumar et al.4 The median age of onset of seizures in the present study was 38.5 hours in term babies and 19.5 hours in preterm babies, with an average of 2.03 seizure episodes per baby in the first 28 days of life. Earlyonset seizures (within first 48 hours of life) were the commonest and contributed to 81% of the total seizures (Fig. 4). Similar findings were observed by Tekgul et al wherein 64% of neonatal seizures occurred within first 24 hours of life.5 Of the total 139 babies with earlyonset seizures, 98 had onset within first 12 hours of life; of these, 90% were due to HIE. Therefore, vigilant monitoring and early recognition of seizures could contribute to decreasing morbidity and mortality in this group. Moreover, unlike older infants, neonates rarely have well-organized generalized tonic-clonic seizures. Premature infants have even less well-organized spells than full-term babies. In the present study, multifocal clonic seizures (51%) were the most common seizure type followed by subtle (43%), generalized tonic (4.6%) and focal clonic (0.6%). Kumar et al reported similar findings, with multifocal seizures being the most common presentation (42.4%).4 However, Mizrahi et al6 and Scher et al7 have reported subtle seizures as the most common type of neonatal seizures in their studies.

Figure 3. EEG showing disorganized sleep pattern in a fullterm 2.3 kg vacuum delivered child with delayed cry.

Figure 4. EEG showing frequent spike and sharp waves in a full-term normal delivered baby with delayed cry with early-onset difficult-to-control seizures.

DISCUSSION Seizures in newborns are mostly identified by clinical observation. However, some of the clinically identified seizures are not accompanied by an EEG correlate and vice versa leading to an overestimation as well as underestimation of neonatal seizures, respectively. National Neonatal-Perinatal Database (NNPD) data report the incidence of neonatal seizures as 1% in intramural deliveries and 18% in the extramural neonates.2 In comparison, our study reported an incidence of 0.77% amongst intramural admissions and 7.3% amongst extramural admissions, respectively. The present study found an incidence of 0.7% in term babies and 1.1% in preterm babies among intramural admissions (Fig. 1), which is comparable to a previous study at SSG Hospital in 2000, which showed an incidence of 2% among preterms and 1.1% among term babies.

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Pediatrics Perinatal asphyxia is the most frequent cause of neonatal seizures (Fig. 2). In various studies, the reported incidence is 15-35%.8,9 But reports of higher incidence have been reported by Kumar et al4 (49%) and Nunes et al10 (51%). In the present study, perinatal asphyxia was the major contributing factor of neonatal seizures, contributing to 77.9% of the total seizures. EEG evidence of diffuse cerebral injury like burst suppression, dysmaturity, attenuation of background and electrical silence is seen in HIE and meningitis,10 but exact incidence of these findings has not been well-established. In the present study, out of 35 EEGs done in babies with HIE, 10 (28.57%) were abnormal (Table 1). Out of these, five showed invariant delta activity, three showed immature for age background abnormalities, while one showed abnormal sleep patterns (Table 2). Rose and Lombroso11 and Mizrahi and Kellaway6 reported abnormalities in standard EEG in HIE in 70% and 46.3%, respectively. Hypocalcemia (8.7%) was the next most common cause of neonatal seizures in the present study (Fig. 2). In comparison, Kumar et al4 (24.7%) and Eghbalian et al3 (35.3%) have reported higher incidence. Hypocalcemia occurs more commonly in infants with trauma, hemolytic disease or asphyxia and may co-exist with HIE, hypoglycemia and hypomagnesemia.12 Earlyonset hypocalcemia occurs in first 2-3 days of life. Of the 15 babies with hypocalcemic seizures, EEG was done in nine babies, out of which three (33.3%) babies had abnormalities on EEG (Table 1). Abnormal record in standard EEG in hypocalcemia has been reported in 34.4% by Keen and Lee13 and in 27.8% by Rose and Lombroso.12 Hypoglycemia is most frequent in low birth weight babies, most of them being small for gestational age and in infants of diabetic mothers. Incidence of hypoglycemia as reported in literature varies from 2 to 32.4%.9,14 Hypoglycemia contributed 4.65% of the total seizures in our present study. Seizures due to hypoglycemia typically occur on the second postnatal day.15 In neonatal hypoglycemic seizures, EEG produces multifocal discharges. However, in the present study, none of the EEGs showed any abnormality. EEGs were done in four of the 14 babies with meningitis, out of which three was abnormal with invariant delta activity in one, lack of sleep pattern in one and immature for age pattern in one. Abnormal standard EEGs in meningitis have also been reported in 33.3% cases by Rose and Lombroso 12 and 17% by Mizrahi and Kellaway.6

Conclusion The overall incidence of neonatal seizures was found to be 0.77%, majority being preterm, low birth weight infants and within first 48 hours of life. EEG abnormalities were found in 28% of the recorded EEGs. HIE (77%) was the most common cause of neonatal seizures with EEG abnormalities. REFERENCES 1. Volpe J. Neonatal Seizures. N Engl J Med 1973;289(8):413-6. 2. National Neonatal-Perinatal Database Report 2002-2003. National Neonatology Forum NNPD Network. January, 2005. 3. Eghbalian F, Monsef A. Neonatal seizures: etiology and frequency. Iran J Child Neurol 2007;2(1):39-42. 4. Kumar A, Gupta A, Talukdar B. Clinico-etiological and EEG profile of neonatal seizures. Indian J Pediatr 2007;74(1):33-7. 5. Tekgul H, Gauvreau K, Soul J, Murphy L, Robertson R, Stewart J, et al. The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics 2006;117(4):1270-80. 6. Mizrahi EM, Kellaway P. Characterization and classification of neonatal seizures. Neurology 1987;37(12):1837-44. 7. Scher MS, Aso K, Beggarly ME, Hamid MY, Steppe DA, Painter MJ. Electrographic seizures in preterm and fullterm neonates: clinical correlates, associated brain lesions, and risk for neurologic sequelae. Pediatrics 1993;91(1): 128-34. 8. Levene MI, Trounce JQ. Cause of neonatal convulsions. Towards more precise diagnosis. Arch Dis Child 1986;61(1):78-9. 9. Goldberg HJ. Neonatal convulsions - a 10 year review. Arch Dis Child 1983;58(12):976-8. 10. Nunes ML, Martins MP, Barea BM, Wainberg RC, Costa JC. Neurological outcome of newborns with neonatal seizures: a cohort study in a tertiary university hospital. Arq Neuropsiquiatr 2008;66(2A):168-74. 11. Rose AL, Lombroso CT. A study of clinical, pathological, and electroencephalographic features in 137 fullterm babies with a long-term follow-up. Pediatrics 1970;45(3):404-25. 12. Taeusch WH, Ballard RA, Gleason CA (Eds.). Averyâ&#x20AC;&#x2122;s Diseases of the Newborn. 8th edition, Saunders 2004: p.1005-25. 13. Keen JH, Lee D. Sequelae of neonatal convulsions. Study of 112 infants. Arch Dis Child 1973;48(7):542-6. 14. Iype M, Prasad M, Nair PM, Geetha S, Kailas L. The newborn with seizures - a follow-up study. Indian Pediatr 2008;45(9):749-52. 15. Volpe JJ, Neonatal seizures. In: Neurology of Newborn. 4th edition, Volpe JJ (Ed.), WB Saunders: Philadelphia 2001:p.178-214.

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Pulmonology

Pulmonary Alveolar Microlithiasis: A Clinicoradiological Dissociation Debaprasad Chakrabarti*, Prabhat Debbarma**, Amrit Kumar Bhattacharyyaâ&#x20AC; 

Abstract Pulmonary alveolar microlithiasis (PAM) is a rare and slowly progressive disease characterized by widespread calcification within the alveoli with a paucity of symptoms in contrast to radiologic findings. We report here a case of pulmonary alveolar microlithiasis who presented to us with minimal chest complaints following chest trauma despite extensive imaging findings.

Keywords: Pulmonary alveolar microlithiasis

P

ulmonary alveolar microlithiasis (PAM) is an uncommon disease characterized by multiple microscopic calculi within the alveolar space in the absence of any known disorder of calcium metabolism.1-5 Symptoms related to PAM usually begin in the third or fourth decade and follow an autosomal recessive pattern.1,6 A hallmark of this disease is a striking dissociation between the radiological findings and the only mild clinical signs and symptoms. Pathogenesis of PAM is yet to be elucidated, though, recently mutation in the type-IIb sodium-phosphate cotransporter gene has been implicated.7 Case report A 27-year-old nonsmoker male presented to us with a history of mild chest pain following a history of blunt chest trauma sustained three months back. There was no history of cough, breathlessness, fever, joint pain or skin lesions. On physical examination, his blood pressure was 118/70 mmHg, pulse rate 68 bpm, respiratory rate 18 cycles/min without any clubbing, cyanosis or peripheral edema. Chest examination revealed bilateral symmetrical chest without deformity. On auscultation, there were very few scattered crackles at the bases. Rest of systemic examination was essentially normal.

were normal. Arterial blood gas analysis, echocardiography, pulmonary function tests (PFTs) and USG abdomen did not reveal any abnormality. As a part of routine test for chest trauma to find out the cause of chest pain, a chest radiograph was asked for, which showed diffuse micronodular calcification in both lungs, more pronounced in mid and lower zones (Fig. 1). A high-resolution computed tomography (HRCT) scan was then obtained, which revealed micronodular calcified opacities throughout both lungs (Figs. 2 and 3). Based on these clinicoradiological findings, a provisional diagnosis of PAM was considered and a lung biopsy was done, which showed round, concentrically laminated microliths in the alveoli confirming the diagnosis of PAM. The bronchoalveolar lavage fluid was negative for acid-fast bacilli (AFB) or fungi.

