IJCP Feb 2013 issue

Indexed with IndMED

ISSN 0971-0876

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Volume 23, Number 9

February 2013, Pages 481-580

Peer Reviewed Journal

yy American Family Physician yy Cardiology yy Drugs and Devices yy Dentistry yy Dermatology yy Diabetology yy ENT yy Obstetrics and Gynecology yy Gastroenterology yy Neurology yy Pediatrics yy Orthopedics and Rheumatology yy Medilaw yy Medifinance

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IJCP Group of Publications Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor Padma Shri and Dr BC Roy National Awardee

Dr KK Aggarwal Group Editor-in-Chief

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

Volume 23, Number 9, February 2013

from the desk of group editor-in-chief 485 The Generic Drug Controversy

from the desk of guest editor 489 Designer Genitalia: Fad, Benefit or Mutilation?

Gastroenterology Dr Ajay Kumar Dermatology Dr Hasmukh J Shroff Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan Journal of Applied Medicine & Surgery Dr SM Rajendran 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.

Anita Kant

American Family Physician 490 Practice Guidelines cardiology 495 Newer Hypolipidemics on the Block

Princy Louis Palatty, Manasa M, Apoorva Naik, Archana Kaveri B, Bhavishya Kirthi Anna Walder, Manohar Prabu, Manjeshwar Shrinath Baliga

drugs and devices 505 Gliptins - The Novel Players in Glucose Homeostasis

G Kannan, N Vanitha Rani, Vasantha Janardhan, Priya Patel, C Uma Maheswara Reddy

508 Look-alike and Sound-alike Drug Brand Names: A Potential Risk in Clinical Practice

ENT Dr Jasveer Singh Dentistry Dr KMK Masthan Dr Rajesh Chandna

KK Aggarwal

Mukundraj S Keny, PV Rataboli

Dentistry 514 Follicular Adenomatoid Odontogenic Tumor

S Loganathan, H Srinivasan, R Veerakumar, M Arul Pari

Dermatology 517 Juvenile Dermatomyositis with Calcinosis Cutis

Sibabratta Patnaik, Manas Ranjan Behera, Nirmal Kumar Mahakud, Aswini Kumar Mohanty

diabetology 520 A Study of Metabolic Syndrome and its Components in Type 2 Diabetes Mellitus Subjects and their Asymptomatic First-degree Relatives

JL Patel, AM Suthar, VB Dalsaniya, AP Parikh, NN Suthar, KL Patel

ENT 534 Common Superficial Tongue Lesions

Anuradha Sunil, Jacob Kurien, Archana Mukunda, Ashik Bin Basheer, Deepthi

Obstetrics and Gynecology 543 Comparative Study of Sublingual versus Vaginal Misoprostol on Preoperative Cervical Priming in First Trimester Abortion

Parneet Kaur, Manjeet Kaur, Balwinder Kaur, Manjit Kaur Mohi, Khushpreet Kaur, Preeti Jindal

547 Sequential Bilateral Torsion of a Normal Ovary at 31 Weeks of Gestation and 12 Months Following Delivery

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

B Poornima R Bhat, Aruna Kamath

Gastroenterology 550 Acute Fatty Liver of Pregnancy

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

Jitesh Mafatlal Shah, Meghana Narendrabhai Mehta, Hiral Babubhai Viradiya

Neurology

© Copyright 2013 IJCP Publications Ltd. All rights reserved.

553 False Localizing Signs in Neurology

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.

Jobin V Joseph

Pediatrics 560 Urinary Iodine Excretion in Urine Samples Among Children in Dahod District, Gujarat

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.

JR Damor, NG Padhiyar, GL Ninama

orthopedics and rheumatology 565 What are the Drugs Used for the Treatment of Rheumatoid Arthritis?

VR Joshi

Medilaw 566 Can a Cardiologist be Liable if the Patient Develops Intracranial Bleed after Angiography?

KK Aggarwal

Medifinance 567 Asset Protection Humor 569 Laugh-A-While Forthcoming events

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.

570 Forthcoming Events eMedinewS Inspiration 571 Alexander The Great’s Last 3 Wishes

GM Singh

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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)

The Generic Drug Controversy

I

n his show Satyamev Jayate, Aamir Khan had asked doctors across the country to not write brand names and instead write only the generic chemical names of the drugs. This generated a lot of controversy in the country. The reason was a huge difference in the cost of various brands. Different divisions of the same company have brands with different prices. This cost difference is even more evident in case of surgical consumables and devices.

Recently, Medical Council of India Code of Medical Ethics 1.5 issued a re-notification and said that the rule 1.5 should be followed in its spirit. The rule says: Medical Council of India Code of Medical ethics: 1.5 Use of Generic names of drugs: “Every physician should, as far as possible, prescribe drugs with generic names and he/she shall ensure that there is a rational prescription and use of drugs.”

The Indian Medical Association recently held a meeting, which was attended by its office bearers along with the Drug Controller of Delhi, Director Health Services, President Gynecological Society of India, representatives from pharma industry and lawyers.

In this meeting, I discussed the Code of Ethics of Medical Council of India 1.5 interpretation in its letter and spirit.

What was the intention of the MCI when the regulation was made? Was it the rational use of drugs with concern on quality and safety or to provide cheaper drugs?

Apparently the first concern was more important.

In MCI regulations, the phrase “Use of Generic Names of Drugs” does not talk about using GENERIC DRUGS. The word ‘generic name’ means the Chemical Name.

It is called INN or International Proprietary Name. For example, for aspirin, it is acetyl salicylic acid.

The phrase “Every physician should” makes it binding.

The only interpretation one can take from this is that the name of the chemical salt should be written in a prescription.

The phrase “As far as possible” means that there will be situations where a person may not be able to write the name of the salt. For example, the name of the salt may be too long to write like ‘Monosorbide nitrate’ or the drug may be a combination of 4-5 drugs and in emergency, it may not be possible to write the chemical name of all the drugs. In that case, not writing chemical name would come under the exception “as far as possible”.

Another example is the drug Nasorest Plus, which contains acrivastine 8 mg, paracetamol 325 mg, caffeine 25 mg and phenylephedrine HCl 5 mg. In this case, a person has to write only the brand name without the generic constituents. Similarly, every multivitamin tablet in the market differs in the dose of the vitamins and other constituents. In Ayurveda, all drugs have over 10-40 ingredients for e.g. chyawanprash has over 40 constituents. Every brand of chyawanprash also differs in the doses of each constituent.

The phrase “Prescribe drugs with Generic name”: It is not the same as prescribing generic drugs, it only means that name of the chemical salt should also be written.

The phrase “Shall ensure that there is a rational prescription” means that prescription of drugs should be evidence-based and/or with informed consent.

It would also include that one should justify the

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from the desk of group editor-in-chief cost-benefit ratio to be decided on case-to-case basis.

Prescribing costlier brands without justification or a brand only from a particular chemist would amount to unethical act under this.

The phrase “And use of drugs” means the above is applicable for dispensing practice also.

Drug terms were also elaborated as under: Patent drug means a drug belonging to the original innovator company, which has researched the molecule.

The company gets the right to sell this drug exclusively for 20 years and during this period no other company can manufacture and sell this compound. After 20 years when the patent is over, the drug becomes a Generic drug.

Brand is the name given to the marketed drug specific to a company for selling. Both patented drugs and generic drugs can be sold under a brand name. Brand names are usually so named that the doctor can easily remember the chemical constitution or its action or the disease in which it has to be used. It is usually a shortcut so that it is easy to remember. For example ‘Ramipril’ is chemical salt and most brands will have the word “ace” as a prefix or suffix, for e.g. HOPace, CARDace, RAMace, etc. reminding the doctor that it is an ACE inhibitor.

Generic name means the name of the chemical salt and is not synonymous with a generic drug.

A drug can be dispensed in the market as under: ÂÂ

The name of the generic salt with no brand name: For e.g., Dr Reddy’s Amlodipine or Zydus Amlodipine. In both the situations, the company’s name becomes a brand. It is available at the cheapest price as there is no marketing cost.

ÂÂ

Unpopular brand: It is usually pitched for a bulk supply in any institution. It is costlier than the company branded generic salt but cheaper than the popular branded drug.

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Popular brand: It is marketed for the individual doctor’s use in a chemist shop and is the costliest.

The company may market all three products under different divisions and there may be a huge cost difference of all three varieties within the same company.

Mr. Atul Gandotra representing the pharma industry said that in India all the drugs are generic drugs, as India hardly has a patent for any drug in the world.

Dr GN Singh, Drug Controller General of Delhi said that the intention of the government is that doctor

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should write only chemical salt names. As per the new notification, the Government is not issuing new licenses for any brand names. License is being issued only for the chemical name of the salt. He also said that under the Drug and Cosmetic Act 1965 11A, a brand name cannot be substituted by the chemist. Government wants that a doctor should not write the chemical salt along with brand name, they will have to write only the actual chemical name.

Dr NV Kamath, Director, Health Services said that Delhi Government, since 1994, has made sure that Delhi Government hospitals only buy drugs with chemical names. No branded drugs are bought. But Delhi Government buys the generic name drugs only from reputed branded companies.

The house however felt that the word ‘reputed branded company’ in this situation becomes a brand. A generic salt name by a branded company is nothing but a brand given a different name. Dr Rajinder Sharma from IMA compared it to a Kachori sold in Haldiram outlets, though it is sold in generic name but it is branded “Haldiram Kachori”.

Dr MC Gupta, Advocate said that doctors, hospitals and healthcare providers should follow the act and law in its spirit. Section 6 of the Consumer Protection Act (CPA) talks about the rights of the Consumers and it mentions that a consumer has a right to choose the medicine. Informed choice is fundamental principle of the Consumer Protection Act. Every doctor should write the name of the salt along with 3-4 brand names and let the patient choose which brand name he should get.

But the house felt that doctors may be under the purview of the CPA but their relationship is beyond CPA. Patients go to a shop to choose a product and do not expect the shop owner to decide for them which brand they should buy. But a patient comes to doctor with an expectation that the doctor would be taking decision on his behalf. If doctors start giving options for everything the patient will get confused. It is the job of a doctor to give choices as well as his decisions and final advice.

It’s a medical fact that one should stick to a single brand as different brands may have different bioavailability.

If the patient changes the brands too frequently, his chronic illness may have fluctuations in its parameters.

Mr Rahul Gupta, Senior Advocate High Court and Supreme Court, said that the interpretation of the MCI clause unless amended does not force a doctor not to write a brand name. But when choosing a brand the doctors should follow the rational prescription that

from the desk of group editor-in-chief would include the cost of different brands also. If he writes a particular brand, if questioned, he should be able to justify the reason of his or choice in the court of law. It’s the duty of the doctor to know what he is writing.

Mr. Girdhar J Giani, formerly at National Accreditation Board for Hospitals and Healthcare Providers (NABH) said that according to him the law does not restrict doctors from writing the brand name but one should write the name of the chemical salt in bracket. He added that the words in the notification “shall ensure that there is a rational prescription and use of drugs” will cover the factor of unnecessary high cost. “If a doctor is purposefully prescribing a drug available in a particular chemist shop having rates which is higher than other standard drugs, it will be an unethical practice under the above section” said Mr. Giani.

Regarding his views, the house felt that if doctors have to write only chemical names then the Government should ban all the branded drugs because if this is not done, then the uneducated chemists decide which brand to give. As of today, no doctors are informed about all the brands available and their prices and every chemist does not keep all the brands. Most of the drugs, which are cheaper, are not stocked by the chemist. One such example is famotidine.

Dr. VK Narang and Dr RN Tandon (JS IMAAMS), from IMA said that the law does not permit a chemist to replace one brand with another. Most chemist shops are run by uneducated nonpharmacist workers not capable of dispensing drugs in the interest of the patients.

Dr CM Bhagat said that drugs available only with the chemical salt name without a brand name are often priced much higher than the branded drugs. Once the Government bans brand names, then name of the company which is making the generic drug will become a brand. Every doctor instead of writing Stamlo will start writing Dr Reddy’s Amlodipine. MCI does not cover hospitals and doctors working in a hospital have to write a brand drug, which is available in their pharmacy. Also, most hospitals often buy the cheapest brands and sell them at the highest rates.

Dr Harish Grover, Past Secretary General, IMA said that it is true that every drug which is approved by Drug Controller of India is a quality drug with near similar bioavailability but giving a free choice to chemist to choose the drug will be a disaster. He said that the purpose of writing chemical name along with brand was to reduce prescription errors such as soundalike drugs and read-alike drugs.

If the intention of the MCI is not to write brands then research in pharmaceutical industry will be over. The same chemical salt because of research is marketed as quick-acting drug, OD drug, Nano particle formulation, as controlled-release tablet, continuous release technology, slow-release tablet etc. Every company has designer brands with different formulations to affect the quick of delayed bioavailability of the drug.

Dr Nomita Gupta, Jt secretary IMA, Dr OP Sharma from Geriatric Society of India and Dr SC Pandey Governing Council Member IMA re-emphasized that banning brands is not the answer as the company name with the generic salt will then become a brand. The President Gynecological Society of India said that if you allow the chemist to choose the drug he will never give the cheapest brand as his interest would be his margin.

Dr DR Rai, Senior Vice President, IMA, warned against the chemist who exploits about all the drugs and he said if government is so concerned about the prices of a drug, they can control the price of the same. It is the government who decides about the price. It’s the government who fixes the MRP of a drug. Once the government is permitting a MRP to be sold in the market they cannot ask the doctors to not write drugs at that MRP. If the government is so concerned about prices, they should limit the cost of any medicine.

Dr Ajay Gambhir Finance Secretary IMA said that all licensed drugs may be good but may vary in postmarketing surveillance results. He further said that major cost differences in different brands are in cancer drugs, biologics vaccines and endocrine drugs. Some vaccines are costlier in India and cheaper in the US. There are mafia in many states of the country who do not allow any other brand to be sold in that state.

Summing up the discussion, Dr VK Saini, Secretary General IMA said that IMA is concerned and is committed in providing cost-effective drugs to the patient. IMA wants a quality safe drug at a cost-effective price to the patient. He said 70% of the expense of a treatment is on drugs; therefore, Government should evolve a mechanism to reduce the cost of drugs to the patient. The government should also come out with website where costs of all the brands are written.

The meeting concluded with the following points by Dr Narender Saini, Secretary General, IMA ÂÂ

Since there was difference of opinion between IMA and Delhi Health officials about the meaning of this statement in the house, IMA will write to MCI for clarification about the interpretation of this phrase.

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from the desk of group editor-in-chief ÂÂ

ÂÂ

The phrase “Prescribe drugs with Generic name”: It is not the same as prescribing Generic drugs; it only means that the name of the chemical salt should also be written.

Whether you write a brand with a salt name or you write name of the salt with name of the pharmaceutical company, it is the same. In one the company derived name of the salt becomes a salt and in the other, the salt linked to a company becomes a brand.

only available with particular chemists should be considered unethical. ÂÂ

ÂÂ

All doctors should write a salt name along with the name of the company or the brand name which is of quality and safety and yet cost-effective.

Since in our country, patients have very limited access about the information of drugs and even persons employed in chemist shops are also not qualified, proper checks and balances are essential to ensure that patients get the best medicine on physician prescription. Doctors along with Govt. machinery and price control are the only mechanisms to ensure patient getting proper medicine.

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Mechanisms have to be evolved so that a quality, safe and affordable drug can be given to the patient.

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One of the answers is price control on MRPs by the government.

ÂÂ

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The IMA members should maintain the rational use of drugs while choosing a drug and ensure it qualifies the criteria: Quality safe drug and yet affordable”.

IMA firmly believes that the Govt. should control the MRP of drugs, generic or branded so that benefit reaches the common man.

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The website of Central Drugs Standard Control Organization should mention the name and addresses of manufacturing and marketing companies authorized by them to ensure the traceability of the product. It should also mention the MRP of drugs.

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The so-called nexus between doctor and chemist or a pharma company, where a doctor is writing a particular brand, a costly brand or a brand ■■■■

Why the Word CPR 10?

All my life, I have taught medicine in the form of formulas. The CPR 10 was created so that the public could remember the process of cardiopulmonary resuscitation or revival after sudden cardiac death.

There is substantial evidence to suggest that CPR is effective in the first 10 minutes of cardiac arrest. After 10 minutes of death, there is practically no chance of recovery unless patient is in hypothermia.

There is also enough evidence that at least 10 minutes of cardiac massage should be given with a speed of 100 per minutes.

So, we created a formula of 10 which means that – within 10 minutes of death (earlier the better), at least for the next 10 minutes (longer the better, up to 25 minutes), compress the centre of the chest of the victim with a speed of 10x10 i.e. 100 per minute.

Numerologically also, the CPR equates to number 10. In English alphabets, ‘C’ comes at number ‘3’, ‘P’ comes at number ‘16’ and ‘R’ comes at number ‘18’. If we add the three i.e. C=3, P=16, R=18 (3 + 16 + 18 = 37) and, if we further add the two digits in ‘3 + 7’, the total we get is ‘10’. So, numerologically ‘CPR 10’ should be an effective way to remember.

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from the desk of guest editor Dr Anita Kant Consultant Gynecologist Asian Institute of Medical Sciences Faridabad

Designer Genitalia: Fad, Benefit or Mutilation?

Q: IS PLASTIC SURGERY OF THE FEMALE EXTERNAL GENITALIA COMMON IN INDIA? A: Yes and it’s not a recent development. Vaginal tightening surgery or vaginoplasty has been a fad since a long time now.