Investigations revealed normal complete blood count (CBC). His blood sugar, serum electrolytes, serum calcium, phosphorus and liver function tests *Associate Professor Dept. of Medicine, Tripura Medical College and Dr BRAM Teaching Hospital, Agartala **Assistant Professor Dept. of Radiodiagnosis, Agartala Govt. Medical College and GB Panth Hospital, Agartala â&#x20AC; Professor and Head Dept. of Medicine, Tripura Medical College and Dr BRAM Teaching Hospital, Agartala

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Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

Figure 1. Chest X-ray showing bilateral diffuse micronodular calcification (sandstorm-like).


Pulmonology

Figure 2. HRCT chest showing septal thickening with bilateral multiple calcified nodules.

include ground glass opacity (most common), subpleural calcification, confluent and diffuse calcified nodules and dense consolidation. Septal thickening, ‘black pleura’ sign due to subpleural cyst and crazy paving pattern have also been described.7 But, imaging studies cannot confirm PAM in the absence of a histological diagnosis on transbronchial lung biopsy. Some findings of PAM like nodular calcification may be seen in tuberculosis, metastatic osteosarcoma, amyloidosis, silicoproteinosis, etc. Measurement of surfactant protein A (SP-A) and surfactant protein D (SP-D) can be considered as an alternative in monitoring disease activity.8 The prognosis is dismal with no effective treatment. Use of disodium etidronate in the treatment of PAM is associated with mixed results. Lung transplantation is the only hope for end-stage PAM. Conclusion Our patient had all the clinical, radiological and histological findings, which make PAM a secure diagnosis. The case is presented because of its rarity. The striking dissociation between the frightening imaging findings and virtually asymptomatic status of the individual will sensitize the clinicians to consider PAM in every such patient to avoid misdiagnosis. References

Figure 3. HRCT thorax showing subpleural calcification and calcification along interlobar septa.

1. Barbolini G, Rossi G, Bisetti A. Pulmonary alveolar microlithiasis. N Engl J Med 2002;347(1):69-70.

Discussion

2. Cluzel P, Grenier P, Bernadac P, Laurent F, Picard JD. Pulmonary alveolar microlithiasis: CT findings. J Comput Assist Tomogr 1991;15(6):938-42.

PAM is an uncommon disease characterized by numerous small calculi in alveolar spaces with a chronic and deteriorating evolution.1 Patients may be asymptomatic for many years and usually become symptomatic between third and fourth decades.2,3 Clinical presentation includes cough, breathlessness and chest pain and a lung disorder with restrictive pattern.3,7 Adult patients show a slowly progressive downhill course with decline in lung function, resulting in respiratory failure and cor pulmonale. Death can occur in midlife. It is an autosomal recessive disease; the etiopathogenesis is still unclear. The role of mutation in type-IIb sodium-phosphate co-transporter gene (SCL34A2 gene) present on chromosome 4, which regulates phosphate homeostasis in various organs including lung has been recently implicated.7 Plain chest x-ray usually shows diffuse bilateral symmetric micronodular calcification (sandstorm) mainly in middle and lower zones; apical bullae and black pleural lines.5 HRCT thorax remains the imaging technique of choice to diagnose PAM. The findings

3. Hoshino H, Koba H, Inomata S, Kurokawa K, Morita Y, Yoshida K, et al. Pulmonary alveolar microlithiasis: highresolution CT and MR findings. J Comput Assist Tomogr 1998;22(2):245-8. 4. Marchiori E, Gonçalves CM, Escuissato DL, Teixeira KI, Rodrigues R, Barreto MM, et al. Pulmonary alveolar microlithiasis: high-resolution computed tomography findings in 10 patients. J Bras Pneumol 2007;33(5):552-7. 5. Korn MA, Schurawitzki H, Klepetko W, Burghuber OC. Pulmonary alveolar microlithiasis: findings on highresolution CT. AJR Am J Roentgenol 1992;158(5):981-2. 6. Castellana G, Gentile M, Castellana R, Fiorente P, Lamorgese V. Pulmonary alveolar microlithiasis: clinical features, evolution of phenotype, and review of the literature. Am J Med Genet 2002;111(2):220-4. 7. Huqun, Izumi S, Miyazawa H, Ishii K, Uchiyama B, Ishida T, et al. Mutations in the SLC34A2 gene are associated with pulmonary alveolar microlithiasis. Am J Respir Crit Care Med 2007;175(3):263-8. 8. Gasparetto EL, Tazoniero P, Escuissato DL, Marchiori E, Frare E Silva RL, Sakamoto D. Pulmonary alveolar microlithiasis presenting with crazy-paving pattern on high resolution CT. Br J Radiol 2004;77(923):974-6.

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Psychiatry

Personality Characteristics in the Patients of Obsessive Compulsive Disorder Krishan Kumar*, Gurpreet Kaur**, Brahmdeep Sindhu†, Rajneesh Kumar‡, Sachin¶

Abstract The relationship between obsessional personality traits and obsessive compulsive disorder (OCD) has long been the subject of debate. Although clinicians have asserted for nearly a hundred years that such a relationship exists, empirical investigations have failed to provide consistent support; however, none of these empirical investigations have undertaken analyses that control for the effect of mood variables. Employing a non-clinical sample, some psychologists found that when mood variables are taken into account, a unique relationship between obsessional traits and obsessional symptoms emerges. A replication was undertaken on a large group of individuals with OCD. After the effects of depression and anxiety were removed from a correlational analysis, obsessional symptoms were found to be significantly associated with obsessional and passive aggressive traits. OCD was not associated with any other grouping of traits as specified in the DSM-1II-R (Axis II) classification system.

Keywords: Obsessive compulsive disorder, mood variable, obsessional traits

T

he relationship between obsessive compulsive disorder (OCD) and various forms of the ‘obsessional personality’ has been under discussion for nearly a hundred years (Janet, 1903). Opinions vary with respect to the exact nature of this relationship. Traditionally, the presence of a premorbid obsessional personality was thought to favor the development of obsessional symptoms (Freud, 1908); however, more recently, it has been suggested that obsessional personality features may develop after the onset of OCD as part of a general coping response (Berg, Rapoport, Whitaker et al, 1989). Theoretically, a mixture of these positions is also possible, whereby specific traits potentiate the emergence of particular symptoms and vice-versa. There have been virtually only a few researches examining the mechanisms that govern the relationship between obsessional traits and symptoms. This is largely because investigations have failed to move beyond repeated and unsatisfactory attempts at confirming that such a relationship exists at all.

*Clinical Psychologist, National Brain Research Centre, Manesar **Scientist C, DIPR, DRDO, New Delhi †Senior Psychiatrist, General Hospital, Gurgaon ‡Neurologist, Paras Hospital, Gurgaon ¶Research Scholar, University of Rajasthan, Jaipur Address for correspondence Dr Krishan Kumar Clinical Psychologist, National Brain Research Centre, Manesar, Gurgaon E-mail: keshusony@rediffmail.com

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Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

The first detailed description of a personality type thought to favor the development of obsessive compulsive symptoms was provided by Janet (1903) in his ‘Les Obsession et La Psychaesthenie.’ The ‘psychasthenic state’ was characterized by a broad range of personality features, many of which still appear in its contemporary successor, obsessive compulsive personality disorder (American Psychiatric Association, 1994). The full complement of psychasthenic features included feelings of incompleteness, doubt, an inner sense of imperfection, a need for uniformity and order, pedantry, a restricted range of emotional experience, excessive cleanliness, poor thought control and a fondness for collecting things. Some five years after Janet’s publication, Freud (1908) also endorsed the distinction between an obsessional personality and obsessional symptoms. For Freud, an ‘obsessional neurosis’ was more likely to arise in an individual showing features of the ‘anal erotic character’, which marked the coincidence of three traits: Obstinacy, parsimony and orderliness. Although, the theoretical framework employed by Freud to explain the development of both the ‘anal erotic character’ and ‘obsessional neurosis’ is widely recognized as weak, all three features of the ‘anal erotic character’ have survived to be included in the diagnostic criteria for obsessive compulsive personality disorder (OCPD). In Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (American