In this surgery, the stretched muscles at the back of vagina are joined together, shortened and the unwanted skin is removed. This tightens the vaginal muscles and the surrounding structures.

It’s our ethical obligation to listen to our patients and to educate them. Some women are really bothered because they think that they are supposed to look a certain way.

And they may have partners who also tell them that they need to look and feel a certain way. So it’s not just about educating women, it’s about educating both men and women. Ethically speaking, they should be evaluated properly and taught about normal anatomy and pelvic support.

sexually active and to live out the myth of bleeding at the time of first intercourse, and also married women to please their husbands. Internet and media make it sound a very simple, pain-free and day care procedure with no hassles and no complications.

Labiaplasty is another procedure many women walk in for, mostly on the complaints of their partners and sometimes due to a genuine discomfort while wearing tight clothes. Hair removing techniques have brought local looks to the forefront.

Q: HOW SHOULD THESE PROBLEMS BE DEALT WITH?

Women with increased body weight need to lose weight for this would be of help to them in many more ways than just good sex.

A: The specific complaints of the couple must be heard out, followed by a thorough examination. The suggested procedure, its implications such as pain, risk of infection, abstinence for a time period and expected outcome need to be discussed. Many a times, it is the distressed wife wanting to reign in her husband, who has been unfaithful and puts the blame on her for his actions. The problem does not go away even after the surgery!

Q: WHAT ARE THE SURGERIES WOMEN COMMONLY COME FOR?

A botched up surgery can lead to dyspareunia and severe rectal pain; pain in the buttock region has also been reported by patients due to nerve injury.

A: Vaginal tightening, as they are distressed because of their partners complaining of loose vagina. Then, hymenoplasty, especially young unmarried women who wish to suppress the fact that they have been

To sum up, esthetic surgery is a woman’s right no doubt, but a gynecologist has to ethically explain everything including the effectiveness of Kegel’s exercises, weight loss, etc.

■■■■

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American Family Physician

Practice Guidelines

ACG Releases Recommendations on the Management of Irritable Bowel Syndrome Irritable bowl syndrome (IBS) is a common disorder characterized by abdominal discomfort and altered bowel function. It affects approximately 7 to 10 percent of persons in the world, and is more common in women, persons with lower socioeconomic status, and persons younger than 50 years. IBS is associated with impaired quality of life and reduced work productivity.

Individual symptoms are of little help in diagnosis; therefore, IBS should be considered as a symptom complex. In persons who fulfill symptom-based criteria of IBS, the absence of selected alarm features (e.g., rectal bleeding; weight loss; iron deficiency anemia; nocturnal symptoms; family history of colorectal cancer, inflammatory bowel disease, or celiac disease) should confirm an IBS diagnosis.

The American College of Gastroenterology (ACG) performed a series of systematic reviews, and developed evidence-based recommendations for the management of IBS. The recommendations were classified as grade 1 (strong) or grade 2 (weak), and the strength of evidence was classified as level A (strong), level B (moderate), or level C (weak).

recommended in persons younger than 50 years with typical IBS symptoms and no alarm features because of the low pretest probability of Crohn’s disease, ulcerative colitis, and colonic neoplasia (grade 1B).

Colonoscopic imaging should be performed in persons who have IBS with alarm features to rule out organic disease. It should also be used in persons older than 50 years to screen for colorectal cancer (grade 1C). When performing a colonoscopy in persons with IBS-D, random biopsies should be considered to rule out microscopic colitis (grade 2C).

Diet Evidence is lacking regarding whether food allergy testing or exclusion diets are effective in treating IBS; routine use outside of a clinical trial setting is not recommended (grade 2C). Research has shown that certain food allergies could cause IBS symptoms, and about 60 percent of persons with IBS believe that food makes their symptoms worse. A systematic review of eight trials involving 540 persons with IBS evaluated symptomatic response to exclusion diets. A positive response in 12.5 to 67 percent of the participants was reported, but there were no control groups in the studies; therefore, it is unclear if these rates are actually just a placebo response.

Recommendations

Dietary Fiber, Bulking Agents, and Laxatives

Diagnostic Testing

Psyllium hydrophilic mucilloid (ispaghula husk) is moderately effective in treating IBS (grade 2C). One study found that calcium polycarbophil improved symptoms. Wheat bran or corn bran is no more effective than placebo for relieving global symptoms, and should not be routinely used (grade 2C). One study showed that polyethylene glycol improved stool frequency in adolescents with constipation-predominant IBS (IBS-C; grade 2C).

Because the likelihood of diagnosing organic disease is low, routine testing with complete blood count, serum chemistries, thyroid function testing, stool ova and parasites examination, and abdominal imaging is not recommended in persons with typical IBS symptoms and no alarm features (grade 1C). Persons with diarrheapredominant IBS (IBS-D) and mixed IBS (IBS-M) should have routine serologic screening for celiac disease (grade 1B). Lactose breath testing can be done when lactose maldigestion is a concern, despite changes in diet (grade 2B); however, there are insufficient data to recommend breath testing for small intestinal bacterial overgrowth (grade 2C). Routine colonic imaging is not

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Most studies of dietary fiber and bulking agents had small sample sizes, short follow-up, and were conducted before the establishment of modern study design standards. Psyllium hydrophilic mucilloid improved global symptoms in four of six studies

American Family Physician that were reviewed, with one meta-analysis showing that the number needed to treat (NNT) was 6 (95% confidence interval [CI], 3 to 50) and the relative risk of IBS symptoms not improving with psyllium was 0.78 (95% CI, 0.63 to 0.96). There have been no placebocontrolled, randomized studies of laxatives in IBS. Antispasmodics Although antispasmodics and some peppermint oil preparations have shown improvement in short-term IBS-associated abdominal pain or discomfort (grade 2C), evidence of long-term effectiveness is not available.

Evidence of safety and tolerability is limited (grade 2C).

Evidence for effectiveness of antispasmodics and some peppermint oil preparations in the treatment of IBS exists; however, the availability of these drugs varies, and few recent data are available. Earlier trials are of poor quality; often do not differentiate between the effects on global versus individual symptoms; and vary in terms of inclusion criteria, dosing schedule, duration of treatment, and end points. The adverse effects of these drugs have not been adequately defined.

Antidiarrheals Loperamide is effective for the treatment of diarrhea, reduction of stool frequency, and improvement of stool consistency, but it is no more effective than placebo for the relief of pain, bloating, or global IBS symptoms (grade 2C). There are no randomized controlled trials (RCTs) comparing loperamide with other antidiarrheals, and data on safety and tolerability are lacking.

Loperamide is the only antidiarrheal that has been adequately assessed in RCTs for IBS-D. Two trials evaluating effectiveness found that loperamide had no notable effects compared with placebo for treating symptoms of IBS-D, including bloating, abdominal discomfort, and global IBS symptoms. Loperamide appeared to improve stool frequency and consistency, but the overall impact on symptoms was not statistically significant. There were inadequate data on adverse effects.

Antibiotics Compared with placebo, short-term nonabsorbable antibiotics are more effective for the treatment of bloating and global improvement of IBS (grade 1B).

No evidence exists on the long-term safety and effectiveness of nonabsorbable antibiotics for the management of IBS symptoms.

Three RCTs of 545 persons with IBS found statistically significant improvements in global IBS symptoms, bloating, or both with rifaximin compared with

placebo. Although not approved by the U.S. Food and Drug Administration (FDA) for the treatment of IBS, rifaximin is approved for the treatment of traveler’s diarrhea. Neomycin, metronidazole, and clarithromycin have also been studied for the treatment of IBS. In one RCT of 111 persons, those treated with neomycin were more likely to have a 50 percent improvement in global symptoms compared with those treated with placebo (43 versus 23 percent; P < .05). Another RCT showed that clarithromycin was not markedly better than placebo for IBS therapy. In a third trial, metronidazole provided notable improvement compared with placebo, but the data were not presented in an extractable form.

Probiotics Lactobacilli do not appear to be effective for the treatment of IBS; however, Bifidobacteria and some combinations of probiotics do appear to be effective (grade 2C).

Available literature on the use of probiotics in IBS is difficult to interpret because the probiotics used in the studies varied in terms of species, strains, preparations, and doses. The studies also had limitations in their design and conflicting data. Dichotomous data suggest that all probiotics trend toward being effective for the treatment of IBS; however, continuous data show that Lactobacilli do not affect symptoms, that Bifidobacteria trend toward improving symptoms, and that probiotic combinations improve symptoms. Most of the studies were short-term; long-term data are lacking.

5-HT3 Receptor Antagonists Compared with placebo, alosetron is more effective for relieving global IBS symptoms in persons with IBS-D. Possible adverse effects include constipation and colon ischemia, which occur more often in persons taking alosetron versus placebo (grade 2A). A balance of benefits and harms is most favorable in women with severe IBS-D who have not responded to conventional therapy (grade 1B). The quality of evidence for the effectiveness of 5-hydroxytryptamine (5-HT) receptor 3 antagonists in IBS is high.

Alosetron is the only 5-HT3 receptor antagonist approved in the United States for the treatment of severe IBS-D in women. Alosetron has been shown to be superior to placebo for the treatment of abdominal pain, urgency, global symptoms, and diarrhea-related symptoms in eight well-designed clinical trials. Using the primary end point of “adequate relief” of abdominal pain and discomfort or urgency, the relative risk of IBS continuing despite treatment was 0.79 (95% CI, 0.69 to 0.91), with an NNT of 8 (95% CI, 5 to 17). One placebo-controlled

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American Family Physician trial found that alosetron provided sustained relief of abdominal pain, discomfort, and urgency in persons with IBS-D for up to 48 weeks. Another randomized placebo-controlled trial demonstrated that alosetron was more effective than placebo for abdominal pain and discomfort in men with IBS-D. A systematic review of seven studies in which patients were randomized to treatment with alosetron or placebo reported that those taking alosetron were more likely to report an adverse event compared with those taking placebo (relative risk of adverse event = 1.18; 95% CI, 1.08 to 1.29). The number needed to harm with alosetron was 10 (95% CI, 7 to 16). Dose-dependent constipation was the most common adverse event.

Another systematic review of clinical and postmarketing surveillance data from persons with IBS and the general population also found a greater incidence of severe complicated constipation and ischemic colitis with alosetron therapy, but the incidence was low, with a rate of 1.1 cases of ischemic colitis and 0.66 cases of constipation per 1,000 patient-years of alosetron use.

nausea, diarrhea, and abdominal pain. It should not be used in persons with mechanical bowel obstruction or preexisting diarrhea. Women of childbearing age should have a documented negative pregnancy test before starting therapy. Studies in men need to be done before lubiprostone can be recommended for this population.

Antidepressants Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) are more effective than placebo for relief of global IBS symptoms. They also appear to help with abdominal pain. There are limited data on the safety and tolerability of these agents in patients with IBS (grade 1B).

The recommended starting dosage of alosetron is 0.5 mg twice daily. After four weeks, if symptoms are not sufficiently controlled, the dosage can be escalated to 1 mg twice daily. Patients should discontinue alosetron if they develop signs or symptoms of severe constipation or ischemic colitis, or if they do not respond to the 1-mg twice-daily dosage after four weeks.

Nine trials have evaluated tricyclic antidepressants for the treatment of IBS. The antidepressants were superior to placebo (NNT = 4; 95% CI, 3 to 6), and there was no evidence that the dose has to be in the antidepressant range. Two trials showed notable benefit with antidepressants for abdominal pain. Five trials evaluated SSRIs and found a benefit over placebo (NNT = 3.5). Theoretically, SSRIs should have the most benefit in persons with IBS-C, and antidepressants should have the most benefit in patients with IBS-D because of their differential effects on intestinal transit time; however, data are lacking. The safety of antidepressants for IBS is poorly documented, but data do suggest that SSRIs are better tolerated than tricyclic antidepressants.

5-HT4 Receptor Agonists

Psychological Therapy

There are no 5-HT4 receptor agonists currently available for use in North America. The FDA had approved tegaserod for use in women with IBS-C; however, it was removed from the market in 2007 because of a small number of cardiovascular events in treated patients.

Tegaserod was evaluated in multiple well-designed RCTs that showed that a dosage of 6 mg daily was superior to placebo for global symptoms.

Psychological therapies (not including relaxation therapy) are more effective than usual care in the relief of global IBS symptoms (grade 1B).

C-2 Chloride Channel Activators Compared with placebo, lubiprostone in a dosage of 8 mcg twice daily is more effective for the relief of global IBS symptoms in women with IBS-C (grade 1B).

Lubiprostone is approved by the FDA for use in women with IBS-C. Two large, well-designed clinical trials showed that lubiprostone improved global symptoms in twice as many persons as placebo (18 versus 10 percent; P < .001). It also improved abdominal discomfort and pain, stool constancy, straining, and constipation severity. Adverse effects of lubiprostone include

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Persons with IBS will typically also have anxiety, depression, or features of somatization. Because psychological disorders tend to overlap with IBS, studies have assessed psychological therapy, including cognitive behavior therapy, dynamic psychotherapy, hypnotherapy, and relaxation therapy, in the treatment of IBS. Twenty RCTs found that, compared with usual care, there was some benefit with cognitive behavior therapy, dynamic psychotherapy, and hypnotherapy, but not with relaxation therapy. Cognitive behavior therapy is the most studied approach, with one large, high-quality trial showing benefit.

Herbal Therapy and Acupuncture Chinese herbal mixtures have shown some benefit in RCTs; however, these studies cannot be combined into a meaningful meta-analysis, and any benefit of

American Family Physician Chinese herbal therapy in IBS can be confounded by the variability in components used and their purity.

There also are concerns about toxicity. A systematic review of acupuncture trials was inconclusive because of heterogeneous outcomes. More studies on acupuncture and herbal therapy are needed before any recommendations can be made.

Emerging Therapy A variety of therapeutic agents for IBS have been identified. Agents are also being developed for IBS with predominantly peripheral effects, and some with peripheral and central effects. Classes of drugs with peripheral effects include agents that affect chloride secretion, calcium channel blockers, opioid receptor ligands, and motilin receptor ligands. Classes of drugs with peripheral and central effects include novel serotonergic agents, corticotropin-releasing hormone antagonists, and autonomic modulators.

Source: Adapted from Am Fam Physician 2009;79(12):1108-1117.

ACG Guidelines for Colorectal Cancer Screening In 2000, the American College of Gastroenterology (ACG) became the first organization to recommend colonoscopy as the preferred screening method for colorectal cancer. The ACG updated its screening recommendations in 2008, and continues to support colonoscopy in average-risk patients every 10 years based on the evidence of effectiveness, cost-effectiveness, and patient acceptance. Recommendations from the 2008 guidelines that differ from the previous guidelines are presented in Table 1.

Cancer Prevention Tests vs. Cancer Detection Tests In 2008, a joint committee of the U.S. Multi-society Task Force, the American Cancer Society, and the American College of Radiology released a guideline that divided colorectal cancer screening tests into two groups: cancer prevention tests and cancer detection tests.

Prevention tests are capable of imaging cancer and polyps, whereas detection tests have low sensitivity for polyps and lower sensitivity for cancer compared with prevention tests. The ACG supports this division of tests and specifies that the preferred prevention test should be colonoscopy every 10 years, and the preferred detection test should be annual fecal immunochemical test (FIT) for occult bleeding (Table 2).

Patients should be offered colonoscopy beginning at 50 years of age. If patients have economic issues that

Table 1. Updates to the 2000 American College of Gastroenterology Recommendations on Screening for Colorectal Cancer Screening tests are divided into cancer prevention and cancer detection tests. Cancer prevention tests are preferred over detection tests.

Screening is recommended in blacks beginning at 45 years of age.

Computed tomography colonography every five years replaces double contrast barium enema as the radiographic screening alternative when patients decline colonoscopy.

Fecal immunochemical test replaces guaiac-based fecal occult blood testing. Fecal immunochemical test is the preferred cancer detection test.

Annual Hemoccult Sensa and fecal DNA testing every three years are alternative cancer detection tests.

A family history of small tubular adenomas in first-degree relatives is not considered to increase the risk of colorectal cancer.

Persons with only one first-degree relative with colorectal cancer or advanced adenomas diagnosed at 60 years or older may be screened as average-risk persons.

preclude primary screening with colonoscopy, or if patients decline colonoscopy, the physician should offer an alternative prevention test or the preferred detection test (i.e., occult blood detection through FIT).

The ACG supports annual FIT as a preferred cancer detection test in place of guaiac-based fecal occult blood testing. Although the guaiac-based Hemoccult Sensa and the fecal DNA test are possible alternative detection tests, FIT is less expensive than fecal DNA testing and has produced more extensive data than the Hemoccult Sensa.

Age to Begin Screening in Persons at Average Risk The ACG recommends that colorectal cancer screening begin at 50 years of age in men and women at average risk (i.e., those without a family history of colorectal neoplasia). However, screening should begin at 45 years of age in black men and women. Evidence supports screening for colorectal cancer before 50 years of age in persons with an extreme smoking history or obesity, although a formal recommendation has not been issued.

Family History Screening The ACG no longer recommends an increased level of screening for a simple family history of adenomas in a first-degree relative. Patients with one first-degree

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American Family Physician Table 2. Colorectal Cancer Screening Recommendations Preferred CRC screening recommendations Cancer prevention tests should be offered first; the preferred CRC prevention test is colonoscopy every 10 years, beginning at 50 years of age (Grade 1 B) Screening should begin at 45 years of age in blacks (Grade 2 C) Cancer detection tests should be offered to patients who decline colonoscopy or another cancer prevention test; the preferred cancer detection test is annual FIT for blood (Grade 1 B) Alternative CRC prevention tests Flexible sigmoidoscopy every five to 10 years (Grade 2 B) Computed tomography colonography every five years (Grade 1 C) Alternative cancer detection tests Annual Hemoccult Sensa (Grade 1 B) Fecal DNA testing every three years (Grade 2 B) Recommendations for screening when family history is positive but evaluation for HNPCC considered not indicated Patients with one first-degree relative with CRC or advanced adenoma diagnosed at 60 years or older should be screened the same as patients at average risk (Grade 2 B) Patients with one first-degree relative with CRC or advanced adenoma diagnosed before 60 years of age, or two first-degree relatives with CRC or advanced adenomas diagnosed at any age, should undergo colonoscopy every five years beginning at 40 years of age or 10 years younger than the age of the youngest affected relative at the time of diagnosis (Grade 2 B) FAP Patients with classic FAP (more than 100 adenomas) should be advised to pursue genetic counseling and genetic testing if they have siblings or children who could potentially benefit from this testing (Grade 2 B) Patients with known FAP and those at risk of FAP based on family history (and in whom genetic testing has not been performed) should undergo annual flexible sigmoidoscopy or colonoscopy, as appropriate, until colectomy is deemed by physician and patient as the best treatment (Grade 2 B) Patients with retained rectum after subtotal colectomy should undergo flexible sigmoidoscopy every six to 12 months (Grade 2 B) Patients with classic FAP, in whom genetic testing is negative, should undergo genetic testing for biallelic MYH mutations; patients with 10 to 100 adenomas can be considered for genetic testing for attenuated FAP and, if negative, MYH-associated polyposis (Grade 2 C) HNPCC Patients who meet the Bethesda criteria for HNPCC should undergo microsatellite instability testing of their tumor or a family member's tumor and/or tumor immunohistochemical staining for mismatch repair proteins (Grade 2 B) Patients with positive tests can be offered genetic testing; those with positive genetic testing, or those at risk when genetic testing is unsuccessful in an affected proband, should undergo colonoscopy every two years beginning at 20 to 25 years of age until 40 years of age, and annually thereafter (Grade 2 B) CRC = colorectal cancer; FAP = familial adenomatous polyposis; FIT = fecal immunochemical test; HNPCC = hereditary nonpolyposis colorectal cancer.

Grade 1 A = strong recommendation, high-quality evidence; Grade 1 B = strong recommendation, moderate-quality evidence; Grade 1 C = strong recommendation, low- or very low-quality evidence; Grade 2 A = weak recommendation, high-quality evidence; Grade 2 B = weak recommendation, moderate-quality evidence; Grade 2 C = weak recommendation, low- or very low-quality evidence.

relative with colorectal cancer or advanced adenoma (i.e., adenoma greater than 1 cm, or with high-grade dysplasia or villous elements) diagnosed at 60 years or older should receive the same screening as averagerisk patients. Patients with one first-degree relative diagnosed before 60 years of age, or with two firstdegree relatives diagnosed at any age, should have a screening colonoscopy every five years beginning at 40 years of age or 10 years younger than the age of the youngest affected relative at the time of diagnosis.

Table 2 summarizes the ACG recommendations for modification of the screening approach when a

family history of colorectal polyps and cancer are not suggestive of hereditary nonpolyposis colorectal cancer (HNPCC).

Familial Adenomatous Polyposis Patients with features of an inherited colorectal cancer syndrome should be encouraged to seek genetic counseling and, if appropriate, genetic testing (Table 2).

Patients with familial adenomatous polyposis (FAP) should undergo APC mutation testing. If this test is negative, MYH mutation testing is recommended.

Contâ&#x20AC;&#x2122;d. on page 502...

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cardiology

Newer Hypolipidemics on the Block Princy Louis Palatty*, Manasa M**, Apoorva Naik†, Archana Kaveri B†, Bhavishya Kirthi Anna WaLder‡, Manohar PrabU‡, Manjeshwar Shrinath Baliga¶

Abstract Hypolipidemics, are much widely used in the present day scenario as the sure prophylactic to tackle cardiovascular diseases and stroke, which are leading causes of death across the world. Moreover, hyperlipidemia is not just a metabolic disorder, it also runs in families, making hypolipidemics more important and necessary. Hence, newer and more efficient drugs are being released. The statins and fibrates, especially rosuvastatin and fenofibrate are associated with much fewer complications then their early counterparts. Ezetemibe or orlistat reduce absorption of cholesterol, beclibrinic acid has a unique action. Chinese red yeast rice has a hyoplipidemic action. Our study has explored in detail the status of newer drugs like micronized fenofibrate, 1-methyl-4-piperidyl bis (chlorophenoxy) acetate, lentysine and gugulipid.

Keywords: Hypolipidemia, hypercholesterolemia, triacylglycerols, phospholipids, apoproteins, ezetimibe

C

ardiovascular diseases (CVDs) are the commonest cause of death the world over (27%). Hyperlipidemia is the harbinger of myocardial infarction and stroke, which accounts for 33.6% in Indian diet.1 The incidence of hyperlipidemia is 42.9% in USA and similar in other countries also.2 Reducing incidence of hyperlipidemia would reduce the death followed by CVD. This review addresses the probable available agents that reduce cholesterol and triglyceride levels.

Plasma lipids are transported in complexes called lipoproteins. Metabolic disorders that involve elevations in any lipoprotein species are termed hyperlipoproteinemias or hyperlipidemias. Hyperlipemia denotes increased levels of triglycerides.3 Hyperlipidemia has become one of the most common problems in day-to-day’s life. The sedentary life today has particularly enhanced its risk. It has become a

*Professor Dept. of Pharmacology **II MBBS †IV MBBS ‡III MBBS ¶Dept of Research and Development Fr. Muller Medical College, Kankanady, Mangalore Address for correspondence Dr Princy Louis Palatty Professor, Dept. of Pharmacology 302, Binany Homes, Kottara, Ashoknagar, Mangalore - 575 006 E-mail: drprincylouispalatty@yahoo.com drprincylouispalatty@gmail.com

house-to-house disorder, especially in higher middle class and higher societies. Intake of fat and high carbohydrate rich diet style of India has also added to its increasing intensity. Some of them include refined low poly- unsaturated fatty acid (PUFA), increased use of egg and meat, ‘refined’ low fiber containing carbohydrate stuffs.4 Hyperlipoproteinemias or hyperlipidemias are included under metabolic disorders; vascular or cyclic vomiting syndrome (CVS) disorders are secondary to them.5 Hence, more importance has to be given to these disorders to prevent further complications.

Lipid and lipoproteins Plasma lipids consist of triacylglycerols (16%), phospholipids (30%), cholesterol (14%) and cholesteryl esters (36%) and a much smaller fraction of unesterified long-chain fatty acids (4%). This latter fraction, the free fatty acids (FFA), is metabolically the most active of the plasma lipids.6 Because fat is less dense than water, the density of a lipoprotein decreases as the proportion of lipid to protein increases (Table 1). Four major groups of lipoproteins have been identified that are important physiologically and in clinical diagnosis. These are: i) Chylomicrons, derived from intestinal absorption of triacylglycerol and other lipids; ii) very-lowdensity lipoproteins (VLDL, or pre-b-lipoproteins), derived from the liver for the export of triacylglycerol; iii) low-density lipoproteins (LDL, or b-lipoproteins), representing a final stage in the catabolism of VLDL and

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cardiology Table 1. Composition of Lipoproteins in Human Plasma Lipoprotein

Source

Density (g/ml)

Protein (%)

Lipid (%)

Main lipid component

Apoproteins

Chylomicrons

Intestine

<0.95

1-2

98-99

Triacylglycerol

A-I, A-II, A-IV, B-48, C-I, C-II, C-III,E

Liver (intestine)

0.95-1.006

7-10

90-93

Triacylglycerol

B-100, C-I, C-II, C-III

IDL

VLDL

1.006-1.019

11

89

Triacylglycerol, cholesterol

B-100, E

LDL

VLDL

1.019-1.063

21

79

Cholesterol

B-100

HDL

Liver, intestine, VLDL, chylomicrons

Phospholipids, cholesterol

A-I, A-II, A-IV, C-I, C-II, C-III, D, E

VLDL

HDL1

1.019-1.063

32

68

HDL2

1.063-1.210

33

67

HDL3

1.125-1.210

57

43

99

1

Pre-β-HDL Alb/Free fatty acid

>1.210 Adipose tissue

>1.281

A-I

iv) high-density lipoproteins (HDL, or b-lipoproteins), involved in cholesterol transport and also in VLDL and chylomicron metabolism.7 Triacylglycerol is the predominant lipid in chylomicrons and VLDL, whereas cholesterol and phospholipids are the predominant lipids in LDL and HDL, respectively (Table 1). Lipoproteins may be separated according to their electrophoretic properties into α-, b- and pre-blipoproteins.8 The nonpolar lipid core consists mainly of triacylglycerol and cholesteryl ester and is surrounded by a single surface layer of amphipathic phospholipid and cholesterol molecules. These are oriented so that their polar groups face outward to the aqueous medium, as in the cell membrane.9 The protein moiety of a lipoprotein is known as an apolipoprotein or apoprotein, constituting nearly 70% of some HDL and as little as 1% of chylomicrons. Some apolipoproteins are integral and cannot be removed, whereas others are free to transfer to other lipoproteins.9 Types of Apolipoproteins Lipids are transported in the plasma as lipoproteins.

Apolipoproteins constitute one of the building blocks of lipoproteins, in turn fat. Some of them are A I-IV, B48, B100, CI, II, III… D and E.10 One or more apolipoproteins (proteins or polypeptides) are present in each lipoprotein. The major apolipoproteins of HDL (β-lipoprotein) are designated are described in Table 1. The main apolipoprotein

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Free fatty acid

of LDL (β-lipoprotein) is apolipoprotein B (B-100), which is found also in VLDL. Chylomicrons contain a truncated form of apo B (B-48) that is synthesized in the intestine, while B-100 is synthesized in the liver.

Apo B-100 is one of the longest single polypeptide chains known, having 4,536 amino acids and a molecular mass of 5,50,000 Da. Apo B-48 (48% of B-100) is formed from the same mRNA as apo B-100 after the introduction of a stop signal by an RNA editing enzyme. Apo C-I, C-II and C-III are smaller polypeptides (molecular mass 7,000-9,000 Da) freely transferable between several different lipoproteins.

Apo E is found in VLDL, HDL, chylomicrons and chylomicron remnants; it accounts for 5-10% of total VLDL apolipoproteins in normal subjects.10 Apolipoproteins carry out several roles: i) They can form part of the structure of the lipoprotein, e.g., apo B; ii) they are enzyme cofactors, e.g., C-II for lipoprotein lipase (LPL), A-I for lecithin:cholesterol acyltransferase (LCAT), or enzyme inhibitors, e.g., apo A-II and apo C-III for LPL, apo C-I for cholesteryl ester transfer protein and iii) they act as ligands for interaction with lipoprotein receptors in tissues, e.g., apo B-100 and apo E for the LDL receptor, apo E for the LDL-receptorrelated protein (LRP), which has been identified as the remnant receptor, and apo A-I for the HDL receptor.

The functions of apo A-IV and apo D, however, are not yet clearly defined, although apo D is believed to be an important factor in human neurodegenerative disorders.6

cardiology Familial hyperproteinEmia

Familial type III hyperlipoproteinemia

Lipoproteins are metabolized in liver. Like all other nutrients defect of lipid metabolism also results in disorders. These are mainly classified as: i) Hypoor hyperlipoproteinemia ii) primary or secondary disorder. and iii) inherited or acquired. Primary disorders are usually inherited once, while acquired involve abnormal lipoprotein patterns secondary to diseases like diabetes mellitus, hypothyroidism, kidney diseases and atherosclerosis. Secondary patterns are very similar to primary inherited conditions. Virtually all primary conditions are defect at various stages in lipoprotein formation, transport or destruction. All abnormalities are not harmfull.11

It is also called broad-beta disease, or remnant removal disease also called ‘familial dysbetalipoproteinemia’ due to deficiency in remnant clearance by the liver as a result of abnormality in apo E. Patients lack isoforms E3 and E4 and have only E2, which does not react with the E receptor (Table 2).11 Familial hypertriacylglycerolemia (type IV)

Familial LPL deficiency (type I) It is a condition of hypertriacylglycerolemia due to LPL deficiency, abnormal LPL or apo C-II deficiency causing inactive LPL (Table 2). Hence, type I is slow clearance of chylomicrons and VLDL, low levels of LDL and HDL and no increased risk of coronary disease.11 Familial hypercholesterolemia (type IIa) Involves defective LDL receptors or mutation in ligand region of apo B-100, causing elevated LDL levels and hypercholesterolemia, resulting in atherosclerosis and coronary disease (Table 2).11

Condition with overproduction of VLDL often associated with glucose intolerance and hyperinsulinemia, resulting in rise of cholesterol level with VLDL (Table 2). LDL and HDL tend to be subnormal. This type of pattern is commonly associated with coronary heart disease (CHD), type 2 diabetes mellitus, obesity, alcoholism and administration of progestational hormones.11 Other hyperlipoproteinemias Other hyperlipoproteinemias involve ‘hepatic lipase deficiency’ i.e., deficiency of the enzyme leading to accumulation of large triacylglycerol-rich HDL and VLDL remnants. Patients have xanthomas and CHD.12 ’Familial LCAT deficiency’ leading to block in reverse cholesterol transport. HDL remains as nascent disks incapable of taking up and esterifying cholesterol hence, plasma concentrations of cholesteryl

Table 2. Frederickson’s Classification Hyperlipoproteinemias Type

Lipoprotein fraction elevated

Cholesterol level

TAG level

Metabolic effect

Features

Management

Chylomicrons

N

++

LPL deficiency

Eruptive xanthomas; hepatomegaly; pain abdomen

Restriction of fat

II A

LDL

++

N

LDL receptor defect; apo B+

Atherosclerosis, coronary artery disease, tuberous xanthoma

Low cholesterol and saturated fat. Give PUFA and drugs (statins)

II B

LDL and VLDL

++

+

Apo B + Apo C II+

Corneal arcus

(Do)

III

Broad-beta; VLDL and chylomicrons

++

+

Abnormal apo E; Palmar xanthoma. High apo CII + incidences of vascular disease

IV

VLDL

+

++

Over production of VLDL; apo CII +

V

VLDL, chylomicrons

N

++

Secondary to other causes

I

Reduction of weight, restriction of fat and cholesterol. Give PUFA and drugs

Reduction of body weight.

Associated with Restrict carbohydrate and diabetes mellitus, cholesterol ischemic heart disease, obesity Ischemic heart diseases

High PUFA intake, hypolipidemic drugs

N: Normal; +: Increased.

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cardiology esters and lysolecithin are low. An abnormal LDL fraction, lipoprotein X, is also found in patients with cholestasis.11 VLDL is abnormal (β-VLDL). ‘Familial lipoprotein excess’, which may result in premature CHD due to atherosclerosis, plus thrombosis due to inhibition of fibrinolysis.12 ’Familial hyperalphalipoproteinemia’ is a defect of increased concentration of HDL. It is a rare condition apparently beneficial to health and longevity.11 Complications of hyperlipoproteinemia Hyperlipoproteinemia results in further complication of which, a serious one is atherosclerosis. It is recognized that triacylglycerols are independent risk factor.10 Atherosclerosis is characterized by deposition of cholesterol and cholesterol ester into artery wall.

Diseases with prolonged elevation of LDL, VLDL, chylomicron remnents, or LDL in blob are often accompanied by premature or more severe atherosclerosis. There is also an inverse relationship between HDL concentrations and CHD, making the LDL: HDL cholesterol as a good predictive parameter.12 Genetic basis of familial dyslipidemia and hypertension The genetic and environmental determinants of hypertension, lipid abnormalities and coronary artery disease (CAD) were studied for 15 years in Utah in population-based multigenerational pedigrees (2,500 subjects among 98 pedigrees), twin pairs (74 monozygous and 78 dizygous), hypertensive siblings (131 sibships), siblings with CAD before age 55 (45 sibships), and anecdotally ascertained pedigrees with type 2 diabetes (271 subjects among 16 pedigrees), LPL deficiency (106 subjects in a single pedigree), and familial hypercholesterolemia (502 heterozygotes among 50 pedigrees). Estimates of heritability ranged from 20 to 75% for blood pressures and blood lipids.

A strong positive family history predicts a future occurrence of hypertension (relative risk [RR] = 3.8) and CAD (RR = 12.7). Segregating single-gene effects were found for several ‘intermediate phenotypes’ associated with hypertension (erythrocyte sodiumlithium countertransport, intraerythrocytic sodium, a relative fat pattern, total urinary kallikrein excretion, and fasting insulin levels). Strong single-gene effects in segregation analysis were also found for LDL cholesterol, lipoprotein (a) (Lp[a]), low HDL cholesterol, and high apolipoprotein (apo) B. Deoxyribonucleic acid (DNA)

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markers of lipid abnormalities or hypertension have included LDL-receptor defects, LPL deficiency, high Lp(a), familial defective apo B, decreased quantitative levels of apo B, apo E phenotype, angiotensinogen and ‘glucocorticoid remediable aldosteronism (GRA) hypertension.13 Hyperlipidemia, pregnancy and pancreatitis Hypertriglyceridemia is a recognized complication of pregnancy.