Psychiatry Psychiatric Association, 1994), OCPD is described as ‘A pervasive pattern of preoccupation with orderliness, perfectionism and mental and interpersonal control, at the expense of flexibility, openness and efficiency’. The diagnostic criteria employed are very similar to those used in International Classification of Diseases, 10th Revision (ICD-10) (World Health Organization, 1992) for the Anankastic personality. A meaningful distinction between OCPD and the Anankastic personality cannot be made, as both sets of criteria are clearly designed to capture the same clinical entity. Although, the obsessional personality has been accepted as a clinical reality (cf. Pollak, 1979), its relationship with OCD remains contentious. Some studies suggest that the relationship exists (Black, 1974), while others do not (Steketee, 1990). After reviewing the literature, Baer and Jenike (1992) concluded that the majority of patients with OCD have at least one personality disorder; however, OCPD is in the minority, often occurring less frequently than mixed, dependent, avoidant and histrionic types. This failure to find a consistent relationship between obsessional traits and symptoms is rather perplexing to clinicians, who, on the whole, have tended to favor the idea that OCD is associated with ‘a certain type’ of character, be that the ‘obstinate’ or ‘vacillating’ types described by Lewis (1936) or the person of ‘strict conscience’ described by Rachman and Hodgson (1980). Moreover, principle component analyses of items included in measures of OCD tend to yield trait like factors. For example, Cooper and Keileher (1973) conducted several such analyses on the Leyton Obsessional Inventory (LOI) (Cooper, 1970). Common to all analyses were three components or factors. Two of these reflected the cardinal features of OCD, namely, washing and checking; however, a third reflected a ‘feeling of incompleteness’. It is interesting to note that the incompleteness component of the LOI bears a strong resemblance to Janet’s (1903) ‘sentiment d’ incompletud’. Rosen and Tallis (1995) have suggested that previous investigations failed to find a specific relationship between OCPD and OCD because the effects of mood were not taken into account. Controlling for mood effects in the analysis of data is of great importance insofar as anxiety and depression may obscure the specific relationship between OCPD and OCD. Employing a non-clinical population, significant correlations were found between obsessional symptoms, as measured by the Maudsley Obsessional-Compulsive Inventory (MOCI), and 10 out of 13 personality disorders as measured by the Personality Diagnostic Questionnaire-

Revised (PDQ-R) (Hyler & Rieder, 1987); however, once the effects of anxiety and depression were removed from the analysis, only one significant relationship remained. This was between OCPD and OCD. The results reported by Rosen and Tallis (1995) appear to support the view that OCPD and OCD are positively related; however, the data were collected from a nonclinical population. It is possible that the method of analysis employed, although capable of yielding promising results on a non-clinical population, would not yield similar results when applied to a large clinical group. Aim To examine the association between obsessional traits and symptoms. METHOD

Sample Seventy-seven individuals suffering from OCD were taken for the present study. Fifty-one were female and 26 were male. All had volunteered their names for entry onto a research data base; initial inclusion on this database was determined if they had scored 11 or above on the MOCI (Hodgson & Rachman, 1977). A subsample of 46 respondents was randomly selected for interview. All but one met DSM-III-R criteria for OCD. This suggests that 98% of the subjects participating in the present study would meet DSM-III-R criteria for a diagnosis of OCD. The mean age of the 77 respondents was 39 (SD = 10.017). The minimum age was 18, while the maximum age was 66.

Instruments PDQ-R (Hyler & Rieder, 1987) is a 151-item, selfadministered, forced-choice; true/false diagnostic instrument measuring all DSM-III-R (American Psychiatric Association, 1987) Axis-II personality disorders and also includes the provisional diagnoses of sadistic and self-defeating personality disorders. It yields a global PDQ-R score indicating overall personality pathology in addition to giving individual threshold scores on each of the Axis-II criteria. Its criteria are identical to DSM-III-R, Axis-II. MOCI (Hodgson & Rachman, 1977) is a 30-item, selfadministered, forced-choice, true/false measure of obsessional symptoms. The MOCI yields a total, global obsessionality score in addition to scores on four subscales: Checking, washing, slowness and doubting. It is stable psychometrically tool (Hodgson & Rachman,

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Psychiatry 1977) and has been used in a variety of studies to assess obsessional symptomatology in both clinical and nonclinical samples (e.g. Sher, Frost, Kushner, Crews & Alexander, 1989; Salkovskis & Harrison, 1984). Beck Depression Inventory (BDI) (Beck, Ward, Mendelson, Mock & Erbaugh, 1961) was included as a measure of depression. It consists of 84 self-evaluative statements grouped into 21 categories that assess the cognitive, motivational and physiological symptoms of depression based on a one-week time frame. For each item there is a graded series of four alternative statements ranging from neutral to a maximum level of severity. The items are scored from 0 to 3 so that the total BDI score range is from 0 to 63. High test-retest values have been reported (Beck et al., 1961) and it has been found to have high levels of internal consistency (e.g. Strober et al., 1981). Spielberger State Trait Anxiety Inventory (STAI): Trait Scale, Form Y (STAI-Y) (Spielberger, Goruch, Lushene, Vagg & Jacobs, 1980) was used as a measure of trait anxiety and consists of a 20-item self-report measure developed to assess the separate concepts of state and trait anxiety. These are scored on a 4-point scale of intensity ranging from ‘almost never’ to ‘almost always’. The trait items are expected to be relatively stable and free from the influence of situational stresses. STAI has been found to possess high internal consistency, and the trait form has demonstrated good test-retest reliability for intervals upto three months (Spielberger et al., 1980).

RESULTS The means and standard deviations for the MOCI, MOCI subscales, the BDI and the STAI-Y are shown in Table 1. All are in ranges suggesting clinical status. Pearson’s correlation coefficients were calculated for the data. All tests were two-tailed. Given the statistical problems associated with analyses employing multiple correlations, only those relationships significant at p < 0.01 and p < 0.001 are reported. MOCI total scores were significantly correlated with PDQ-R total scores and scores for nine out of 13 personality disorders (antisocial, avoidant, borderline, histrionic, narcissistic, obsessive compulsive, passive aggressive, sadistic and self-defeating). The washing subscale was significantly correlated with PDQ-R total scores, and scores for borderline, histrionic, obsessive compulsive, passive aggressive and self-defeating personality traits. The doubting subscale was significantly correlated Table 1. Mean and Standard Deviations (in Parentheses) for the MOCI, MOCI Subscales, BDI and the STAI-Y MOCI

Total

14.13

(5.59)

Slowness

2.83

(1.34)

Washing

3.82

(2.74)

Doubting

4.57

(1.84)

4.69

(2.27)

BDI

Checking

17.39

(11.43)

STAI-Y

54.04

(12.85)

Table 2. MOCI and Personality Disorder Bivariate Correlation Coefficients Personality disorder

MOCI total

Slowness

Washing

Doubting

Checking

PDQ-R total

0.568**

0.144

0.316*

0.589**

0.409**

Antisocial

0.288*

0.148

0.158

0.191

0.259

Avoidant

0.341*

-0.081

0.241

0.375*

0.232

Borderline

0.464**

0.235

0.273*

0.415**

0.332*

Dependent

0.260

0.025

0.185

0.325*

0.108

Histrionic

0.446**

0.152

0.281*

0.401**

0.290*

Narcissistic

0.350*

-0.044

0.197

0.338*

0.275*

Obsessive compulsive

0.514**

0.192

0.330*

0.591**

0.348*

0.169

-0.031

-0.031

0.168

0.235

Passive aggressive

0.491**

0.213

0.266*

0.611**

0.336*

Sadistic

0.317*

0.034

0.199

0.222

0.276*

Schizoid

0.108

-0.096

0.033

0.237

0.007

Schizotypal

0.258

0.062

0.258

0.243

0.220

0.477**

0.167

0.477**

0.552**

0.339*

Paranoid

Self-defeating *P < 0.01, **P < 0.001

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Psychiatry Table 3. MOCI and Personality Disorder Correlation Coefficients with BDI and STAI Partial Out Personality disorder PDQ-R total

MOCI total

Slowness

Washing

Doubting

Checking

0.288*

0.066

0.152

0.321*

0.169

Antisocial

0.195

0.149

0.097

0.045

0.180

Avoidant

0.047

-0.195

0.102

0.093

-0.013

Borderline

0.227

0.156

0.136

0.179

0.135

Dependent

0.009

-0.004

0.055

0.075

-0.091

Histrionic

0.252

0.111

0.167

0.169

0.120

Narcissistic Obsessive compulsive Paranoid Passive aggressive

0.102

-0.109

0.054

0.067

0.102

0.320*

0.176

0.216

0.413**

0.170

0.042

-0.069

-0.049

0.032

0.165

0.302*

0.184

0.149

0.471**

0.155

Sadistic

0.153

-0.020

0.106

0.039

0.146

Schizoid

-0.162

-0.216

-0.101

0.032

-0.210

Schizotypal

0.109

0.003

-0.005

0.109

0.094

Self-defeating

0.202

0.098

0.060

0.307*

0.120

*P < 0.01, **P < 0.001

with PDQ-R total scores, and scores for avoidant, borderline, dependent, histrionic, narcissistic, obsessive compulsive, passive aggressive and selfdefeating personality traits. The checking subscale was significantly correlated with PDQ-R total scores, and scores for borderline, histrionic, narcissistic, obsessive compulsive, passive aggressive, sadistic and selfdefeating personality traits. All these relationships are shown in Table 2. When partial correlations were calculated, controlling for the effects of depression and anxiety (as measured by the BDI and the STAI-Y), most of these significant relationships disappeared. The MOCI total scores remained significantly correlated with PDQ-R total scores (r = 0.288, p < 0.01) and scores for obsessive compulsive (r = 0.320, p < 0.01) and passive aggressive personality traits (r = 0.302, p < 0.01) only. Doubting subscale scores remained significantly correlated with PDQ-R total scores (r = 0.321, p < 0.01) and scores for obsessive compulsive (r = 0.413, p < 0.01), passive aggressive (r = 0.471, p < 0.01) and self-defeating (r = 0.301, p < 0.01) personality traits. These relationships are shown in Table 3. DISCUSSION The present study demonstrated that obsessional symptoms, as measured by the MOCI, are associated with a wide range of personality traits, as measured by the PDQ-R. Significant associations were found between the MOCI and traits subsumed under the following DSM-III-R Axis-II headings: Antisocial, avoidant, borderline, histrionic, narcissistic, obsessive

compulsive, passive aggressive, sadistic and selfdefeating. When subsequent analyses were undertaken controlling for the effects of depression and anxiety, only two significant relationships were preserved. That is between the MOCI and obsessive compulsive personality traits and between the MOCI and passive aggressive personality traits. The doubting subscale of the MOCI accounted for much of the relationship observed between MOCI total and PDQ-R total scores. The doubting subscale was also significantly correlated with self-defeating personality traits after partialling out the effects of anxiety and depression. In an initial investigation employing a non-clinical population (Rosen & Tallis, 1995), the same method of analysis demonstrated a significant association between obsessional symptoms and obsessive compulsive personality traits only. This suggests that increasing severity of obsessional symptoms captures a specific association with passive aggressive characteristics. The relationship between obsessional symptoms and passive aggressive personality traits will be considered before the main findings of the present study are discussed in detail. It should be noted that Passive Aggressive Personality Disorder (PAPD) is no longer listed in the Axis-II section of the DSM-IV. Evidence in favor of the construct was considered insufficient to warrant inclusion as an official diagnostic category; however, PAPD may appear in future editions of the DSM under a new heading, i.e. â&#x20AC;&#x2DC;Negativistic Personality Disorderâ&#x20AC;&#x2122;. Given that PAPD has been excluded from the current DSM and that the

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Psychiatry PDQ-R was based on the DSM-III-R system, DSM-III-R will be used as a basis for the present discussion. PAPD is described as: “A pervasive pattern of passive resistance to demands for adequate social and occupational performance.” Although individual criteria show some overlap with obsessional traits and symptoms (e.g. procrastination and slowness), the overlap is no more significant than can be found in several other personality disorders. For example, sensitivity to criticism is found in Avoidant Personality Disorder (Beck, Freeman, Pretzer, Davis, Fleming, Ottaviani, Beck, Simon, Padesky, Meyer & Trexler, 1990) and is also strongly associated with compulsive checking (Rachman, 1976). Overlapping criteria may be less relevant than the beliefs that are shared by individuals with OCD and PAPD. Central beliefs associated with PAPD include: “Being controlled or dominated by others is intolerable”, “I have to do things my own way” and “it is best not to express my anger directly but to show my displeasure by not conforming” (Beck et al., 1990). These reflect several common features found in OCD, namely, preoccupation with control (McFall & Wollersheim, 1979), rigidity (Guidano & Liotti, 1983) and difficulty expressing anger (Rachman, 1993; Tallis, 1994). It is interesting that the inadequate occupational performance described in PAPD is also a feature of OCD. For example, Rachman (1993) suggests that avoidance of excessive responsibility in individuals with OCD often leads to underachievement at work. Although some beliefs associated with PAPD may be relevant to OCD, the passive aggressive style of social interaction may represent a coping response. As such, traits associated with PAPD may develop as a consequence of existing obsessional problems. Many patients with OCD suffer a unique conflict that arises between rigidity and difficulty expressing anger. If an individual with OCD insists that significant others participate in certain rituals and anger cannot be employed to overcome resistance, then alternative strategies to gain compliance must be adopted. A passive aggressive attitude may provide the means of encouraging collusion without violating the selfimposed prohibition of the expression of anger. Shafran, Ralph and Tallis (1995) found that 60% of relatives are involved to some extent with the rituals of an affected family member. This suggests that individuals with OCD are able to develop sophisticated and effective methods of manipulating those who share their domestic environment. The main finding of the present study suggests that obsessional traits and symptoms are associated,

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consistent with some observations recorded in the clinical literature; however, it should be noted that the relationship between OCD and OCPD appears to be largely attributable to scores on the doubting subscale of the MOCI. This has important implications with respect to how the concept of the obsessional personality is interpreted. There is certainly some overlap between the items included in the doubting subscale of the MOCI and the obsessional trait items included in the PDQ-R, particularly those that appear to reflect constructs such as perfectionism and moral sensitivity. Nevertheless, the vast majority of items do not overlap. There are no specific ‘doubt’ items included in the PDQ-R, and the doubting subscale of the MOCI does not include any specific items that reflect rigidity, dedication to work, indecisiveness and restricted range of affect, parsimony and difficulty discarding possessions. In addition, although it might be argued that the doubtrelated items on the MOCI reflect a trait, Hodgson and Rachman (1977) underscore the efforts made during the development of the instrument to exclude items that might reflect traits. As such, all of the subscales of the MOCI should be regarded as measures of symptoms or complaints. Conclusion The main finding from the present study suggests that a relationship exists between a subset of obsessive compulsive symptoms and the personality traits that constitute OCPD. The doubting subscale of the MOCI includes items such as ‘I have a strict conscience’, “I tend to get behind in my work because I repeat things over and over again”, and “I usually have serious doubts about the simple everyday things I do.” These suggest that the obsessional patient with OCPD traits is likely to exhibit a symptom cluster characterized by unwanted intrusive thoughts (particularly those that violate a strict moral code), repetition (particularly when accompanied by a sense of incompletion) and doubts about everyday actions. This is consistent with Rachman and Hodgson (1980), who, although questioning the validity of the obsessional personality, suggested that specific obsessional traits might be related to specific obsessional symptoms. It is relatively easy to see how moral sensitivity will result in much of the ‘stream of consciousness’ being regarded as unwanted or intrusive. Similarly, a trait such as perfectionism will more than likely produce symptoms that reflect concern over detail; however, it is unclear why obsessional traits such as restricted affect or parsimony should be related to doubts about everyday actions or ‘repeating’. It seems plausible


Psychiatry therefore, to suggest that the diagnostic criteria of OCPD conceal a set of core personality features that relate very closely to the symptom subset captured by the doubting subscale of the MOCI. This set of core personality features might form the basis of a reformulated obsessional personality type. Although there is insufficient evidence to infer all the elements of such a personality type, moral sensitivity could certainly be granted a central position. The determinants of moral sensitivity may be closely associated with elements of the obsessional belief system already under investigation, most notably, exaggerated responsibility, thought action fusion and extended personal influence (Salkovskis, 1985; Rachman, 1993; Tallis, 1995). If the core features of a reformulated obsessional personality could be understood in terms of underlying beliefs, then such beliefs might serve as legitimate targets for modification in therapy. As such, the treatment of patients exhibiting doubt related symptoms might routinely include specific â&#x20AC;&#x2DC;schema focusedâ&#x20AC;&#x2122; components. Suggested Reading 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders III (3rd edition Review), American Psychiatric Association: Washington, DC, 1987. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders IV (4th edition), American Psychiatric Association: Washington, DC, 1994. 3. Baer L, Jenike MA. Personality disorders in obsessive compulsive disorder. Psychiatr Clin North Am 1992;15(4):803-12. 4. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561-71. 5. Beck AT, Freeman A, Pretzer J, Davis D, Fleming B, Ottaviani R, et al. Cognitive Therapy of Personality Disorders. Guilford: New York, 1990. 6. Berg CZ, Rapoport JL, Whitaker A, Davies M, Leonard H, Swedo SE, et al. Childhood obsessive compulsive disorder: a two-year prospective follow-up of a community sample. J Am Acad Child Adolesc Psychiatry 1989;28(4):528-33. 7. Black A. The natural history of obsessional neurosis. In: Obsessional States. Beech HR (Ed.), Methuen: London 1974:p.1-23. 8. Cooper J. The Leyton obsessional inventory. Psychol Med 1970;1(1):48-64. 9. Cooper J, Kelleher M. The Leyton Obsessional Inventory: a principal components analysis on normal subjects. Psychol Med 1973;3(2):204-8. 10. Freud S. Character and anal eroticism. In: Collected Papers. 2. Hogarth: London,1908. 11. Guidano VL, Liotti G. Cognitive Processes and Emotional Disorders. Guilford: New York, 1983.