In patients with familial hypertriglyceridemia, the biochemical changes are greatly enhanced during pregnancy and may be associated with acute pancreatitis, a potentially fatal triad. Three patients were studied, in one of whom previously undiagnosed hyperlipidemia resulted in a fatal attack of fulminant acute pancreatitis. In the other two patients, this complication was avoided by close monitoring and restriction of dietary facts. A history of episodic abdominal cramps, often beginning in early childhood, or the presence of lipemic fasting plasma should alert the clinician to the presence of severe familial hypertriglyceridemia. Early diagnosis allows for the institution of relatively simple management strategies, which diminish the risk of pancreatitis.14 Pharmacotherapy Treatment for hyperlipoproteinemias or hypolipidemias is very important. Hyperlipidemia needs to be controlled by means of diet mainly. Drugs serving this purpose are very useful and are the succour in familial disorders, which cannot be controlled by diet.15 Moreover, bringing down cholesterol levels is necessary to reduce risk of mortality and morbidity.15 Drugs are started after at least a trial of or three month period of low fat diet with exercise. Along with the use of drugs, dietary restriction is to be followed throughout (Table 3).

Many drugs have been introduced over the years for the treatment of hyperlipidemia. These drugs are mainly involved in reducing body cholesterol by either decreasing the synthesis (statins), increasing its metabolism (fibrates), or by obstructing the absorption and increasing excretion (resins). The summary of these hyperlipidemics are in Table 4.

Ezetimibe CHD is the leading cause of death in United States. The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III recommends new lower cholesterol levels, particularly for patients at moderate

cardiology Table 3. Classification HMG-CoA reductase inhibitor Levostatin Simvastatin Pravastatin Atovastatin Rosuvastatin Flustatin Fibric acid derivatives Gemfibrozil Clofibrate Colesevalam Fenofibrate Bezafibrate Ciprofibrate Bile acid binding resins Cholestyramine Colestipol Colesvalam Others Ezetemibe- sterol absorption inhibitor Beclobrinic acid- PG synthesis inhibitors Lentysine, Gugulipid- plant products Chinese red-yeast rice- genetically modified

Fibric acid derivatives: Micronized fenofibrate Fenofibrate reduces serum triglyceride, total cholesterol, and LDL-cholesterol, and raises HDL-cholesterol to clinically relevant degrees. Its spectrum of activity appears to exceed that recommended for types IV and V hyperlipidemia to encompass types IIa, IIb and III hyperlipidemias as well. To this extent, it may be considered a broader-spectrum fibrate than is indicated by its FDA approval. Adverse effects of fenofibrate appear to be similar to those of other fibrates and require routine monitoring (clinical, liver function).

Long-term safety data are readily available from drug registries in many countries where the product has been available for nearly two decades. Costeffectiveness studies comparing fenofibrate with other hypolipidemics demonstrate benefits of fenofibrate over simvastatin in types IIa and IIb hyperlipidemia.

The need for dosage titration of the micronized preparation from 67 mg/day upward to a final dose of 200 mg/day is also not supported by peer-reviewed literature (except in the case of renal impairment).

Although preliminary data on plaque regression are encouraging, published clinical studies evaluating the impact of fenofibrate on cardiovascular morbidity and mortality are awaited. Micronized fenofibrate is worthy of formulary inclusion.17 Prostaglandin synthesis inhibitors

and high-risk for coronary disease. LDL cholesterol is primarily the target of hypolipidemic drugs. The NCEP ATP III recommends an LDL cholesterol goal of <100 mg/dl in high-risk patients and an LDL cholesterol goal of <70 mg/dl as a therapeutic option, especially in patients with very high-risk of CHD. Statins are potent LDL cholesterol-lowering drugs, but they are not as effective as fibrates and niacin in improving levels of triglycerides or HDL cholesterol.

Ezetimibe represents a new class of hypolipidemic drugs that inhibit cholesterol absorption in the small intestine. The combination of ezetimibe with statins has been more effective than monotherapy alone in many randomized trials. LDL cholesterol reduction with statin occurs mainly with the initial dose, with relatively smaller reductions seen at higher doses.

Ezetimibe was also shown to be useful in various population subgroups such as African-Americans, men and women, elderly and aged, and also those with kidney disease.16

Beclobrinic Acid A new hypolipidemic agent - inhibits in vitro human platelet activation by blocking prostaglandin synthesis.

Effects and the mechanism of the antiplatelet actions of beclobrinic acid, free acid form of a new hypolipidemic agent beclobrate [(+)-2-[d-(P-chlorophenyl)p-tolyl) oxy)-2-methyl-butyrate), were examined using human platelets. Platelet-rich plasma (PRP), which was prelabeled with (14C)-serotonin was incubated with beclobrinic acid (BBA) for one minute before the addition of various agonists. BBA (0.1-1.5 mM) inhibited platelet aggregation and serotonin secretion induced by ADP, epinephrine, arachidonic acid and collagen in a concentration-dependent manner. BBA also inhibited arachidonic acid-induced production of malondialdehyde (MDA), a byproduct of prostaglandins, in a concentration-dependent manner. However, upto 1.0 mM BBA did not inhibit platelet aggregation induced by U46619, a stable analog of prostaglandin H2. In other experiments, BBA also blocked

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cardiology Table 4. Summary of Activity and ARD of Hypolipidemics Subclass

Mechanism of action

Effects

Clinical applications

Pharmacokinetics, toxicities, interactions

Inhibit HMGCoA reductase

Reduce cholesterol synthesis and upregulate LDL receptors on hepatocytes modest reduction in triglyceride

Atherosclerotic vascular disease (primary and secondary prevention) acute coronary syndromes

Oral duration 12-24 hour Toxicity: Myopathy, hepatic dysfunction Interactions: CYP-dependent metabolism (3A4, 2C9) interacts with CYP inhibitors

Statins Atorvastatin, simvastatin, rosuvastatin

Fluvastatin, pravastatin, lovastatin: Similar but somewhat less efficacious Fibrates Fenofibrate, gemfibrozil

Peroxisome proliferatoractivated receptor-a (PPAR-a) agonists

Decrease secretion of VLDL increase LPL activity increase HDL

Hypertriglyceridemia, low HDL

Oral duration 3-24 hours Toxicity: Myopathy, hepatic dysfunction

Decreases LDL

Elevated LDL, digitalis toxicity, pruritus

Oral taken with meals not absorbed, Toxicity: Constipation, bloating interferes with absorption of some drugs and vitamins

Bile acid sequestrants Colestipol

Binds bile acids in gut prevents reabsorption increases cholesterol catabolism upregulates LDL receptors

Cholestyramine, colesevalam: Similar to colestipol Sterol absorption inhibitor Ezetimibe

Blocks sterol transporter NPC1L1 in intestine brush border

Inhibits reabsorption of cholesterol excreted in bile decreases LDL and phytosterols

Elevated LDL, phytosterolemia

Oral duration 24 hour; Toxicity: Low incidence of hepatic dysfunction, myositis

Niacin

Decreases catabolism of apo AI reduces VLDL secretion from liver

Increases HDL decreases Lp(a), LDL, and triglycerides

Low HDL elevated VLDL, LDL, Lp(a)

Oral large doses; Toxicity: Gastric irritation, flushing, low incidence of hepatic toxicity may reduce glucose tolerance

thrombin-induced release of (3H)-arachidonic acid from platelet phospholipids. These findings suggest that: (a) BBA inhibits platelet aggregation and serotonin secretion by inhibiting prostaglandin synthesis at two steps. First by interfering in the release of arachidonic acid from platelet phospholipids and second by inhibiting its conversion into prostaglandins and (b) BBA does not inhibit the action of prostaglandins on human platelets.18

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1-methyl-4-piperidyl bis (p-chlorophenoxy) acetate (SaH 42-348): A new hypolipidemic agent Animal studies have shown the hypolipidemic properties of (SaH-2-438), which is chemically 1-methyl4-piperidyle bis (p-chlorophenoxy) acetate. This agent is 8-9 times more active on a weight for weight basis than chlorphenoxy isobutyric acid ethyl ester (CPIB) (Atromid-S), and in common with CPIB lowers the level of all major classes of serum lipid. No increase in liver lipid content was seen in animals treated with

cardiology SaH 42-348, although hepatomegaly was seen after treatment with SaH 42-348 or with CPIB. Evidence suggests that the mechanism of action of SaH 42-348 in lowering serum cholesterol in the rat differs from that of CPIB. Thus, it was not possible to demonstrate that SaH 42-348 inhibited cholesterol biosynthesis in vivo, while the inhibitory effect of CPIB was readily demonstrated. In addition, n-propylthiouracil (PTU) inhibited the hypocholesterolemic activity of CPIB in both normolipemic and hyperlipemic rats, where as the activity of SaH 42-348 was unaffected by PTU.19 Plant sterols and steroids Consumption of diet, which is low in saturated and trans-fats yet high in fibers, lowers the ‘bad cholesterol’ (LDL) and keeps the heart and blood vessels healthy.

‘Phytosterols’ in fruits, vegetables, vegetable oils, nuts and seeds amounts to ‘plant sterols’ and ‘plant stenols’ that reduce absorption of cholesterol.

Source: Wheat, peanut, vegetable oil (corn, sesame, canola and olive oil), almonds, brussels sprouts, etc.

Mechanism of Action Sterols and stenols (similar chemically to cholesterol) Cholesterol absorbed in intestine LDL levels in blood Plant sterols and stenols resemble cholesterol in terms of chemical structure. They prevent intestinal cholesterol absorption, thus lowering LDL. Studies have shown that, sterols and stenols lower LDL cholesterol by average 6% and perhaps 14% in four weeks.

Daily requirement: 2 g/day as by NCEP.

Adverse Effects Plant sterols and stenols have been studied for >50 years. They are both safe and effective in lowering cholesterol. However, large doses may cause nausea, indigestion, diarrhea and also interferes with absorption of fat-soluble vitamin. Pregnant and breastfeeding women should be cautious in consumption. Moreover, they cannot be a substitute for cholesterol-lowering medications and are advocated in combination, not as monotherapy.16

These can be either obtained naturally from plants and their products (e.g., lentysine, gugulipid) or from genetically modified sources (e.g., red yeast rice). Few of plant hypolipidemidic agents are discussed below.16

Lentysine Lentysine is one of the naturally obtained hypolipidemic agent. It was recently discovered that few of the edible mushrooms contained a chemical named lentysine, which was found to act as a hypolipidemic agent.

Hence, in patients with high fat diet consumption of these mushrooms were found to be useful. Its actions on serum and liver lipids in rats have been investigated.

Lentysine markedly reduced serum cholesterol, phospholipids and triglycerides, both in intact rats and in animals fed a high fat diet. However, it showed no effect on liver lipid levels, and enlargement of liver was not observed in rats treated with lentysine.20

Gugulipid Gugulipid, the resin of the Commiphora mukul tree has been used in Ayurvedic medicine for more than 2,000 years to treat a variety of ailments. Studies in both animal models and humans have shown that this resin, termed gum guggul, can decrease elevated lipid levels. The stereoisomers E- and Z-guggulsterone have been identified as the active agents in this resin.

Recent studies have shown that these compounds are antagonist ligands for the bile acid receptor farnesoid X receptor (FXR), which is an important regulator of cholesterol homeostasis. It is likely that this effect accounts for the hypolipidemic activity of these phytosteroids.21

Red-yeast-rice Red-yeast-rice is one of the genetically modified rice, which contains hypolipidemic agent from yeast. The cholesterol-lowering effects of a proprietary Chinese red-yeast-rice supplement was examined in an American population consuming a diet similar to the American Heart Association Step I diet using a double-blind, placebo-controlled, prospectively randomized 12-week controlled trial at a university research center. Eightythree healthy subjects with hyperlipidemia who were not being treated with lipid-lowering drugs participated.

Subjects were treated with red-yeast-rice (2.4 g/d) or placebo and instructed to consume a diet providing 30% of energy from fat, <10% from saturated fat and <300 mg cholesterol daily. Main outcome measures were total cholesterol, total triacylglycerol, and HDL

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cardiology and LDL cholesterol measured at Weeks 8, 9, 11, and 12. Cholesterol concentrations decreased significantly between baseline and eight weeks in the red-yeastrice–treated group compared with the placebo-treated group. LDL cholesterol and total triacylglycerol were also reduced with the supplement. HDL cholesterol did not change significantly. Hence red yeast rice was proven to a new, novel, food-based approach to lower cholesterol in the general population.22 References 1. US census bureau population estimates. Available at: http:// www.census.gov/popest.

2. Centers for Disease Control and Prevention (CDC).

Behavioral Risk Factor Surveillance System Survey Data.

Atlanta, Georgia: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention.

3. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al; American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112(17):2735-52.

4. Kromhout D, Menotti A, Kesteloot H, Sans S. Prevention of coronary heart disease by diet and lifestyle: evidence from prospective cross-cultural, cohort, and intervention studies.

Circulation 2002;105(7):893-8.

5. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105(9):1135-43.

6. Goldberg IJ, Merkel M. Lipoprotein lipase: physiology, biochemistry, and molecular biology. Front Biosci 2001;6:D388-405.

7. Christi WW. Lipid analysis. 3rd edition, The Oily Press, 2003.

8. Gurr MI, Harwood JL, Frayn K. Lipid biochemistry.

Blackwell Publishing, 2002.

9. Dowhan W, Bodanov H. Functional roles of lipid metabolism.

In: Biochemistry of Lipids, Lipoproteins and Membranes.

Vance DE, Vance JE (Eds), 4th Edition.

10. Shelness GS, Sellers JA. Very-low-density lipoprotein

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

assembly and secretion. Curr Opin Lipidol 2001;12(2): 151-7.

Arner P. Human fat cell lipolysis: biochemistry, regulation and clinical role. Best Pract Res Clin Endocrinol Metab 2005;19(4):471-82.

Russell DW. Cholesterol biosynthesis and metabolism.

Cardiovasc Drugs Ther 1992;6(2):103-10.

Williams RR, Hunt SC, Hopkins PN, Wu LL, Hasstedt SJ, Berry TD, et al. Genetic basis of familial dyslipidemia and hypertension: 15-year results from Utah. Am J Hypertens 1993;6(11 Pt 2):319S-327S. De Chalain TM, Michell WL, Berger GM. Hyperlipidemia, pregnancy and pancreatitis. Surg Gynecol Obstet 1988;167(6):469-73.

Kromhout D, Menotti A, Kesteloot H, Sans S. Prevention of coronary heart disease by diet and lifestyle: evidence from prospective cross-cultural, cohort, and intervention studies.

Circulation 2002;105(7):893-8.

Katragadda S, Rai F, Arora R. Dual inhibition, newer paradigms for cholesterol lowering. Am J Ther 2010;17(4):e88-99.

Guay DR. Micronized fenofibrate: a new fibric acid hypolipidemic agent. Ann Pharmacother 1999;33(10): 1083-103.

Anwer K, Gabis J, Romstedt K, Gojer C, Huzoor-Akbar.

Beclobrinic acid - a new hypolipidemic agent - inhibits in vitro human platelet activation by blocking prostaglandin synthesis. Life Sci 1985;37(1):63-70.

Timms AR, Kelly LA, Ho RS, Trapold JH. Laboratory studies of 1-methyl-4-piperidyl bis(p-chlorophenoxy) acetate (SaH 42-348)— A new hypolipidemic agent. Biochem Pharmacol 1969;18(8):1861-71.

Rokujo T, Kikuchi H, Tensho A, Tsukitani Y, Takenawa T, Yoshida K, et al. Lentysine: a new hypolipidemic agent from a mushroom. Life Sci 1970;9(7):379-85.

Urizar NL, Moore DD. Gugulipid: a natural cholesterollowering agent. Annu Rev Nutr 2003;23:303-13.

Heber D, Yip I, Ashley JM, Elashoff DA, Elashoff RM, Go VL. Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement. Am J Clin Nutr 1999;69(2):231-6.

...Cont’d from page 494

Patients with FAP and those at risk of FAP should be screened annually with flexible sigmoidoscopy or colonoscopy until the patient and physician determine that a colectomy is the best treatment. Endoscopic assessment every 6-12 months after surgery is recommended for patients with a retained rectum after subtotal colectomy. Genetic counseling, APC and MYH mutation testing, and individualized colonoscopy surveillance should be considered in patients who have fewer than 100 colorectal polyps. Upper endoscopic surveillance is recommended for patients with FAP or MYH-associated polyposis.

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Hereditary Nonpolyposis Colorectal Cancer Patients who meet the Bethesda criteria for HNPCC should undergo microsatellite instability testing of their tumor or an affected family member’s tumor (Table 2). This may be combined with tumor immunohistochemical staining for mismatch repair proteins. Patients with positive tests may be offered genetic counseling and should undergo colonoscopy every two years beginning at 20-25 years of age until 40 years of age, and annually thereafter.

Source: Adapted From Am Fam Physician. 2009;80(6):647-651.

drugs and devices

Gliptins - The Novel Players in Glucose Homeostasis G Kannan*, N Vanitha Rani, Vasantha Janardhan, Priya Patel, C Uma Maheswara Reddy

Abstract Type 2 diabetes mellitus is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action.

Tight glycemic control is considered to be important in the therapy of type 2 diabetes mellitus, but treatment with a single agent is not sufficient to achieve this for the majority of patients. So, there is a need for new antidiabetic agents with favorable side effect profiles to use in combination therapy. The gliptins, an emerging new class of oral drugs for type 2 diabetes mellitus, lower blood glucose levels by a novel mechanism of inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4) that inactivates incretin, released from the intestine following a meal to increase pancreatic insulin secretion. Gliptins enhance the circulating levels of incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and improve glycemic control. This therapeutic approach carries a low-risk of interprandial hypoglycemia, does not cause weight gain and is well-tolerated. The first gliptin, sitagliptin (Januvia), was introduced in the UK in April 2007 as add-on therapy for patients with type 2 diabetes inadequately controlled with oral hypoglycemic agents. Other gliptins, notably vildagliptin (Galvus), saxagliptin and melogliptin are advanced in clinical development. This article reviews the current evidence on the effectiveness of gliptins and suggests several ways in which these agents could be used in diabetes treatment.

Keywords: Diabetes, gliptins, incretin

D

iabetes is now one of the most common noncommunicable diseases globally. It is the fourth or fifth leading cause of death in most developed countries and there is substantial evidence that it is reaching epidemic proportions in many developing and newly industrialized nations. Complications from diabetes, such as coronary artery and peripheral vascular disease, stroke, diabetic neuropathy, amputations, renal failure and blindness result in increasing disability, reduced life expectancy and enormous health costs for virtually every society. Diabetes is certain to be one of the most challenging health problems of the 21st century.1 The anticipated increase in regional diabetes prevalence from 6.0 to 7.4% in 2025, is very much a consequence of the increasing life expectancy in India, where the proportion of the population over 50 years

*Assistant Professor Dept. of Pharmacy Practice Sri Ramachandra College of Pharmacy Sri Ramachandra University, Porur, Chennai Address for correspondence Mr G Kannan Assistant Professor Dept. of Pharmacy Practice Sri Ramachandra College of Pharmacy Sri Ramachandra University, Porur, Chennai - 600 116 E-mail: kannagg2@yahoo.ca

is expected to increase from 16 to 22% between 2007 and 2025,2 and the urban proportion from 31 to 43%.3 Evidence suggests that in the more affluent parts of the country, the rural prevalence is higher than in the less affluent rural areas, indicating that increasing economic growth will increase diabetes prevalence in India even more than what these possibly conservative estimates have indicated.4 Current strategies for the treatment of type 2 diabetes have focused on reducing insulin resistance and increasing insulin secretion. Biguanides (metformin) and SUs have been the mainstay of therapy for diabetes for many years. More recently, thiazolidinediones have found an important role in augmenting the amelioration of insulin resistance, although there have been recent concerns over safety.5 Meglitinide analogs and a-glucosidase inhibitors have some role in treatment of diabetes, although their role is limited by cost and side effects. Insulin therapy is frequently required in many people with long duration of type 2 diabetes, due to inexorable b-cell decline.

Despite current therapeutic options, only a lesser percentage of diabetes patients achieve a glycated hemoglobin (HbA1C) <6.5%.6 This may in part be due to the fact that traditional treatments for type 2 diabetes do not address the progressive decline in b-cell function.7

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drugs and devices Incretins and glucose homeostasis Advances in the understanding of the actions of endogenous glucoregulatory peptide hormones, known as incretins in glycemic control, have identified new therapeutic targets for type 2 diabetes. These peptides are secreted from endocrine cells (L-cells) in the gastrointestinal tract, and are released in response to ingestion of food. The two main incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), with GLP-1 being responsible for most of the incretin effect on pancreatic b-cell function. GLP-1 regulates glucose homeostasis in the postprandial period by a number of mechanisms, including stimulation of insulin synthesis, inhibition of glucagon secretion, delay in gastric emptying and promotion of satiety which leads to weight loss in the majority of treated subjects.8 However, although native GLP-1 (7-36) amide effectively lowers blood glucose, it is rapidly degraded by the ubiquitous serine protease dipeptidyl peptidase-4 (DPP-4), a complex molecule widely expressed in many tissues, including the capillary bed of the gut mucosa.

DDP-4 cleaves the N-terminal amino acids of GLP-1, and its close presence to GLP-1-secreting endocrine cells results in the rapid degradation of GLP-1 within minutes of release.9 Gliptins Focus on the inhibition of the proteolytic activity of DPP-4 to prevent the degradation of GLP-1 and GIP, thus enhancing the incretin effect led to the emergence of new class of drugs - DPP-4 inhibitors termed gliptins. By preventing GLP-1 and GIP inactivation, GLP-1 and GIP are able to potentiate the secretion of insulin and suppress the release of glucagon by the pancreas. This drives blood glucose levels towards normal. As the blood glucose level approaches normal, the amounts of insulin released and glucagon suppressed diminishes thus tending to prevent an ‘overshoot’ and subsequent low blood sugar (hypoglycemia), which is seen with some other oral hypoglycemic agents. There is evidence to suggest that DPP-4 inhibition as a strategy for improving glycemic status is more effective in mild and moderate hyperglycemic type 2 diabetes than in severe diabetes. This may reflect greater b-cell reserve in earlier stages of disease development.10 Sitagliptin Sitagliptin is the first gliptin to be approved by the US FDA to treat type 2 diabetes.

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F F F N

F

N N NH2

F

N

O

F Figure 1. Chemical structure of sitagliptin.

Structure Systematic name: (R)-4-oxo-4-[3-(trifluoromethyl)-5,6dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5trifluorophenyl)butan-2-amine (Fig. 1).

Sitagliptin is an oral antihyperglycemic (antidiabetic drug) of the DPP-4 class. It is the only secondgeneration DPP-4 inhibitor currently available. It is highly selective, given once-daily. This enzymeinhibiting drug is used either alone or in combination with other oral antihyperglycemic agents (such as metformin or a thiazolidinedione) for treatment of type 2 diabetes mellitus.11 PHARMACOKINETICS OF SITAGLIPTIN Sitagliptin is rapidly absorbed, with 100 mg reaching a Cmax of 950 nM in 1-4 hours. The bioavailability is approximately 87%. Volume of distribution is approximately 198 L. Plasma protein binding is 38%.5 Metabolism by CYP3A4 and, to a lesser degree, CYP2C8 is a minor pathway in the clearance of sitagliptin.

Terminal t½ is ∼12.4 hours. Approximately 13% is excreted in feces and 87% in urine via active tubular secretion (79% as unchanged drug).12

Indications and Dosage It is used in the treatment of type 2 diabetes mellitus as monotherapy or as dual therapy with metformin, a sulfonylurea, or a thiazolidinedione. Triple therapy using sitagliptin with metformin and a sulfonylurea may be given if dual therapy is inadequate. Sitagliptin is given as the phosphate, 100 mg/oral once-daily with or without food.

For patients with moderate renal function impairment (creatinine clearance 30 to <50 ml/min) and severe renal impairment (creatinine clearance <30 ml/min), dose may be adjusted as 50 mg once-daily and 25 mg oncedaily, respectively.13

drugs and devices Adverse Effects

References

Common adverse effects reported include headache, nasopharyngitis, diarrhea, nausea and upper respiratory tract infection.

1. World Diabetic Foundation-Diabetic Atlas. 3rd edition.

Available from: http://www.worlddiabetesfoundation. org/composite-1090.htm.

Precautions and Contraindications Sitagliptin has to be used with caution in pregnancy and its safety and efficacy is not determined for children and in lactation. The drug is contraindicated in patients with type 1 diabetes or diabetic ketoacidosis.

Drug Interactions Cyclosporine: Sitagliptin plasma concentrations may be increased modestly (approximately 68%), which is not expected to be clinically important.

Digoxin: Digoxin plasma levels may be increased slightly (approximately 18%); no dosage adjustment is recommended.

Symptoms of Overdosage Symptoms include hypoglycemia, increased appetite, headache, confusion, irritability, drowsiness, weakness, tremors, sweating, palpitations, seizures, fainting and coma.14 Sitagliptin versus Other Hypoglycemic Agents Sitagliptin presents some advantages over other drugs used in the management of diabetes. One advantage is its oral administration; another is its low incidence of hypoglycemia, similar to that of a placebo. The benefit of this medicine is its lower side effects like lesser incidence of hypoglycemia and weight gain. Sitagliptin also has an effect on appetite. By slowing down gastric motility, it induces a feeling of satiety. This reduction of appetite can help patients to lose weight, a useful effect in patients with diabetes. Animal studies have shown that it can help prevent β-cell apoptosis and improve β-cell functioning; therefore, it may have a role in control of diabetes, although human data are currently lacking.15 Gliptins on the Way Other drugs that are under FDA approval or late stage clinical trials include vildagliptin (to be sold, when approved, as Galvus by Novartis) and saxagliptin being developed by Bristol-Myers Squibb. Melogliptin

by Glenmark is under Phase II trial. Glaxo suspended the Phase III studies for denagliptin due to toxicity.16

2. United Nations Population Division. World Population Prospects: The 2004 Revision. Geneva: United Nations: Geneva, 2005.

3. United Nations Population Division.

World Urbanization Prospects: The 2003 Revision. Population Database. United Nations: Geneva, 2003.

4. Kutty VR, Soman CR, Joseph A, Pisharody R, Vijayakumar K. Type 2 diabetes in southern Kerala: variation in prevalence among geographic divisions within a region. Natl Med J India 2000;13(6):287-92.

5. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356(24):2457-71.

6. Mahler RJ, Adler ML. Clinical review 102: Type 2 diabetes mellitus: update on diagnosis, pathophysiology, and treatment. J Clin Endocrinol Metab 1999;84(4):1165-71.

7. Barnett A. DPP-4 inhibitors and their potential role in the management of type 2 diabetes. Int J Clin Pract 2006;60(11):1454-70.

8. Drucker DJ, Nauck MA. The incretin system: glucagonlike peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368(9548):1696-705.

9. Reimer MK, Holst JJ, Ahrén B. Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice. Eur J Endocrinol 2002;146(5):717-27.

10. Idris I, Donnelly R. Dipeptidyl peptidase-IV inhibitors: a major new class of oral antidiabetic drug. Diabetes Obes Metab 2007;9(2):153-65.

11. Deacon CF. Therapeutic strategies based on glucagonlike peptide 1. Diabetes 2004;53(9):2181-9.

12. Vincent SH, Reed JR, Bergman AJ, Elmore CS, Zhu B, Xu S, et al. Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C]sitagliptin in humans. Drug Metab Dispos 2007;35(4):533-8.

13. Florentin M, Liberopoulos EN, Mikhailidis DP, Elisaf MS. Sitagliptin in clinical practice: a new approach in the treatment of type 2 diabetes. Expert Opin Pharmacother 2008;9(10):1705-20.

14. Karasik A, Aschner P, Katzeff H, Davies MJ, Stein PP. Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr Med Res Opin 2008;24(2):489-96.

15. Herman GA, Bergman A, Liu F, Stevens C, Wang AQ, Zeng W, et al. Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middleaged obese subjects. J Clin Pharmacol 2006;46(8):876-86.

16. Green BD, Flatt PR, Bailey CJ. Dipeptidyl peptidase IV (DPP IV) inhibitors: A newly emerging drug class for the treatment of type 2 diabetes. Diab Vasc Dis Res 2006;3(3):159-65.

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Drugs and devices

Look-alike and Sound-alike Drug Brand Names: A Potential Risk in Clinical Practice Mukundraj S Keny*, PV Rataboli**

Abstract Objective: Indiaâ&#x20AC;&#x2122;s pharmaceutical industry is now the third largest in the world in terms of volume. With this growth, various drugs with catchy brand names have been introduced. The potential for error due to confusing drug names amongst the healthcare personnel is significant. Numerous case reports and studies have thrown light on the confusion over similar drug names.

Despite these efforts, new names that are similar to the existing names continue to be approved. Aim: The study was carried out to isolate confusing brand names, which are used currently in the Indian market and to categorize these names depending on their effect on therapeutic success. Material and methods: Recent issue of the drug formulary Indian Drug Review (IDR) (Vol. XVII Issue No. 2, March-April 2011) was referred to and all the potentially confusing brand names were analyzed. Results: Many of the brand names were similar looking (orthographic) and similar sounding (phonetic). Certain observations regarding brand naming techniques and their possible implications were noted. Conclusion: The Indian pharmaceutical industry is growing at a fast pace. Hence, India needs a competent Medication Error Reporting Program to report the brand name confusion. Also, we need to create more awareness about confusing brand names and their implications.

Keywords: Drug name, look-alike, sound-alike, therapeutic success, implications, confusing

I

ndiaâ&#x20AC;&#x2122;s pharmaceutical industry is now the third largest in the world in terms of volume. The Indian Pharmaceutical sector is highly fragmented with more than 20,000 registered units. Following the delicensing of the pharmaceutical industry, industrial licensing for most of the drugs and pharmaceutical products has been done away with. Manufacturers are free to produce any drug duly approved by the Drug Control Authority.1

With this growth, various drugs with catchy brand names have been introduced. With tens of thousands of drugs currently on the market, the potential for error due to confusing drug names amongst the practicing doctors, pharmacists and patients is significant.

Confusion over the similarity of prescription and over-the-counter (OTC) drug names has accounted for as many as 25% of all reports to the United States Pharmacopeia Medication Errors Reporting (USP MER) Program.2 *Postgraduate Student **Director-Professor Dept. of Pharmacology, Goa Medical College, Bambolim, Goa Address for correspondence Dr Mukundraj S Keny H. No. 881, Abhyudaya Apartments, Vidyanagar Margao, Goa - 403 601 E-mail: mukundkeny@yahoo.com

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The proposed names are subjected to pre-approval screening by the pharmaceutical manufacturers to various organizations like US Pharmacopeia (USP) and US Food and Drug Administration (US FDA).

Numerous case reports and studies have thrown light on the confusion over similar drug names.3-10 Despite these efforts, new names that are similar to the existing names continue to be approved. We carried out the study to isolate confusing brand name products, which are used currently in the Indian market and to describe potential effect of this confusion on the therapeutic success.

Material and Methods Recent issue of the drug formulary Indian Drug Review (IDR) (Vol. XVII Issue No. 2, March-April 2011) was referred to and all the potentially confusing brand names were analyzed.11 The brand names were presented in the form of tables along with the generic names and the manufacturer of the drug. The possible implication of this confusion was assessed.

Results The IDR lists more than 10,000 brands. Many of the brand names were similar looking (orthographic) and similar sounding (phonetic). The brand names were

drugs and devices Table 1. Major Effect on Therapeutic Success Brand name

Generic name

Manufacturer

Benzol

Danazol 100 mg

Solitaire

Benzole

Albendazole 400 mg/Ivermectin 6 mg

Flamingo

Alparazole

Alprazolam 0.5 mg

Laborate

Adprazole

Omeprazole 20 mg

Admac

Amsat

Ampicillin 250 mg/Cloxacillin 250 mg

Vensat

Amset

Amlodipine 5 mg

Pulse

Adcom

Telmisartan 40 mg

Intel Pharma

Adcon

Fluconazole 150 mg

Admac

Alflox

Norfloxacin 400 mg

Alkem

Alfox

Oxcarbazepine 300 mg

Medi Health

Bromolin

Amoxycillin 500 mg/Bromhexine 8 mg

Cipla

Bromotin

Bromocriptine 2.5 mg

RPG LS

Dialox

Tinidazole 300 mg/Diloxanide 375 mg/ Methyl polysiloxane 25 mg

Aglowmed

Diamox

Acetazolamide 250 mg

Wyeth

Dazolic

Ornidazole 500 mg

Sun

Dazolin

Sertraline 50 mg

Daksh

Depik

Imipramine 25 mg

Aarpik

Depin

Nifedipine 5 mg

Zydus Cadila

Felix

Cefpodoxime 100 mg

Positif

Feliz

Citalopram 10 mg

Torrent

Flex

Ofloxacin 400 mg

Siomond

Flexi

Ondansetron 4 mg

Adley

Flunat

Fluoxetine 10 mg

Sun

Flunaz

Fluconazole 150 mg

BMV

Glucar

Acarbose 50 mg

Glenmark

Glucart

Glucosamine 500 mg

Juggat

Hycin

Roxithromycin 150 mg

Saga Labs

Hymin

Albendazole 400 mg

Intra Labs

Lodol

Haloperidol 5 mg

Symbiosis

Lodoz

Bisoprolol 2.5 mg/Hydrochlorothiazide 6.25 mg

Merck

Lorvan

Lorazepam 1 mg

Cipla

Lorvas

Indapamide 2.5 mg

Torrent

Norten

Propranolol 10 mg

Baroda

Nortin

Nortriptyline 25 mg

La Pharma

Ocimix

Ciprofloxacin 500 mg/Ornidazole 500 mg

Panacea

Ocimax

Omeprazole 20 mg

Pidek

Rispod

Cefpodoxime 100 mg

Symbiosis

Rispond

Risperidone 2 mg

Microsynapse

Topdep

Citalopram 10 mg

Orchid

Topdip

Amlodipine 10 mg

RPG LS

Zolep

Zolpidem 5 mg

Taj Pharma

Zolet

Letrozole 2.5 mg

United Biotech

Wypan

Pantoprazole 40 mg

YACCA

Wypar

Nimesulide100 mg/Paracetamol 500 mg

YACCA

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drugs and devices Table 2. Minor Effect on Therapeutic Success Brand name