12. Hodgson RJ, Rachman S. Obsessional-compulsive complaints. Behav Res Ther 1977;15(5):389-95. 13. Hyler SE, Rieder RO. Personality Diagnostic Questionnaire-Revised (PDQ-R). New York State Psychiatric Institute: New York, NY, 1987. 14. Janet P. Les Obsessions et la Psychaesthenie. Paris: Alcan, 1903. 15. Lewis A. Problems of Obsessional Illness: (Section of Psychiatry). Proc R Soc Med 1936;29(4):325-36. 16. McFall ME, Wollersheim JP. Obsessive-compulsive neurosis: a cognitive-behavioural formulation and approach to treatment. Cogn Ther Res 1979;3(4):333-48. 17. Pollak JM. Obsessive-compulsive personality: a review. Psychol Bull 1979;86(2):225-41. 18. Rachman S. Obsessional-compulsive checking. Behav Res Ther 1976;14(4):269-77. 19. Rachman S. Obsessions, responsibility and guilt. Behav Res Ther 1993;31(2):149-54. 20. Rachman SJ, Hodgson R. Obsessions and Compulsions. Englewood Cliffs, NJ: Prentice-Hall. International: Hemel Hempstead, 1980. 21. Rosen KV, Tallis F. Investigation into the relationship between personality traits and OCD. Behav Res Ther 1995;33(4):445-50. 22. Salkovskis PM. Obsessional-compulsive problems: a cognitive-behavioural analysis. Behav Res Ther 1985;23(5):571-83. 23. Salkovskis PM, Harrison J. Abnormal and normal obsessions - a replication. Behav Res Ther 1984;22(5):54952. 24. Shafran R, Ralph J, Tallis F. Obsessive-compulsive symptoms and the family. Bull Menninger Clin. 1995;59(4):472-9. 25. Sher KJ, Frost RO, Kushner M, Crews TM, Alexander JE. Memory deficits in compulsive checkers: replication and extension in a clinical sample. Behav Res Ther 1989;27(1):65-9. 26. Spielberger CD, Goruch RL, Lushene R, Vagg PR, Jacobs GA. Manual for the State-Trait Anxiety Inventory. Consulting Psychologists Press: Palo Alto, CA, 1980. 27. Steketee GS. Personality trait and disorders in obsessive compulsives. J Anx Dis 1990;4:351-64. 28. Strober M, Green J, Carlson G. Utility of the Beck Depression Inventory with psychiatrically hospitalized adolescents. J Consult Clin Psychol 1981;49(3):482-3. 29. Tallis F. Obsessions, responsibility and guilt: two case reports suggesting a common and specific aetiology. Behav Res Ther 1994;32(1):143-5. 30. Tallis F. Obsessive Compulsive Disorder: A Cognitive and Neuropsychological Perspective. New York: Wiley, 1995. 31. Tallis F. Compulsive washing in the absence of phobic and illness anxiety. Behav Res Ther 1996;34(4):361-2. 32. World Health Organization. The ICD-IO Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. World Health Organization: Geneva, 1992.

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Surgery

A Rare Case of Superior Mesenteric Vein Aneurysm Anjana V Trivedi*, Maulik C Jethva**, Jatin G Bhatt†, Daxa L Chavda‡

Abstract Aneurysms of the superior mesenteric vein (SMV) are rare. Many aneurysms are asymptomatic and the diagnosis is established from radiologic findings. We present a case report of superior mesenteric vein aneurysm. The diagnosis of this anomaly was made after investigation of pain in abdomen. Computed tomography ( CT) scans demonstrated the mass. Case was treated by medical treatment.

Keywords: Venous aneurysm, superior mesenteric vein, CT scan

V

enous aneurysms are less common than arterial aneurysms in clinical practice, and the occurrence of isolated cases is a topic of publication. Aneurysms of superior mesenteric vein (SMV) are rare. The etiology of this aneurysm is unclear, as they are found in both asymptomatic individuals and in those with concurrent disease. Here, we present a case with no predisposing factor.

Case report A 55-year-old woman presented with pain in abdomen since last two months. This was not accompanied by any alteration in intestinal habits, increase in abdominal volume or weight loss. There was no history of abdominal trauma. Physical examination revealed good general health. Chest auscultation was normal. Clinically, the abdomen appeared normal except enlarged spleen. Vascular physical examination demonstrated normal arterial pulses and absence of edema. There was no evidence of collateral venous circulation in the abdomen. To find out the cause of pain in abdomen, sonography of abdomen was done, which showed splenomegaly

*Associate Professor **Radiologist Dept. of Radiology †Professor, Dept. of Surgery ‡Assistant Professor, Dept. of Radiology PDU Medical College and Sanya GIC Imaging Centre, Rajkot, Gujarat Address for correspondence Dr Anjana V Trivedi 3-Africa Colony,150-feet Ring Road, Near Water Tank, Rajkot - 360 007, Gujarat E-mail: dranjanatrivedi@yahoo.co.in

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and dilated portal vein with possibility of aneurismal dilatation of SMV. Liver and other structures were normal. For further evaluation, computed tomography (CT) was performed, which showed SMV dilated upto 3.5 cm, without internal thrombus (Fig. 1) near the level of the portal confluence. With contrast study, opacification of SMV up to (Fig. 2). Esophagoscopy was done To rule out esophageal varices, which showed esophageal varices. Case was treated by splenectomy and medical line of treatment. Discussion The portal vein is formed by the confluence of the SMV and splenic veins at the level of pancreatic head. It extends into the hepatoduodenal ligament and is divided into the right and left branches to supply both lobes of the liver.

SMV aneurysm

Figure 1. CT scan axial section shows a dilated (3.5 cm AP diameter) superior mesenteric vein without internal thrombosis.


Surgery use of iodinated intravenous contrast medium.5 Venous phase mesenteric angiography can be performed to confirm the diagnosis.6 The multiplaner capability of magnetic resonance imaging (MRI) along with the capacity to render angiogram-like images of vascular structures make MRI well-suited to the evaluation of such an aneurysm.

Figure 2. CT scan (contrast) axial section shows a dilated (3.5 cm AP diameter) superior mesenteric vein with opacification.

The SMV is located anteriorly and to the right side of the superior mesenteric artery and posteromedial to the head of pancreas. Normally, the SMV measures 1.2 cm in diameter.1 Its size was reported as abnormal if it measured >1.6 cm in diameter. SMV aneurysm is a rare condition; the first case was reported by Barzilai and Kleckner in 1956.2 The origin of this aneurysm is unknown, but some theories have been put forward. Weakness of the vessel wall may give rise to venous dilatation, even under normal venous pressure.3 Another possibility involves an embryologic mechanism; i.e., the persistence of a remnant of the right vitelline vein during development of the portal system forms a diverticulum, which may persist and develop into an aneurysm.3 In clinical practice, venous aneurysms are not common; most patients with intra-abdominal venous aneurysm seek medical assistance because of vague abdominal pain. Some patients may have gastrointestinal bleeding, acute venous occlusion or pulmonary embolism.4 In most cases reported, sonography was the first imaging technique performed, because it is noninvasive. The aneurysm appeared as an anechnoic structure near the head of pancreas. Their vascular nature is confirmed with color Doppler. Sonography, which also reveals that these aneurysms fill completely with color flow unless they contain thrombosis. Duplex Doppler sonography demonstrates a monophasic wave form characteristic of the superior mesenteric vein. Flow within the superior mesenteric vein is directed toward the portal confluence. CT scan reveals the size and extent of the lesion, and confirms its vascular origin, but requires

However, due to invasiveness of angiographic procedure, sonography, CT and MRI are preferred in most instances. The number of cases of SMV aneurysm is small, so the natural history and clinical evolution of such aneurysms are not clear. First-line management has changed over time, with there being a shift from surgical to conservative management. Initially, it was thought that surgical intervention with either shunting or aneurysmorrhaphy procedure was the treatment of choice, particularly in cases with evidence of portal hypertension.7 However, instead of the surgical approach, it may now be appropriate to follow-up patients conservatively with serial imaging.6 Conclusion Because an SMV aneurysm is a rare anomaly and its long-term evolution is not known, patients should be clearly informed of possible complications, including rupture and thrombosis. References 1. Bolondi L, Gandolfi L, Arienti V, Caletti GC, Corcioni E, Gasbarrini G, et al. Ultrasonography in the diagnosis of portal hypertension: diminished response of portal vessels to respiration. Radiology 1982;142(1):167-72. 2. Barzilai R, Kleckner MS Jr. Hemocholecyst following ruptured aneurysm of portal vein; report of a case. AMA Arch Surg 1956;72(4):725-7. 3. Schild H, Schweden F, Braun B, Lang H. Aneurysm of the superior mesenteric vein. Radiology 1982;145(3):641-2. 4. Nishinari K, Wolosker N, Yazbek G, Nakagawa WT, Lopes A. Idiopathic aneurysm of inferior vena cava associated with retroperitoneal ganglioneuroma: case report. J Vasc Surg 2003;37(4):895-8. 5. Sedat J, Padovani B, Chanalet S. Aneurysm of the superior mesenteric vein. AJR Am J Roentgenol 1993;161(4):903-4. 6. Fulcher A, Turner M. Aneurysms of the portal vein and superior mesenteric vein. Abdom Imaging 1997;22(3):28792. 7. Perret WL, de Silva A, Elzarka A, Schelleman A. Portal circulation aneurysms: two case reviews. Australas Radiol 2007;51(1):87-90.