Generic name

Manufacturer

Aquamide

Furosemide 50 mg/Spironolactone 20 mg

Sun

Aquazide

Hydrochlorothiazide 12.5 mg

Sun

Disprin

Aspirin 350 mg/Calcium carbonate 105 mg

Reck and Benckiser

Dospin

Aspirin 75 mg/Clopidogrel 75 mg

Ajanta

Epitab

Phenytoin 100 mg

East West

Epitan

Phenobarbitone 60 mg

Reliance

Glide

Glipizide 5 mg

Franco Indian

Gliden

Gliclazide 80 mg

BMW

Heal gel

Silver sulfadiazine/Chlorhexidine/Metronidazole

ORDAIN

Healin ointment

Povidone iodine/Metronidazole

Speciality Meditech

Moxycarb

Amoxicillin 500 mg/Carbocisteine 150 mg

AHPL

Moxycare

Amoxicillin 500 mg/Clavulanate 125 mg

TRITAG

Ostofit

Glucosamine/Chondroitin

Torrent

Ostrobit

Calcium carbonate 500 mg/Vitamin D3

Cubit

Serip

Diclofenac 50 mg/Serratiopeptidase 10 mg

Bennet

Serit

Serratiopeptidase 5 mg

Sunrise

Wormnil

Mebendazole 100 mg

Wings Pharma

Wormonil

Albendazole 400 mg

PDC

Table 3. No Significant Effect on Therapeutic Success Brand name

Generic name

Manufacturer

Avcif

Cefixime 200 mg

Positif

Avcip

Ciprofloxacin 500 mg

Positif

Atmox

Amoxicillin 250 mg

A to Z

Atrox

Roxithromycin 150 mg

A to Z

Afcal

Calcium carbonate 1250 mg/Vitamin D3 250 IU

Alcure

Atcal

Calcium carbonate 625 mg/Vitamin D3 125 IU

A to Z

Cefit

Cefixime 200 mg

Cubit

Cefiz

Cefpodoxime 200 mg

Medi Health

Ceftab

Cefuroxime 250 mg

Sienna

Ceftas

Cefixime 200 mg

Intas

Cufex syrup

Chlorpheniramine/codeine/menthol

Ind-Swift

Cuffix syrup

Terbutaline/Ambroxol/Guaiphenesin/Menthol

Amra

Oflomil

Ofloxacin 200 mg

Glenmark

Oflomix

Cefixime 200 mg

Orion

Recocef

Cefetamet 250 mg

Zydus Cadila

Recocif

Ciprofloxacin 250 mg

Zydus Cadila

Deplin

Sertraline 50 mg

Sykocure

Depnil

Clomipramine 25 mg

Cipla

Biolex

Cephalexin 500 mg

Cubit

Biolexi

Amoxicillin 250 mg/Dicloxacillin 250 mg

Biochemix

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drugs and devices creating confusion. For example, the word ‘Aqua’ has been used to depict diuresis.

divided into three categories based on their effect on therapeutic success (Tables 1-3).

DISCUSSION Branding is so crucial to the success of a new drug that pharmaceutical companies spend years and millions just to come up with a name. The branding agencies strive to create a name that consumers will find comforting, fast-acting and miraculous. Above all, they want it to be easy to remember and pronounce.

Many drug names look or sound like other drug names leading to confusion errors. Databases of anonymously reported errors are maintained jointly by the Institute of Safe Medication Practices (ISMP), the USP MERP and the FDA’s MedWatch Program.12,13 According to the eighth annual MEDMARX Data Report published by the USP, 1,470 different drugs are implicated in medication errors due to similarities between their brand or generic names. Based on a review of more than 26,000 records submitted to the MEDMARX database from 2003 to 2006, USP compiled a list of 3,170 look-alike and sound-alike drug name confusions. This list contains nearly twice as many medication name errors as the last MEDMARX report, which was issued in 2004.14 In India, the extent of this problem is unknown.

In a study, the effect of orthographic and phonetic similarity on the probability of making recognition memory errors (i.e., false recognitions) was examined.

It was concluded that these similarities increase the probability that experts will make false recognition errors when trying to remember drug names.15 Contributing to this confusion are illegible handwriting, incomplete knowledge of drug names, similar packaging or labeling, similar clinical use, similar strengths, dosage forms, frequency of administration and the failure of manufacturers and regulatory authorities to recognize the potential for error for drug names, prior to approving new product names.9 Various methods have been used to categorize the brand names in previous studies. In our study, we have categorized the names into three categories based on the effect they will have on the treatment and progression of the disease. The brand names were correlated with the drug action.

The brand naming techniques used by the branding agencies, which are evident in our study are as follows: ÂÂ

Certain pharmaceutical companies try to use a fancy brand name to depict the effect of drug;

ÂÂ

ÂÂ

ÂÂ

zz

Aquamide-/Furosemide 50 mg/Spironolactone 20 mg/Sun

zz

Aquazide-/Hydrochlorothiazide 12.5 mg/Sun

Certain companies use initial letters of the disease for which the drug is used in the brand names; creating confusion. For example, the word ‘Epi’ has been used from the disease epilepsy. zz

Epitab/Phenytoin 100 mg/East West

zz

Epitan/Phenobarbitone 60 mg/Reliance

To take advantage of name recognition among consumers and doctors, manufacturers like to give their new products names that are similar to the names of well-established brands. This practice can confuse users of these drugs. zz

Wormnil - Mebendazole 100 mg - Wings Pharma

zz

Wormonil - Albendazole 400mg - PDC

Another potential problem arises when manufacturers include certain letters in the proprietary name that differentiates their company from others and/or indicates a particular product range (e.g., antibiotic group). For example: zz

Avcif Cefixime 200 mg Ciprofloxacin 500 mg/Positif

Positif/Avcip

zz

Atmox Amoxycillin 250 mg A to Z/Atrox Roxithromycin 150 mg/A to Z

zz

Recocef Ceftamet 250 mg Zydus Cadila/Recocif Ciprofloxacin 250 mg/Zydus Cadila

zz

Cefit Cefixime 200 mg CUBIT/Cefiz Cefpodoxime 200 mg/Medi Health

zz

Ceftab Cefuroxime 250 mg SIENNA/Ceftas Cefixime 200 mg/Intas

It was noted that since the drugs forming the pair had strikingly different indications, different doses and schedule, there is less chance of drug name confusion.

But, in case the drug dose is not specified, it can create confusion. And, although some drug names and symbols may not necessarily sound-alike or look-alike, they could cause confusion in prescribing errors when handwritten or communicated verbally.

It was noted that drug pairs, which can have a major effect on therapeutic success included drugs-acting on central nervous system in most of the examples (sertraline, imipramine, zolpidem, risperidone, nortriptyline, haloperidol and lorazepam). This category has highest risk of therapeutic failure, drug

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drugs and devices toxicity and aggravation of disease. So practitioners should be more careful while prescribing these drugs.

ÂÂ

Include the purpose of the medication in the prescription.

Another important observation was that the drug pairs, which belong to the ‘no significant effect on therapeutic success’ category were mostly antibiotics (in bold font). Hence, there is a risk that the antibiotics not indicated for a particular condition may be administered or that a stronger antibiotic is used for a minor infection without patient noticing any difference.

The patients harmed by a medical error may never learn of the error. Some antibiotics whose doses are same are more likely to be confused. For example, Oflomil = Ofloxacin 200 mg/Oflomix = Cefixime 200 mg. These factors can lead to antibiotic resistance.

ÂÂ

Avoid verbal orders. Do not prescribe over the phone.

ÂÂ

Avoid the use of confusing drug mnemonics.

ÂÂ

Write in legible handwriting.

Also, there is some crossover between the above three categories for e.g. Epitab and Epitan mentioned in the minor effect category could also be included in the major effect category depending on the type of epilepsy they are used for.

The treatment of the side effect of the wrong drug may in turn lead to increased cost on medications required to rectify the error.

Thus wrong drug administration can lead to therapeutic failure, aggravation of the disease, serious toxicity, antibiotic resistance and increased cost on medications.

The limitation of this study is that it has included the brand names only from one drug formulary (IDR).

Brand names from other drug formularies and which are not mentioned in these formularies but are still available with the pharmacist are not included.

The above mentioned categorization has been done without any scale to quantify the risk of particular drug pair confusion. Further studies are needed to assign a particular confusing drug pair to the appropriate category using risk assessment scales.

STEPS FOR REDUCING DRUG NAME CONFUSION ERRORS16,17

Role of Prescribers ÂÂ

ÂÂ

ÂÂ

512

Doctors should be well-versed with generic name and the brand names that are available in their local setting.

Role of Organizations ÂÂ

The FDA uses computer software to analyze how close the name is to drugs already on the market.

Potentially confusing names are rejected. To minimize confusion between drug names that look or sound-alike, the FDA reviews about 300 brand names a year before they are marketed. About onethird are rejected.18

ÂÂ

The FDA encourages pharmacists and other health professionals to report any actual or potential medication errors to the agency’s Adverse Event Reporting System.

ÂÂ

The licensing authorities and regulatory agencies should exercise more control over the naming of a new formulation.

Role of Pharmacists ÂÂ

Dispensers should refer back to the doctor if there is confusion and should have basic knowledge of dosing regimens, at least for commonly used drugs.

ÂÂ

According to the MEDMARX report, “pharmacists as a group identified, prevented, and reported” more errors than any other health providers.

ÂÂ

Install a computerized reminder for the most serious confusing name pairs so that an alert is generated when entering prescriptions for either drug.

ÂÂ

Affix ‘name alert’ stickers to areas where look- or sound-alike products are stored

Role of Patients ÂÂ

Confirm the name and strength of prescribed drugs before leaving the doctor’s office.

ÂÂ

Illiterate patients should verify the drug names and instructions.

Role of Manufacturers

Clearly specify dosage form, drug strength and complete directions on prescriptions.

ÂÂ

Proper packaging labels and color code.

ÂÂ

OTC drugs should be given unique names.

Use both brand and generic names when writing a prescription.

ÂÂ

Take reports of confusion seriously.

ÂÂ

Use of mixed-case or enlarged letters to emphasize

Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

drugs and devices the differing portions of two drug names: (e.g., DOBUTamine/DOPamine).

similarity of drug names. Eur J Intern Med 2008;19(2): 135-6.

It is very important that we circulate the list of confusing brand names among the practicing doctors, pharmacists and also to the drug manufacturers. The general practitioners should be the major target as they deal with a greater variety of brand names.

4. Dooley M, Van de Vreede M. Proprietary names for glaucoma drugs: potential for error. Lancet 2006;368(9545):1419-20.

Preventing confusion between already marketed products typically involves collecting voluntary reports of names involved in confusion errors, posting warnings and alerts both electronically and in areas where drugs are used.19

6. Damodaran RT. Brand confusion causes dermatitis. J Postgrad Med 2005;51(3):242.

The fear of malpractice lawsuits and public embarrassment has made the physicians and nurses reluctant to report medication errors. It is more important to create the open environment that encourages the reporting of errors than to develop less meaningful comparative error rates.

8. Gremillion L, Hogan DJ. Dermatologic look- or soundalike medications. J Drugs Dermatol 2004;3(1):61-4.

One possible approach to improving medical error reporting involves the use of anonymous standardized reporting systems. This type of system should also enable internal tracking, trending and comparative analyses. We need to have such systems in India.

Besides those listed above there could be many more confusing brand names available in the Indian drug market with or without being listed in the drug formularies. Therefore, we need a wellstructured Medication Error Reporting Program and an organizational surveillance over drug naming in India. This program should be at par with the Pharmacovigilance Program of India. A combined effort from prescribers, pharmacists, organizations and manufacturers is required.

REFERENCES 1. Indian Pharmaceutical Industry http://www. pharmaceutical-drug manufacturers.com/ pharmaceutical-industry/. Accessed April 2, 2012.

2. National Coordinating Council for Medication Error Reporting and Prevention: Recommendations to reduce medication errors associated with verbal medication orders and prescriptions. Feb. 20, 2001. http://www. nccmerp.org/council/council2001-02-20.html. Accessed April 2, 2012.

3. Chiche L, Thomas G, Canavese S, Branger S, Jean R, Durand JM. Severe hemorrhagic syndrome due to

5. Rataboli PV, Garg A. Confusing brand names: nightmare of medical profession. J Postgrad Med 2005;51(1):13-6. allergic

7. Aronson JK. Medication errors resulting from the confusion of drug names. Expert Opin Drug Saf 2004;3(3):167-72.

9. Hoffman JM, Proulx SM. Medication errors caused by confusion of drug names. Drug Saf 2003;26(7):445-52.

10. Lilley LL, Guanci R. Sound-alike cephalosporins. How drugs with similar spellings and sounds can lead to serious errors. Am J Nurs 1995;95(6):14.

11. Indian Drug Review (Vol. XVII Issue No. 2, March-April 2011) published by UBM Medica India Pvt Ltd. 12. MedWatch, the FDA safety information and adverse reporting program. Available at: http://www.fda.gov/ Safety/MedWatch/default.htm. Accessed April 7, 2012.

13. USP Transitions Medication Error Reporting Programs.

Available at: http://www.usp.org/search/site/ medication%20error%20reporting. Accessed April 7, 2012.

14. U.S. Pharmacopeia 8th Annual MEDMARX Report Indicates Look-Alike/Sound-Alike Drugs Lead to Thousands of Medication Errors Nationwide. Available at: http://www.usp.org/search/site/medication%20 error%20reporting. Accessed April 7, 2012.

15. Lambert BL, Chang KY, Lin SJ. Effect of orthographic and phonological similarity on false recognition of drug names. Soc Sci Med 2001;52(12):1843-57.

16. ISMP. What’s in a name? Ways to prevent dispensing errors linked to name confusion. ISMP Medication Safety Alert! 7(12) June 12, 2002.

17. JCAHO. Sentinel Event Alert. Issue 19 - May 2001.

18. Strategies to Reduce Medication Errors: Working to Improve Medication Safety, The US Food and Drug Administration [Website] Accessed October 26, 2009. http://www.fda.gov/Drugs/ResourcesForYou/ Consumers/ucm143553.htm. Accessed April 3, 2012.

19. Lambert BL, Lin SJ, Tan H. Designing safe drug names.

Drug Saf 2005;28(6):495-512.

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Dentistry

Follicular Adenomatoid Odontogenic Tumor S Loganathan*, H Srinivasan**, R Veerakumar†, M Arul Pari‡

Abstract Adenomatoid odontogenic tumor is an uncommon odontogenic lesion, composed of odontogenic epithelium, characterized histologically by duct like structures with amyloid like deposits, noninvasive lesion with slow but progressive growth. Here we are reporting a case of adenomatoid odontogenic tumor in a 16-year-old female patient in the maxillary region. This paper provides the controversies regarding its origin and management in light of recent findings, clinical, radiographic, histopathologic and therapeutic features of the adenomatoid odontogenic tumor.

Keywords: Adenomatoid odontogenic tumor, dentigerous cyst, impacted teeth

A

denomatoid odontogenic tumor, is an uncommon benign epithelial lesion of odontogenic origin, accounting for 3-7% of odontogenic tumors, and was first described by Drieibaldt in 1907.1 According to the second edition of the World Health Organization (WHO) “Histological typing of odontogenic tumors”,2 adenomatoid odontogenic tumor is defined as “A tumor of odontogenic epithelium with duct-like structures and with varying degrees of inductive change in the connective tissue. The tumor may be partly cystic, and in some cases the solid lesion may be present only as masses in the wall of a large cyst.”

The epithelial lining of the odontogenic cyst may transform into an odontogenic neoplasm like ameloblastoma. There are three variants of adenomatoid odontogenic tumor, follicular variant (73%), which has a central lesion associated with an embedded tooth, the extrafollicular variant (24%), which has a central lesion and no connection with the tooth and the peripheral variety (3%).3 The report describes a intraosseous follicular adenomatoid odontogenic tumor in the maxilla illustrating the clinical, histopathological and biological features of the tumor and emphasizes the importance of the relation between the dental follicle and the tumor tissue. *Senior Lecturer, Dept. of Oral and Maxillofacial Surgery Priyadarshini Dental College, Pandur, Thiruvallur, Tamil Nadu **Reader, Dept. of Oral Surgery †Reader ‡Senior Lecturer, Dept. of Pedodontia Address for correspondence Dr S Loganathan Priyadarshini Dental College, Pandur, Thiruvallur, Tamil Nadu E-mail: drloganathans@gmail.com; srini11@hotmail.com

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Case Report A 16-year-old female patient reported with a chief complaint of unerupted tooth and pain in the upper anterior left maxillary region. The medical history was insignificant. Intraoral examination disclosed a nontender, expansible lesion of the left maxilla, surrounded by normal mucosa and retained deciduous canine and missing left permanent canine (Fig. 1).

Orthopantomogram (OPG) and maxillary occlusal view revealed the presence of a significant unilocular radiolucent area with well-defined sclerotic borders, involving an impacted upper left permanent canine (Figs. 2 and 3). According to the clinical and radiological findings, the lesion was diagnosed as an adenomatoid

Figure 1. Intraoral picture showing asymmetry on the left maxillary region and missing left permanent canine, retained deciduous canine and malpositioned left lateral incisor.

Dentistry odontogenic tumor. Under local anesthesia, excisional biopsy was performed with excavation of upper left canine (Fig. 4).

The differential diagnosis was dentigerous cyst, calcified epithelial odontogenic tumor and odontogenic keratocyst.

Histopathological Features

Figure 2. Panoramic radiograph reveals radiolucency surrounding the impacted left permanent canine, retained deciduous canine and displaced lateral incisor.