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85


Urology

Phytotherapy for Lower Urinary Tract Symptoms due to Benign Hyperplasia of Prostate Tapas Maitra

Abstract Phytotherapy, the use of plant extracts is long established in France and Germany, and so products containing extracts of Serenoa repens and Pygeum africanum, among others, have a market share of upto 50% of all preparations used for the treatment of symptomatic benign prostatic hyperplasia (BPH). In these countries, plant extracts are prescribed drugs, their costs being totally or partially reimbursed by the healthcare system, in contrast to the UK, where they are neither approved nor reimbursed. More commonly used medicines for BPH are a-blockers (reduce smooth muscle tone at bladder neck and adenoma) and 5a-reductase inhibitors (reduce the volume of adenoma), but in sexually active patients 5a-reductase inhibitors reduce the libido. Although, these plant extracts help to reduce lower urinary tract symptoms (LUTS) due to BPH but their use is limited and controversial because of the lack of established mechanism of action, efficacy and safety. Clinical trials of large scale, long duration with controlled group is not available.

Keywords: Phytotherapy, lower urinary tract symptoms, benign prostatic hyperplasia

P

hytotherapy is thought to have its roots in Chinese herbal medicine, a practice that has evolved during the past 5,000 years. Traditional medicine (also known as indigenous or folk medicine) and phytotherapy continue to play a central role in the healthcare of about one-third of the world’s population in developing countries and accounts for 80% of primary healthcare in Africa due to the lack of essential medicine.1 According to some US urologists, 50-90% of newly referred patients with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) have already tried or are using some form of alternative medicine at the time of their presentation. ‘Natural agents’ are commonly believed to be devoid of any side effects and are thought to might be as efficacious as synthetic and chemical products. Another factor for increased use of phytotherapeutic agents in the United States is the availability and ease with which consumers can obtain them. They are readily available in supermarkets, food stores, pharmacies. Due to patient demand, urologists

Associate Professor Dept. of Urology North Bengal Medical College, Sushrutanagar, West Bengal Address for correspondence Dr Tapas Maitra SUBINA, Sarat Bose Road, Hakimpara, Darjeeling, Siliguri, West Bengal - 734 001 E-mail: urmi_811@yahoo.com

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Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013

have to be familiar with these agents, their advantages and disadvantages, side effects, proposed mechanism of action, interaction with other drugs. Origin of some of the commonly used phytotherapeutic agents is given in Table 1. Proposed Mode of Action The proposed mechanism of action of many products has yet to be elucidated, although antiestrogenic and proapoptotic effects have been reported for some preparations, along with inhibition of 5a-reductase activity (see Table 2). Proposed active constituents of plant extracts are phytosterols, phytoestrogens, free fatty acids, lectins, flavonoids, plant oils and polysaccharides. In 1994, US Food and Drug Congress expanded the definition of ‘Dietary supplement’ to include herbal medicine, botanicals and other forms of phytotherapy.2 Before the passage of the act, few queries regarding these agents have to be addressed like: ÂÂ

Bioavailability of these agents

ÂÂ

Correct dosages and duration of therapy

ÂÂ

Is there a dose dependency?

ÂÂ

Standardization of the amount of active ingredient in each pill

ÂÂ

Is the mechanism of action clearly understood?


Urology Table 1. Origin of Phytotherapeutic Agents Used for LUTS due to BPH Common term

Source

American dwarf palm, saw palmetto

Fruit

South African star grass

Root

Pine

Root

Spruce

Root

African plum tree

Bark

Stinging nettle

Root

Rye

Pollen

Pumpkin

Seeds

Table 2. Proposed Mechanism of Action of Phytotherapeutic Agents Mechanism of action Inhibition of 5Îą-reductase activity

Extract Serenoa repens

Antiestrogenic effect

Pygeum africanum

Antiandrogenic effect

Serenoa repens

Induction of apoptosis Interference with prostaglandin metabolism

Serenoa repens Pygeum africanum

Inhibition of proliferative growth factor

Urtica dioica

Decrease of sex hormone binding globulin

Urtica dioica

Alteration of cholesterol metabolism

Pygeum africanum

Common Phytotherapeutic Compounds Use

African Plum Tree Extracts from the bark of the African plum tree (Pygeum africanum) are widely used in France andâ&#x20AC;ŻUS. The extract is believed to have anti-inflammatory and antiestrogenic effect as well as it inhibits fibroblast proliferation. Eleven constituents have been identified in the crude extract, including high levels of myristic acid, which is thought to affect membrane fluidity directly and to reduce the contact between propagating free radicals and unsaturated lipid substances, thereby slowing the process of hydrolysis and membrane degradation.3 Ishani et al4 examined 18 doubleblind clinical trials of P. africanum (n = 1,562) and assessed physician reported symptom improvement, nocturia, Qmax, post-void residual (PVR). Studies were methodologically difficult to perform. The meta-analysis showed that men receiving P. africuanum were more than twice as likely as those receiving placebo to be rated by their physician as

having symptom improvement (65% P. africanum group versus 30% placebo group; n = 430). Nocturia was decreased by 19% in three separate trials in man taking P. africanum over those taking placebo (n = 325), Qmax was increased by 23% in the P. africanum group in four studies (n = 363) compared with placebo. Finally, in two studies (M-264), PVR decreased by 24% in those taking P. africanum.4

Saw Palmetto The extract from the berries of the American dwarf palm (Serenoa repens) are the most popular plant-based products used in the treatment of symptomatic BPH.5 In Germany alone, >30 different products contain S. repens.5 Permixon (Pierre Fabre, Burlats, France), an n-hexane liposterolic extract of the saw palmetto berry, is the most common form of S. repens. The action of permixon is considered to be through uncompetitive inhibition of 5a-reductase resulting in lower level of dihydrotestosterone (DHT) formation from testosterone in the prostate gland.6 Lower level of DHT and higher level of testosterone have been identified in the prostates of permixontreated BPH patients, however, superficially at variance with an action as a 5a-reductase inhibitor, no significant effect on serum PSA or prostate volume has been demonstrated in several studies.7 The data on several potential mechanisms of action of S. repens are often confusing and contradictory and many of the effects described have only been demonstrated in vitro, often with considerably higher dosages of the extract than are recommended for clinical treatment. The commonly recommended dose of S. repens is 320 mg daily, often divided into two doses. A dose of 160 mg of permixon twice-daily seems to be as efficacious as two pills of 160 mg once-daily. Apart from occasional gastrointestinal side effect no significant side effects have been reported with the extract, in contrast to most other medical or surgical approaches.

Pumpkin Seed Pumpkin seed extracts (Cucurbita pepo) are usually used in combination with other extracts in the management of BPH. The use of pumpkin seed extracts in the management of LUTS due to BPH is common in Germany. The seeds contain a sweet, oily substance composed of linolic acid sterols, selen magnesium and carotinoid, the mechanism of action is thought to be antiandrogenic and antiphlogistic.8

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Urology One trial examined the efficacy of pumpkin seed extract alone. In this placebo-controlled, year-long study, 476 patients were randomly assigned to receive placebo or 500 mg/day of seed extract. Although, there was an identical effect in both groups in Qmax, quality-of-life, and PVR at study end, the group that received phytotherapy showed a decrease in International Prostate Symptoms Score (IPSS) (6.7 points) over the placebo group (5.5 points). This 1.2 point is statistically significant.9 CONCLUSION Uncontrolled studies with low patient numbers and of short duration, not performed according to accepted standards and guidelines, are of questionable value. Meta-analysis are only acceptable if the quality of the studies included is assessed and shown to be appropriate. Due to the widely controversial and partly insufficient ‘hard’ data about the efficacy of phytotherapy for the treatment of LUTS due to BPH, the International Consultation on BPH were reluctant to recommend phytotherapy. However, a review of the role of phytotherapy in the management of LUTS due to BPH is needed. REFERENCES 1. Mahady GB. Global harmonization of herbal health claims. J Nutr 2001;131(3 Suppl):11205-35. 2. Young AL, Bass IS. The Dietary Supplement Health and Education Act. Food Drug Law J 1995;50(2):285-92.

3. Dreikorn K, Borkowsi A, Braeckman J, et al. Other medical therapies. In: Proceedings of the fourth International Consultation on Benign Prostatic Hyperplasia (BPH) 1997. Denis L, Griffiths K, Khoury S, et al (Eds.), Plymouth: Plymbridge Distributor 1998:p.633-59. 4. Ishani A, MacDonald R, Nelson D, Rutks I, Wilt TJ. Pygeum africanum for the treatment of patients with benign prostatic hyperplasia: a systematic review and quantitative meta-analysis. Am J Med 2000;109(8): 654-64. 5. Dreikon K, Lowe F, Braeckman J, et al. Other medical therapies. In: Proceedings of the 5th International Consultation on Benign Prostatic Hyperplasia. Denis L, Griffiths K, Khoury S, et al (Eds.), Plymouth. Plymouth Distributors, 2001. 6. Bayne CW, Donnelly F, Ross M, Habib FK. Serenoa repens (Permixon): a 5 alpha-reductase types I and II inhibitornew evidence in a coculture model of BPH. Prostate 1999;40(4):232-41. 7. Strauch G, Perles P, Vergult G, Gabriel M, Gibelin B, Cummings S, et al. Comparison of finasteride (Proscar) and Serenoa repens (Permixon) in the inhibition of 5-alpha reductase in healthy male volunteers. Eur Urol 1994;26(3):247-52. 8. Levin RM, Riffaud JP, Bellamy F, Rohrmann D, Krasnopolsky L, Haugaard N, et al. Effects of tadenan pretreatment on bladder physiology and biochemistry following partial outlet obstruction. J Urol 1996;156(6): 2084-8. 9. Madersbacher S, Berger I, Ponholzer A, Marszalek M. Plant extracts: sense or nonsense? Curr Opin Urol 2008;18(1):16-20.

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Top 10 Ways to Keep the Kidneys Healthy We all want our kidneys to last for a lifetime. We should all show our love for kidneys by adopting 10-step program for protecting kidney health. One should begin with monitoring blood pressure and controlling weight and then move on to the rest of the kidney-healthy tips. ÂÂ

Monitor blood pressure and cholesterol.

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Control weight.

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Don't overuse over-the-counter painkillers.

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Monitor blood glucose.

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Get an annual physical exam.

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Know if chronic kidney disease (CKD), diabetes or heart disease runs in your family. If so, you may be at risk.

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Don't smoke.

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Exercise regularly.

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Follow a healthy diet.

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Get tested for chronic kidney disease if you're at risk.

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Medifinance

Financial Advisory Team

W

hen most people think of a successful careerist like a medical professional, they think of someone who can afford a lavish lifestyle and its entrapments—a home in a gated highrise community, a swanky car or two, and the best educational institutions for their children. The correlation between a high-income occupation and net worth is not inherently a positive one. The concepts of finance and accounting are alien for many doctors, since they go to medical school to learn medicine and not business. If these successful careerists are queried on their savings, generally they have purchased a few insurance policies and perhaps some stocks and mutual fund policies, mostly to oblige a friend or relative or based on the advice of a colleague or friend. However, if you look in greater detail at the investments these careerists have made, you may find that their life insurance is woefully inadequate, health insurance has not even been considered, and the investments are not customized to the needs of the individual. No matter how well-educated or financially sophisticated, medical professionals are busy people who don’t have the time or inclination to effectively manage their own financial affairs. Attending a seminar, reading books on personal finance, casual discussion of money management or using computer software can help measure the dimension of their concern about these issues. They can also help doctors focus on the areas that need the immediate attention, such as education funding or liability protection. However, these steps cannot help doctors determine:

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How to reorganize their present investments in order to increase their net after-tax investment return

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How to structure the investments held by them and their family in order to maximize the potential financial aid for education funding or long-term care

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How to select and purchase the best mix of investments and insurance to pre-fund education, survivor needs and retirement income expenses

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What changes should be made in their estate plan and retirement plan as result of a thorough needs analysis and goal setting.

Achieving one’s financial goals requires a coordinated, integrated approach. Peace of mind is achieved from knowing that they have planned well. To prepare a financial plan with the same attention to detail as that of a professional advisory team would just take too much time away from their personal life, occupation, business or civic responsibilities. If a doctor’s financial situation is being monitored by a financial advisory team, he can be assured that his ‘financial house’ is in order. His time and attention can be focused on effective management of his business and pursuing his personal interests. An ideal financial advisory team would consist of people with a wide range of skills like accountants, psychologists, solicitors, training consultants, management consultants, financial planners, real estate agents and property consultants. Working with an advisory team before making a purchase is more likely to make a doctor feel informed and confident about a product without the pressure to buy because they can separate the advice stage from the actual purchase. Integrating the accounting processes with the financial planning processes is the most cost-efficient way of advising a doctor. The aim is to manage the financial affairs and work hard to make sure that doctors grow their practice and investments as fast, as efficiently and as safely as possible. Reasons for Financial Planning

Confirming that Financial Objectives are being Met By evaluating a doctor’s total financial situation, they can coordinate strategies that do not interfere with any of the stated goals and objectives. By focusing on the whole, rather than on a part, recommendations can be made that are consistent with the long-term financial strategy.

Monitoring Implementation A financial plan that is not implemented becomes merely an educational experience. The stated goals and objectives can never be met without putting the plan into action. Follow-through is crucial. A financial advisory team will ensure that all phases of your plan are properly implemented by selected

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Medifinance agents, not only in terms of the types and categories of investments, but with respect to estate, tax and retirement planning. All areas of risk assessment are important. Any area if overlooked could wipe out the rewards of years of work and saving.

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Liabilities: Present and anticipated debt obligations.

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Income tax analysis: Projections for 10 years, with review of personal tax returns for last two years.

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Cash flow management: Projections for 10 years, determine effective use of anticipated surplus, managing deficits.

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Investment review: Analysis and recommendations.

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Insurance review: Analysis and recommendations.

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Employee benefits: Review and recommendations; coordinate with personal assets and spousal plans.

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Disability income: Analysis and recommendations; 10-year projections of taxes, cash flow and net worth.

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Estate distribution: Costs and taxation analysis methods of reducing probate costs and estate duties.

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Capital needs and survivor income analysis: Analysis and recommendations.

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Retirement income: Analysis and recommendations inflation, qualified plans and increasing net cash flow.

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Financial organizer file: For all documents, policy records.

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Income tax organizer file: Used each year to accumulate and store vital records to support tax returns.

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Master implementation checklist: To monitor your financial progress and be aware of advisor performance.

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Periodic review sessions: Verify progress evaluation of investments, benefit plans and document completion.

Frequent Reviewing to Remain on Schedule Financial planning is a dynamic process and should be reviewed on a continuing basis to verify that the goals are being met and that they are remaining on your financial schedule. Since “nothing is as constant as change itself” the goals, attitudes toward financial risks and family circumstances will change. Even if, we as individuals were to remain the same, the financial world around us changes so frequently that constant monitoring is a necessary part of the planning process. The political, tax, legislative and economic changes increase in frequency. Reviews also ensure that any necessary adjustments are made before it is too late.

Providing Peace of Mind Dealing with a financial advisory team gives the doctor the peace of mind knowing that his financial situations are being handled by full-time professionals who are dedicated to his financial needs and who are in constant pursuit of his goals. Planning Process Components ÂÂ

Review of your objectives and risk/reward attitudes: Short-term, medium range and longterm goals as well as perceptions of risks and expected rewards.

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Asset structure: Review of current holdings, present value, cost basis, growth and expected purchases.

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Cash flow management is a mechanism, not a budget. It allows the doctor to assess his financial situation from a long-term, systematic perspective.

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Time is a doctor’s greatest ally. The more time one has, then less money one will need to save and invest.

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Most people lose control over cash flow because they have no system to handle periodic known expenses of a substantial nature.

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It is important to assign a portion of each paycheck for the savings and investment program. Consider it an obligation just as important as any other monthly obligation.

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Risk profiles are all about a person’s tolerance for risk, tolerance for loss, and how a loss might emotionally affect him and the subsequent decisions the person may choose to make.

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Medilaw

Proof of Age MC Gupta

Q. Why do the courts insist on school certificate etc. for proof of age instead of the scientific approach of bone ossification? There is a possibility that documents may be false. For example, a main accused in the recent Delhi gang rape case (Nirbhaya case) appears to be an adult by all appearances. Is it fair? Ans. ÂÂ

It is not a valid question. Courts are bound by law. They cannot import their own idea of fairness into their judgments in violation of law.

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The courts insist on school certificate, etc. for proof of age instead of the scientific approach of bone ossification because Rule 12(3) of the Juvenile Justice (Care and Protection of Children) Rules, 2007, reads as follows: “3) In every case concerning a child or juvenile in conflict with law, the age determination inquiry shall be conducted by the court or the Board or, as the case may be, the Committee by seeking evidence by obtaining–

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It is clear from the above that the ossification test can be done only when documentary evidence is not available.