Figure 3. Occlusal radiograph reveals radiolucency surrounding the impacted left permanent canine, retained deciduous canine and displaced lateral incisor.

Figure 4. Picture showing the tumor and the impacted canine.

Odontogenic epithelium is arranged in the form of sheets, rods and few odontogenic cells, arranged in duct like structures with eosinophilic material in the center. A well-defined firm thick fibrous tissue capsule is seen at the periphery, which confirms the diagnosis of adenomatoid odontogenic tumor.

Discussion Adenomatoid odontogenic tumor is a slow growing lesion, constituting only 3% of all odontogenic tumors with a predilection for the anterior maxilla (ratio 2:1)4 Rick et al have reported adenomatoid odontogenic tumor to occur with many types of cysts and neoplasmâ&#x20AC;&#x2122;s including dentigerous cyst, calcifying odontogenic cyst, odontoma and ameloblastoma, etc.5 In relation with a dentigerous cyst the adenomatoid odontogenic tumor may demonstrate, grossly and microscopically, one or more associated cystic cavities. Some of these cysts are lined by nonkeratinized stratified squamous epithelium, which is similar to the lining of the dentigerous cyst or lined by less structured membrane that may demonstrate bud like extensions into the connective tissue. In our case, a moderate amount of the inflammatory component was evident in the sections, which could cause the cystic epithelium to lose its characteristic features and hence restrict the typing to an odontogenic cyst alone.

Odontogenesis is a complex process wherein neoplastic or hamartomatous lesions can occur at any stage of odontogenesis. The secondary development of an ameloblastic proliferation, whether hyperplastic or neoplastic is well-known, but remains controversial.

In the present case, the multifocal cellular proliferation had the structure of an AOT although larger lesions reported in the literature are usually in the dimensions of 2-3 cm. Radiographically they usually appear as unilocular lesion, may contain fine calcifications with or without root resorption.6,7 This appearance must be differentiated from various types of disease, such as calcifying odontogenic tumor or cysts. The differential diagnosis can also be made with ameloblastoma, ameloblastic fibroma and ameloblastic fibro-odontoma.

The tumor is well-encapsulated and shows an identical

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Dentistry benign behavior. Therefore, conservative surgical enucleation produces excellent outcome without recurrence.8,9 Our patient has been under follow-up for eight months.

Conclusion Our case report supports the general description of adenomatoid odontogenic tumor in the previous studies. We conclude that the rarity of adenomatoid odontogenic tumor may be associated with its slowly growing pattern and symptomless behavior. Therefore, it should be distinguished from more common lesions of odontogenic origin in routine dental examinations.

References 1. Neville BW, Damm DD, Allen CM, Bouquot JE. Oral and maxillofacial pathology. In: Odontogenic Cysts and Tumors. Warldon CA (Ed.), WB Saunders: Philadelphia, Pa, USA 2002:p.589-642.

2. Jing W, Xuan M, Lin Y, Wu L, Liu L, Zheng X, et al.

Odontogenic tumours: a retrospective study of 1642 cases in a Chinese population. Int J Oral Maxillofac Surg 2007;36(1):20-5.

3. Bravo M, White D, Miles L, Cotton R. Adenomatoid odontogenic tumor mimicking a dentigerous cyst. Int J Pediatr Otorhinolaryngol 2005;69(12):1685-8.

4. Swasdison S, Dhanuthai K, Jainkittivong A, Philipsen HP. Adenomatoid odontogenic tumors: an analysis of 67 cases in a Thai population. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105(2):210-5.

5. Nigam S, Gupta SK, Chaturvedi KU. Adenomatoid odontogenic tumor - a rare cause of jaw swelling. Braz Dent J 2005;16(3):251-3.

6. Larsson A, Swartz K, Heikinheimo K. A case of multiple AOT-like jawbone lesions in a young patient - a new odontogenic entity? J Oral Pathol Med 2003;32(1): 55-62.

7. Dayi E, Gürbüz G, Bilge OM, Ciftcioğlu MA. Adenomatoid odontogenic tumour (adenoameloblastoma). Case report and review of the literature. Aust Dent J 1997;42(5): 315-8.

8. Philipsen HP, Reichart PA, Nikai H. The adenomatoid odontogenic tumor (AOT): an update. J Oral Pathol Med 1997;2:55-60.

9. Motamedi MH, Shafeie HA, Azizi T. Salvage of an impacted canine associated with an adenomatoid odontogenic tumour: a case report. Br Dent J 2005; 199(2):89-90.

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BPA Leaching into Urine, Saliva from Dental Composites?

Bisphenol A (BPA), a potentially toxic compound, gets into patients’ saliva and urine when composite resin restorations are placed on their teeth, a new study shows. (Source: Medscape)

Soft Drinks can Cause Tooth Decay Consumption of sugary beverages, particularly soft drinks and sports drinks, could be hard on your teeth and cause dental decay, researchers say “Tooth decay carries with it significant physical, social and health implications, and we believe the risk of tooth decay should be included in any warnings relating to sweet drinks,” the American Journal of Public Health, quoting Armfield, reported.

“Essentially, we need to ensure that children are exposed less to sweet drinks and have greater access to fluoridated water, which will result in significantly improved dental outcomes for children,” adds Armfield.

Gingivitis Makes Immune System Shut Down Processes that could Destroy It Researchers have identified how the bacterium Porphyromonas gingivalis, which causes gum disease, manages to manipulate the body’s immune system to shut down the normal process which could destroy it, a new study published in the Journal of Leukocyte Biology reveals.

Specifically, the report shows that this pathogen prompts the production of the anti-inflammatory molecule Interleukin-10 (IL-10). This, in turn, inhibits the function of T-cells, which would otherwise help to protect the host from this particular microbial infection.

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Dermatology

Juvenile Dermatomyositis with Calcinosis Cutis Sibabratta Patnaik*, Manas Ranjan Behera**, Nirmal Kumar Mahakud**, Aswini Kumar Mohanty†

Abstract A 6-year-old girl presented with irregular fever for last two months and difficulty in standing from sitting position for last 1½ months. She had pathognomonic heliotrope rashes on both eyelids, Gottron’s papules in proximal interphalangeal and metacarpophalangeal joints of both hands and papules on elbow, knee and ankle joints. She had elevated serum muscle enzyme levels and electromyogram was in favor of juvenile dermatomyositis (JDM). She is now under steroid treatment and showing signs of improvement.

Keywords: Juvenile dermatomyositis, heliotrope rashes, Gottron’s papule, proximal myopathy, MRI CASE REPORT A 6-year-old girl presented with irregular fever for last two months and difficulty in standing from sitting position for last 1½ months. She had pruritic, erythematous rashes on face, trunk and extremities.

She was treated for malaria and enteric fever elsewhere and was referred to our hospital as the symptoms did not improve.

Her anthropometric measures were normal for age, she had shiny erythematous papules on proximal interphalangeal joints, metacarpophalangeal joints (Fig. 2), elbow, knee and ankle joints of both sides suggestive of Gottron’s papule. There were erythematous rashes on face and bridge of nose along with violaceous rashes on both eyelids consistent with heliotrope rashes (Fig. 1). There was weakness of proximal muscles of legs with positive Gower sign.

There was no neurodeficit and deep tendon jerks were normal.

Investigations revealed normal hemogram, erythrocyte sedimentation rate (ESR) was 70 in first hour, rheumatoid factor, antinuclear antibodies (ANA),

*Senior Resident **Assistant Professor †Professor and Head Dept. of Pediatrics Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha Address for correspondence Dr Sibabratta Patnaik Maruti Residency, Plot No: 103 Raghunathpur, Barang Nandankanan Road, Bhubaneswar - 754 005, Odisha E-mail: drsbpatnaik@yahoo.co.in

lupus erythematosus cell phenomena were negative, C-reactive protein (CRP) level was elevated (>0.6 mg/ dl). Creatine phosphokinase (CPK) was 72 U/l (21215), alanine transaminase (ALT) = 63 (normal 3-65), aspartate transaminase (AST) = 48 (15-37), lactate dehydrogenase (LDH) = 379 (100-190). Electromyogram (EMG) revealed denervation along with myopathic changes characteristic of juvenile dermatomyositis (JDM). Magnetic resonance imaging (MRI) of muscles revealed hyperintense signals in bilateral gluteal muscles. Muscle biopsy from biceps was normal.

She was diagnosed as a case of JDM and treated with oral prednisolone 2 mg/kg/day. Follow-up after three weeks showed improvement in muscle power and decrease in rashes with resumption of normal day-today activity. However, at second follow-up, she had an ulceration around left elbow joint with whitish discharge, which was diagnosed as calcinosis cutis.

DISCUSSION JDM is a rare autoimmune vasculopathy of childhood that preferentially affects dermal and muscular vessels.

By definition, the onset of JDM is prior to the age of 18, whereas the average onset is in the 7th to 8th year of life, with a slight preference for the female gender.1 The disorder is rare, with a prevalence of 1-3.2 cases per million in children.2 While the etiology of JDM remains unclear, the working hypothesis is that this involves environmental triggers, immune dysfunction and specific tissue responses (in particular those of muscle, skin and small vessel endothelium) in genetically susceptible

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dermatology individuals. Environmental factors such as bacterial and viral infections (Group A β-hemolytic streptococci, Enterovirus, Coxsackie virus) and exposure to UV light have to be considered as important trigger factors.

Anecdotal reports of JDM onset after exposure to drugs, biological therapies, vaccines also exist.3

Figure 1. Heliotrope rashes.

At present, the most widely used set of criteria remain those defined by Bohan and Peter in 1975,4 which require the presence of one of the characteristic rashes, combined with three of the following features, for definite JDM: Symmetric proximal muscle weakness, raised serum muscle enzymes (which may include creatine kinase (CK), transaminases, LDH and aldolase) and abnormal findings on muscle biopsy and EMG. The presence of the rash with two of these features make a diagnosis of probable JDM. These criteria, now over 30 years old, no longer reflect modern diagnostic investigation of suspected cases of JDM. Although MRI findings are not part of the Bohan and Peter criteria, MRI is now widely used to detect typical inflammatory changes in proximal muscles, and quantitation of such changes has been shown to correlate with disease activity. Myopathy, mostly affecting the proximal muscles, is present in about 95% of dermatomyositis cases.5 In the international consensus survey of the diagnostic criteria for JDM, MRI was appreciated as one of the most important diagnostic methods to be added to the revised criteria.6

Figure 2. Gottronâ&#x20AC;&#x2122;s papules on hand.

Figure 3. Calcinosis cutis in elbow joint.

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Approximately 50% of children present with rash as their initial symptom and 25% present with weakness as their first symptom.7 Early diagnosis is often hampered by the nonspecific nature of the initial signs of JDM, such as fatigue, fever, weight loss, irritability, myalgia and arthralgia. Identification of characteristic skin lesions may help establish an early diagnosis.

Typical cutaneous lesions include a characteristic periorbital heliotrope rash (present in more than twothirds of patients), facial malar rash, Gottron papules (livid scaly plaques on the extensor surface of joints), and nailfold changes that may present as periungual infarcts.5 Calcinosis is common in JDM.3 Our patient developed calcinosis around elbow joint, two months after starting treatment.

Blood tests to measure specific markers of muscle inflammation should be ordered including creatine kinase, LDH, aldolase, ALT and AST. Because muscle inflammation is patchy, EMG and muscle biopsy is not always diagnostic. MRI scans have become more

dermatology widely used and can be helpful in choosing the correct muscle biopsy site.8 The course of the disease is difficult to predict, but it is known to have a long course with remissions and exacerbations or, in some cases, a chronic course with a severe debilitating morbidity. Systemic glucocorticosteroids are the mainstay of therapy; they are administered orally (upto 2 mg/kg/day of prednisolone) or as intravenous pulses (usually 30 mg/kg/day of methylprednisolone). Therapy is continued until there is improvement of clinical and laboratory parameters.6 The incidence of calcinosis is decreasing but, for some patients, it remains a debilitating and disfiguring problem. Many treatments have been tried, including diltiazem, aluminum hydroxide, probenecid, bisphosphonates and local corticosteroid injections, amongst others. No treatment has been proven to be effective. Calcinosis in many patients tends to regress over time (often years).9

Therapeutic Options for JDM3 Prednisolone, intravenous methylprednisolone, methotrexate are used as first-line therapy and adjunctive therapies to these are hydroxychloroquine, physical therapy, photoprotective measures, topical therapies for skin rashes, calcium and vitamin D for bone protection.

Second-line therapies include intravenous gammaglobulin, cyclosporine, azathioprine, while third-line therapies include cyclophosphamide, mycophenolate mofetil, tacrolimus, rituximab and anti-tumor necrosis factor alpha agents.

Combinations of the above agents as first-line therapies are among those most often used in the initial treatment of JDM, whereas second- and thirdline therapies are most often used in the treatment of refractory patients, patients considered to have severe features, or patients with unacceptable medication toxicities.

SUMMARY JDM is a very rare autoimmune disorder characterized by skin changes like Gottron’s papule and heliotrope rashes along with proximal myopathy. MRI is helpful in demonstrating muscle edema and choosing the site of muscle biopsy. The disease has a long course with remissions and exacerbations. Steroid therapy is the cornerstone in the management of JDM. REFERENCES 1. Pachman LM, Lipton R, Ramsey-Goldman R, Shamiyeh E, Abbott K, Mendez EP, et al. History of infection before the onset of juvenile dermatomyositis: results from the National Institute of Arthritis and Musculoskeletal and Skin Diseases Research Registry. Arthritis Rheum 2005;53(2):166-72.

2. Callen JP. Collagen vascular diseases. J Am Acad Dermatol 2004;51(3):427-39.

3. Wedderburn LR, Rider LG. Juvenile dermatomyositis: new developments in pathogenesis, assessment and treatment. Best Pract Res Clin Rheumatol 2009;23(5): 665-78.

4. Bohan A, Peter JB. Polymyositis and dermatomyositis (Rist of two parts). Engl J Med 1975;292:344-7.

5. Schmieder A, Komorowski G, Peitsch WK, Goerdt S, Goebeler M. Juvenile dermatomyositis in an 8-year-old boy. Dermatol Online J 2009:15(6):3.

6. Brown VE, Pilkington CA, Feldman BM, Davidson JE; Network for Juvenile Dermatomyositis, Paediatric Rheumatology European Society (PReS). An international consensus survey of the diagnostic criteria for juvenile dermatomyositis (JDM). Rheumatology (Oxford) 2006;45(8):990-3.

7. Feldman BM, Rider LG, Reed AM, Pachman LM. Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood. Lancet 2008:371(9631): 2201-12.

8. Schneider M, Murphy K. J Pediatr Health Care 2011;25(1): 38-43.

9. Stringer E, Feldman BM. Advances in the treatment of juvenile dermatomyositis. Curr Opin Rheumatol 2006;18(5):503-6.

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Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

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diabetology

A Study of Metabolic Syndrome and its Components in Type 2 Diabetes Mellitus Subjects and their Asymptomatic First-degree Relatives JL Patel*, AM Suthar*, VB Dalsaniya*, AP Parikh**, NN Suthar†, KL Patel‡

Abstract Objectives: To study clinical profile of metabolic syndrome and its individual components in type 2 diabetes mellitus subjects and their asymptomatic first-degree relatives. To identify risk factors of glucose intolerance. Material and methods: Randomly selected type 2 diabetes mellitus (T2DM) subjects age >40 years (n = 20, 10 males, 10 females) and their asymptomatic first-degree relatives age >30 years (excluding pregnant women) (n = 80; 46 males; 34 females) subjected to regression analysis with reference to components of metabolic syndrome (waist circumference, serum triglyceride, serum high-density lipoprotein (HDL), fasting plasma glucose, hypertension) and other variables. Student t-test was used for comparison of results.

Results: Among T2DM subjects: Ninety percent were hypertensive, 85% had low HDL, 30% males and 80% females had central obesity, 85% had metabolic syndrome. Among asymptomatic first-degree relatives of T2DM subjects: 48.7% had metabolic syndrome; hypertension, low HDL, central obesity, impaired glucose tolerance, T2DM were present in 52.5%, 68.7%, 48.7%, 26.2%, 35%, respectively. In subjects with abnormal glucose level (n = 49) 59.18% subjects and in subjects with normal glucose level (n = 31) 32.25% met the criteria for metabolic syndrome (p = 0.023). Impaired fasting glucose, increased hip circumference and low HDL independently determined two hours glycemia value in OGTT. (R2 = 0.7; p = 0.001). Conclusion: In T2DM and their asymptomatic first-degree relatives, hypertension and low HDL were commonest components of metabolic syndrome, females were more obese. Glucose intolerance was significantly associated with other components of metabolic syndrome.

Impaired fasting glucose, increased hip circumference and low HDL levels were risk factors for glucose intolerance.

Keywords: Metabolic syndrome, diabetes mellitus, first-degree relatives of type 2 diabetes mellitus subjects, impaired glucose tolerance

M

etabolic syndrome is a constellation of metabolic abnormalities that includes central obesity, hypertension, elevated fasting glucose, low high-density lipoprotein (HDL) cholesterol, high triglyceride (National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III]). It is associated with increased risk of coronary artery disease and stroke.

ATP III proposed metabolic syndrome based on clinical parameters. The European Group for the study of Insulin Resistance (EGIR) has also developed its own definition.