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It is also clear that ossification test report cannot be given by a single doctor. It must be given by a duly constituted board. This is clear from a recent direction given by Delhi High Court as follows: “Allowing a plea, a bench of HC said, “The Juvenile Justice (Care and Protection of Children) Rules envisage that to determine the age of the offender based on the ossification test, the report must come from a duly constituted medical board and not from any single member team who alone may not be competent to give the correct opinion.” Therefore, HC said, this matter deserves to be remanded back to the trial court with a direction to call for a fresh report from a duly constituted medical board of a government hospital comprising a minimum of one dentist, one general physician and one radiologist.” (Times of India, 26 February 2013, http://timesofindia. indiatimes.com/city/delhi/HC-throws-out-bone-test-bysingle-doctors/articleshow/18683819.cms)

(a) (i) the matriculation or equivalent certificates, if available; and in the absence whereof;

(ii) the date of birth certificate from the school (other than a play school) first attended; and in the absence whereof;

(iii) the birth certificate given by a corporation or a municipal authority or a panchayat;

(b) and only in the absence of either (i), (ii) or (iii) of clause (a) above, the medical opinion will be sought from a duly constituted Medical Board, which will declare the age of the juvenile or child. In case exact assessment of the age cannot be done, the Court or the Board or, as the case may be, the

Committee, for the reasons to be recorded by them, may, if considered necessary, give benefit to the child or juvenile by considering his/her age on lower side within the margin of one year and, while passing orders in such case shall, after taking into consideration such evidence as may be available, or the medical opinion, as the case may be, record a finding in respect of his age and either of the evidence specified in any of the clauses (a)(i), (ii), (iii) or in the absence whereof, clause (b) shall be the conclusive proof of the age as regards such child or the juvenile in conflict with law.” http://wcd.nic.in/icpsmon/pdf/jjrules2007.pdf

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Advocate and Medicolegal Consultant, New Delhi

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Padma Shri & Dr BC Roy National Awardee

Dr SM Rajendran


2013


Confederation of Medical Associations in Asia and Oceania

Be Human Stop Child Abuse Dear Colleague, Greetings from the Organizing Committee of the 28th CMAAO Congress & 49th Council Meet. The conference will be held from September 12-14, 2013 and will be a mix of scientific bonanza and cultural feast. You are requested to block the above dates. Other details of the conference will be intimated in due course of time. The theme of the conference is ‘Be Human Stop Child Abuse’, as it is appropriate not only for India but also for all Asian Countries. The venue of the event will be Hotel Eros Shangri-La, Ashoka Road, New Delhi. We will be posting more details in our weekly bulletin.

Child abuse some basic facts ÂÂ

Child abuse involves a child under the age of 18.

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Child maltreatment is defined as unintentional harm or threat or harm to a child by a person who is acting in the role of caretaker. The caretaker means parents or an employee of a residential facility or any staff/person providing out of home care.

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The four major types of child abuse are – physical abuse, sexual abuse, emotional abuse and child neglect; 79% of the child abuse cases involve physical abuse. An abused child has as much as 50% chances of undergoing further abuse and 10% chances of dying, if the abuse is not detected at the initial presentation. More than 40% of deaths from child abuse occur among children younger than 12 months of age.

Child Neglect Child neglect is the most prevalent form of child abuse and is defined by the National Center of Child Abuse and Neglect as failure to provide for a child’s basic physical, emotional, educational or medical needs. ÂÂ

Physical neglect: Failure to provide adequate food, clothing, shelter, hygiene, protection; inadequate supervision with risk of harm to the child.

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Emotional neglect: Failure to provide love, affection, security, and emotional support; failure to provide psychological care when needed; spouse abuse in presence of the child.

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Educational neglect: Failure to enroll the child in school or ensure school attendance or home schooling; failure to address specific educational needs.

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Medical neglect: Refusal to seek or delay in seeking medical care resulting in damage or risk of damage to the child’s health.

Physical abuse in children ÂÂ

Physical abuse is a significant injury inflicted upon a child by a parent or caretaker.

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Significant injury means redness of the skin or any inflicted injury that lasts longer than 24 hours.

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Physical child abuse accounts for over 1,56,000 global pediatric deaths annually.

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The most common perpetrators in descending order of frequency, are fathers, mothers’ boyfriends, female babysitters and mothers.

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Parental risk factors include young or single parents, parents with lower levels of education and unstable family situations.

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Parents who abuse their children often were abused or neglected themselves as children.

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Stressors: Financial difficulties, divorce or interpersonal conflict, illness, job loss or difficulties.

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High risk children: Infants and toddlers under three years of age, children with mental or physical disabilities and children with a past history of abuse.


eMedinewS Inspiration

Alexander The Great’s Last 3 Wishes GM Singh

A

lexander, after conquering many kingdoms, was returning home. On the way, he fell ill and it took him to his death bed. With death staring him in his face, Alexander realized how his conquests, his great army, his sharp sword and all his wealth were of no consequence. He now longed to reach home to see his mother’s face and bid her his last adieu. But, he had to accept the fact that his sinking health would not permit him to reach his distant homeland. So, the mighty conqueror lay prostrate and pale, helplessly waiting to breathe his last. He called his generals and said, “I will depart from this world soon, I have three wishes, please carry them out without fail.” With tears flowing down their cheeks, the generals agreed to abide by their king’s last wishes.

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“My first desire is that”, said Alexander, “My physicians alone must carry my coffin.”

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After a pause, he continued, “Secondly, I desire that when my coffin is being carried to the grave, the path leading to the graveyard be strewn with gold, silver and precious stones, which I have collected in my treasury”.

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The king felt exhausted after saying this. He took a minute’s rest and continued. “My third and last wish is that both my hands be kept dangling out of my coffin”.

The people who had gathered there wondered at the king’s strange wishes. But no one dared bring the question to their lips. Alexander’s favorite general kissed his hand and pressed them to his heart.

“O king, we assure you that all your wishes will be fulfilled. But tell us why do you make such strange wishes?” At this Alexander took a deep breath and said: “I would like the world to know of the three lessons I have just learnt. Lessons to be learnt from last 3 wishes of King Alexander... I want my physicians to carry my coffin because people should realize that no doctor on this earth can really cure any body. They are powerless and cannot save a person from the clutches of death. So, let not people take life for granted. The second wish of strewing gold, silver and other riches on the path to the graveyard is to tell-people that not even a fraction of gold will come with me. I spent all my life greed of power, earning riches but cannot take anything with me. Let people realize that it is a sheer waste of time to chase wealth. And about my third wish of having my hands dangling out of the coffin, I wish people to know that I came empty handed into this world and empty handed I go out of this world. With these words, the king closed his eyes. Soon he let death conquer him and breathed his last. . . . Remember, your Health is in your own hands, look after it. Wealth is only meaningful if you can share and also enjoy while you are still alive, kicking and healthy. What you do for yourself dies with you. But what you do for others will live for ever. Leave the ‘Legacy’ behind.

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lighter reading

Lighter Side of Medicine Quote

Make Sure

During Medical Practice A patient intolerant to penicillin was denied rheumatic prophylaxis.

“We are all travelers in the wilderness of the world, and the best that we can find in our travels is an honest friend.” −Robert Louis Stevenson

Mind Trivia Oh my God! Why was he not put on a sulfa drug?

1. What number comes next?

2, 2, 4, 12, 48, ___

2. What is the next number in this series?

1, 2, 6, 42, 1806?

3. What do the following numerals represent? ©IJCP Academy

11111121113122223222

Make sure that patients who cannot tolerate penicillin are put on sulfadiazine or sulfisoxazole. This antibiotic class is effective for preventing Group A streptococcal (GAS) infection although it cannot be used to achieve eradication. KK Aggarwal

Dr. Good & Dr. Bad Situation: A child presented with focal convulsions

with onset of high-grade fever.

These are not simple febrile convulsions

Lesson: Simple benign febrile convulsions are always

generalized.

Dr KK Aggarwal

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8, 5, 4, 9, 1, 7, 6, 10, 3, 2, 0

5. Which two numbers are missing and where do they go in the sequence?

8, 11, 5, 14, 1, 7, 6, 10, 13, 3, 12, 2

Ans. (1) 240. (2) To get the next number, multiply the previous number in the series by itself plus one: n * (n+1). For example, to get 6, multiply 2 * 2+1. To get 42 multiply 6 * 6+1. Thus, 1806 * 1807 = 3263442. (3) The syllables in the numbers from 1 to 20. (4) It’s the numbers 0 through 10 in alphabetical order. (5) The missing numbers are 4 and 9. The list is sorted alphabetically by the English spelling of the numbers, so four belongs after five and nine comes after fourteen.

ILLUSION

©IJCP Academy

These are simple febrile convulsions

4. What is special about the following number sequence?

Indian Journal of Clinical Practice, Vol. 24, No. 1, June 2013


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 –

– –

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). –

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.

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

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

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 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.

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. –

Do not use clips/staples on photographs and artwork.

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 summary, etc.)_______________________________ 2. Total number of pages ________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________

Books

5. Special requests _____________________________

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

Indian 1.____________Foreign 1._ _______________

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.____________

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. 24, No. 1, June 2013

6. Suggestions for reviewers (name and postal address)

4._ _______________

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


R.N.I. No. 50798/90 Date of Publication 13th of Same Month Date of Posting 13-14 Same Month

DL (S)-01/3200/2012-2014 Posted in N.D. PSO New Delhi


Ijcp june 2013