In 1988, Reaven proposed the concept of syndrome X. In 1988, WHO proposed a formal definition of metabolic syndrome. Three years later, the NCEP *Final Year Resident **Professor †Associate Professor ‡Assistant Professor Dept. of Medicine, Vadilal Sarabhai General Hospital, Ellisebridge Ahmedabad, Gujarat Address for correspondence Dr JL Patel Final Year Resident E-7, Doctor Quarters, VS Hospital Campus, Ellisebridge, Ahmedabad E-mail: jigsp2008@gmail.com

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Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

Different terminologies used for metabolic syndrome: ÂÂ

Beer-Belly syndrome

ÂÂ

Atherothrombogenic syndrome

ÂÂ

Deadly quarter

ÂÂ

Dysmetabolic syndrome

ÂÂ

Insulin resistance syndrome

ÂÂ

Syndrome X

NCEP ATP III 2001 criteria for metabolic syndrome The purpose of ATP III was to identify people at higher long-term risk for cardiovascular diseases (CVDs) who deserved clinical lifestyle intervention to reduce risk. Presence of three of the following five factors is required for diagnosis of metabolic syndrome.

diabetology ÂÂ

Central obesity: Abdominal waist circumference: Men >102 cm, women >88 cm

ÂÂ

Fasting plasma glucose >110 mg/dl or diagnosed type 2 diabetes mellitus (T2DM)

ÂÂ

Fasting plasma medication

ÂÂ

Fasting plasma HDL cholesterol: Men <40 mg/dl, women <50 mg/dl or medication

ÂÂ

Blood pressure ≥130/85 mmHg or medication.

triglyceride

>150

mg/dl

or

ATP III specifically noted that some individual having only two criteria of metabolic syndrome appear to be insulin resistance when the waist circumference is only marginally elevated. If so they should be benefited from clinical intervention similarly to others who have greater increases in waist circumference.

Recent definitions In 2003, the American Association of Clinical Endocrinologist (AACE) modified ATP III criteria to refocus on insulin resistance as the primary cause of metabolic risk factors. No specified number of factors qualified for diagnosis, which was left to clinical judgment. Other factors used for clinical judgement were a family history of CVD or T2DM, polycystic ovary syndrome and hyperuricemia.

ÂÂ

Family history of noninsulin-dependent diabetes mellitus (NIDDM) is associated with increased risk of diabetes. First-degree relatives of NIDDM patients have 40% lifetime risk of developing diabetes.

ÂÂ

Diabetes occurs a decade earlier in Asian population. India has a large and growing population of diabetic patients, its prevalence will reach 350 million by 2025. Diabetes is associated with increased risk for CVD, stroke and other risk factors of metabolic syndrome. So, early recognition of metabolic syndrome in such subjects and timely intervention along with lifestyle modification can delay emergence of diabetes mellitus (DM), CVD, stroke and subsequent mortality.

AIMS AND OBJECTIVES ÂÂ

To study clinical profile of metabolic syndrome and its individual components in T2DM subjects and their asymptomatic first degree relatives.

ÂÂ

To study clinical profile of metabolic syndrome and its individual components in asymptomatic first degree relatives of T2DM subjects.

ÂÂ

To identify risk factors of glucose intolerance.

MATERIAL AND METHODS

In 2005, the International Diabetes Foundation (IDF) published new criteria that again modified the ATP III definition. They considered that abdominal obesity is so highly correlated with insulin resistance. The IDF clinical definition thus makes the presence of abdominal obesity necessary for diagnosis.

For this study, 20 T2DM patients and their family members were subjected to analysis at a large teaching general hospital.

ÂÂ

Patient with T2DM with age >40 years

Insulin resistance syndrome is associated with:

ÂÂ

All asymptomatic first-degree relative age >30 years (men and nonpregnant women).

Inclusion Criteria

ÂÂ

T2DM

ÂÂ

CVD

Excluding Criteria

ÂÂ

Essential hypertension

ÂÂ

Polycystic ovary syndrome (PCOS)

Patient with T2DM age <40 years

ÂÂ

ÂÂ

Nonalcoholic fatty liver disease

All first-degree relative age <30 years

ÂÂ

ÂÂ

Certain forms of cancers

Pregnant women

ÂÂ ÂÂ

Sleep apnea

One of the most important reasons for introducing concept of metabolic syndrome is to heighten the awareness of the increased risk associated with metabolic abnormalities. ÂÂ

Metabolic syndrome is associated with increased risk of diabetes, coronary artery disease, stroke and cardiovascular mortality more than individual components.

Family selection was random.

Study Design Retrospective and cross-sectional study.

Study Size Randomly selected T2DM subjects age >40 years (n = 20, 10 males, 10 females) and their asymptomatic first-degree relatives age >30 years (excluding pregnant women) (n = 80; 46 males; 34 females).

Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

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diabetology Table 1. Physical, Clinical and Metabolic Characteristics of Diabetic Patients Mean ± Standard deviation Males (n = 10)

Females (n = 10)

Total (n = 20)

Age (years)

62.20 ± 6.80

64.30 ± 10.11

63.25 ± 8.45

Ht (cm)

1.63 ± 0.11

1.56 ± 0.12

1.60 ± 0.12

Wt (kg)

66.90 ± 9.86

80.15 ± 19.51

73.53 ± 16.51

Waist (cm)

97.50 ± 7.91

105.95 ± 17.39

101.73 ± 13.84

Hip (cm)

98.30 ± 4.57

117.40 ± 17.24

107.85 ± 15.71

BMI (kg/m2)

66.90 ± 9.86

80.15 ± 19.51

73.53 ± 16.51

BP systolic (mmHg)

143.00 ± 26.13

145.00 ± 19.89

143.50 ± 22.88

BP diastolic (mmHg)

87.80 ± 12.20

84.60 ± 12.40

86.20 ± 11.91

FBS (mg/dl)

133.00 ± 59.25

117.80 ± 41.88

125.40 ± 50.54

2 hr (mg/dl)

219.50 ± 68.79

193.50 ± 67.11

206.50 ± 67.48

S. TG (mg/dl)

138.50 ± 63.25

159.20 ± 88.65

148.85 ± 75.70

S. HDL (mg/dl)

35.70 ± 3.30

41.00 ± 9.24

38.35 ± 7.28

S. LDL (mg/dl)

111.27 ± 41.11

100.12 ± 25.28

105.70 ± 33.70

S. VLDL (mg/dl)

87.43 ± 120.04

33.53 ± 17.78

57.11 ± 81.82

Total (mg/dl)

627.61 ± 295.42

693.22 ± 141.35

662.35 ± 222.06

Ht: Height; Wt: Weight; s.: Serum.

Table 2. Physical, Clinical and Metabolic Characteristics of First-degree Relatives of T2DM Patients Mean ± Standard deviation Males (n = 46)

Females (n = 34)

Total (n = 80)

41.93 ± 10.53

42.94 ± 10.51

42.36 ± 10.47

Ht (cm)

1.68 ± 0.08

1.56 ± 0.08

1.63 ± 0.10

Wt (kg)

73.26 ± 12.56

71.24 ± 12.38

72.40 ± 12.45

Waist (cm)

94.89 ± 11.01

99.38 ± 14.55

96.80 ± 12.75

Hip (cm)

97.76 ± 8.92

107.47 ± 11.83

101.89 ± 11.27

26.01 ± 3.92

29.21 ± 5.58

27.37 ± 4.93

BP systolic (mmHg)

127.22 ± 18.32

134.53 ± 17.22

130.33 ± 18.12

BP diastolic (mmHg)

80.96 ± 11.34

82.29 ± 8.97

81.53 ± 10.36

FBS (mg/dl)

111.98 ± 67.51

107.06 ± 38.48

109.89 ± 56.75

1 hr (mg/dl)

166.59 ± 64.91

144.81 ± 45.02

157.88 ± 58.39

2 hr (mg/dl)

169.52 ± 101.44

138.35 ± 57.72

156.28 ± 86.56

S. TG (mg/dl)

167.62 ± 110.05

163.79 ± 76.49

166.00 ± 96.68

S. HDL (mg/dl)

40.84 ± 13.42

42.32 ± 8.00

41.47 ± 11.39

S. LDL (mg/dl)

104.44 ± 33.85

122.89 ± 116.29

112.38 ± 80.33

S. VLDL (mg/dl)

34.59 ± 22.57

33.29 ± 15.27

34.03 ± 19.64

711.23 ± 179.31

718.35 ± 150.96

714.25 ± 166.78

Age (years)

BMI

(kg/m2)

Total (mg/dl)

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Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

diabetology Table 3. Physical, Clinical and Metabolic Characteristics of First-degree Relatives Age-wise Mean ± Standard deviation 30-39 years

40-49 years

50-59 years

≥ 60 years

Age (years)

33.44 ± 2.88

43.88 ± 2.91

53.17 ± 2.90

63.67 ± 4.23

Ht (cm)

1.63 ± 0.10

1.65 ± 0.09

1.62 ± 0.11

1.58 ± 0.04

Wt (kg)

69.84 ± 12.96

78.18 ± 11.04

73.97 ± 11.69

68.00 ± 10.94

Waist (cm)

92.62 ± 11.74

102.82 ± 13.24

102.22 ± 11.54

90.67 ± 9.71

Hip (cm)

99.36 ± 10.51

106.29 ± 11.78

104.28 ± 9.74

98.67 ± 15.88

BMI (kg/m2)

26.22 ± 4.73

28.83 ± 4.79

28.51 ± 5.42

27.31 ± 4.28

BP systolic (mmHg)

124.31 ± 15.78

133.18 ± 17.39

133.67 ± 18.61

151.33 ± 16.33

BP diastolic (mmHg)

78.97 ± 10.07

82.24 ± 8.30

82.67 ± 10.98

92.67 ± 9.44

FBS (mg/dl)

97.62 ± 43.03

99.29 ± 22.69

140.06 ± 89.08

129.17 ± 53.69

1 hr (mg/dl)

148.19 ± 56.35

179.27 ± 65.97

159.58 ± 56.92

161.50 ± 13.44

2 hr (mg/dl)

142.39 ± 78.72

147.12 ± 52.53

182.22 ± 117.45

194.67 ± 97.92

S. TG (mg/dl)

157.25 ± 110.77

192.76 ± 87.55

151.06 ± 59.53

191.83 ± 114.94

S. HDL (mg/dl)

42.41 ± 14.61

38.62 ± 6.12

39.72 ± 8.39

42.17 ± 8.18

S. LDL (mg/dl)

115.60 ± 111.46

104.61 ± 37.96

115.17 ± 32.49

105.65 ± 12.75

S. VLDL (mg/dl)

32.86 ± 22.88

38.51 ± 17.55

30.83 ± 11.90

36.72 ± 23.24

Total (mg/dl)

695.01 ± 190.01

756.53 ± 123.79

701.33 ± 101.80

739.00 ± 295.05

Tenure

Oral Glucose Tolerance Test (OGTT)

August 2010 to October 2012.

After a 12-hour overnight fast, the subject ingested a solution that contained 75 g dextrose and venous blood samples were obtained at 0, 60 and 120 minutes for determination of plasma glucose. Stages of plasma glucose were classified as per American Diabetic Association (ADA).

Protocol Participant were interviewed at home and were invited to attend the OPD at VS General Hospital, where they were asked to complete additional questionnaires, undergo various examinations and provide blood samples for: Glucose tolerance test (GTT) if they were undetected asymptomatic relatives of the patients with diabetes, or fasting blood glucose (FBS) and postprandial blood glucose (PPBS) levels in diabetic patients and serum lipid profile. Blood pressure was measured with a mercury sphygmomanometer and the mean of three seated resting values recorded. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meter.

Waist Circumference Measurement Technique Place measuring tape, holding it parallel to the floor, around abdomen at the level of the iliac crest. Hold tape snug but don’t compress the skin and measure circumference at the end of normal expiration.

Hip Circumference Measurement Technique Place measuring tape, holding it parallel to the floor, around the hip at the level of greater trochanter of femur. Hold tape snug but don’t compress the skin and measure circumference.

Blood glucose was measured using glucose oxidase/ peroxidase method. Low-density lipoprotein (LDL) and HDL fractions were separated from fresh serum by ultracentrifugation, CHOD-PAP method. Lipoprotein fraction cholesterol and triglycerides were measured by standard enzymatic spectrophotometric technique.

Definition and Diagnostic Criteria We counted participants who reported currently using antihypertensive or antidiabetic medication (insulin or oral agents). Or antihyperlipidemic as participant with high blood pressure or diabetes or dyslipidemic, respectively. According to NCEP/ATP III report, participant who had ≥3 of the following criteria were defined as having the metabolic syndrome: ÂÂ

Central obesity: Abdominal waist circumference: Men >102 cm, women >88 cm

ÂÂ

Fasting plasma glucose >110 mg/dl or diagnosed T2DM

ÂÂ

Fasting plasma medication

triglyceride

>150

mg/dl

Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

or

523

diabetology Table 4. Clinical and Metabolic Characteristics of NGT, IGT and DM Subjects Among First-degree Relatives P (T < t) two-tail Mean ± Standard deviation

T-test: two sample assuming equal variance

NGT (n = 31)

IGT (n = 21)

DMl (n = 28)

NGT vs IGT

NGT vs DM

IGT vs DM

Age (years)

40.84 ± 9.40

38.71 ± 9.40

46.79 ± 11.12

0.43

0.03

0.01

Ht (cm)

1.62 ± 0.10

1.62 ± 0.08

1.65 ± 0.10

0.95

0.32

0.37

Wt (kg)

68.97 ± 12.12

76.90 ± 13.74

72.82 ± 10.99

0.03

0.32

0.25

Waist (cm)

94.19 ± 11.77

98.52 ± 15.15

98.39 ± 11.78

0.25

0.18

0.97

Hip (cm)

98.97 ± 9.73

104.57 ± 12.12

103.11 ± 11.86

0.07

0.15

0.67

(kg/m2)

26.27 ± 4.12

29.54 ± 6.41

26.96 ± 4.07

0.03

0.03

0.09

BP systolic (mmHg)

128.39 ± 19.60

128.76 ± 17.07

133.64 ± 17.33

0.94

0.94

0.33

BP diastolic (mmHg)

80.45 ± 11.99

82.38 ± 9.02

82.07 ± 9.59

0.53

0.57

0.91

FBS (mmHg)

84.90 ± 11.71

86.14 ± 15.20

155.36 ± 76.16

0.74

0.00

0.00

2 hr (mmHg)

101.19 ± 26.23

129.10 ± 29.82

237.65 ± 97.86

0.00

0.00

0.00

S. TG (mmHg)

153.28 ± 79.55

149.71 ± 63.05

192.28 ± 127.53

0.86

0.17

0.17

S. HDL (mmHg)

40.38 ± 7.26

42.12 ± 6.84

42.18 ± 16.87

0.38

0.59

0.99

S. LDL (mmHg)

122.71 ± 9.46

113.75 ± 37.25

120.34 ± 35.77

0.74

0.34

0.18

ÂÂ

ÂÂ

Fasting plasma HDL cholesterol: Men <40 mg/dl, women <50 mg/dl or medication Blood pressure ≥130/85 mmHg or medication.

First-degree degree relatives were classified as normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and NIDDM after an OGTT.

Classification of OGTT as per ADA ÂÂ

ÂÂ

ÂÂ

FBS zz

Normal <110 mg/dl

zz

IGT >110 mg/dl and <126 mg/dl

zz

DM >126 mg/dl

First hour blood glucose zz

Normal <140 mg/dl

zz

IGT >140 mg/dl and <200 mg/dl

zz

DM >200 mg/dl

Second hour blood glucose zz

Normal <140 mg/dl

zz

IGT >140 mg/dl and <200 mg/dl

zz

DM >200 mg/dl

Statistical Analysis All the data were computed on Excel database and statistical analysis were done using SPSS PC Windows.

Student’s t-test was used for comparison of means of frequencies. We calculated prevalence of metabolic syndrome by age and sex. Subjects with diabetes and

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Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

120 100 Prevalence

BMI

100 80

80

90

90

80

85

90

80

60

80

85

Male Female Total

55 40 40 40

40

30

20 0

HTN

Low HDL

High TG

Central obesity

Metabolic syndrome

Figure 1. Prevalence of metabolic syndrome and its individual components in diabetic patients.

IGT were grouped together as glucose intolerance for regression analysis. Variables like age, sex, waist, BMI, waist-hip ratio, systolic and diastolic blood pressure, family history of diabetes were used as independent variables for the regression analysis. The step wise multiple linear regression applied to first-degree relatives to assess the independent contribution of IGT (glycemia at 120 mins) to separate components of metabolic syndrome.

RESULTS In diabetic population, there were 10 males and 10 females. Among first-degree relatives, 46 were males and 34 were females.

Tables 3 shows anthropometric, clinical and metabolic characteristics of first-degree relatives of patients with NIDDM globally and age-wise. Blood pressure, FBS, 2nd hour glucose, and total lipid tend to rise with age.

diabetology

25

No. of components

MS5

40

10

MS4

Table 5.

Total Female Male

No. of first-degree relatives of T2DM patients

40

20

60 85

MS

80 90

Metabolic syndrome Present

Absent

With IGT/T2DM

29

20

49

With NGT

10

21

31

Total

39

41

80

0 20 40 60 80 100 Percentage

MS5

11.76 2.17

20.58

Figure 3. Percentage of first-degree relatives of diabetic patients with 4, 5 components of metabolic syndrome.

90 80 70 60 50 40 30 20 10 0

82.35

Male Female Total

79.41

68.75 58.69

59 47.82

52.5 45.65

50 48.75

48.75

HTN

22.4

Low HDL High TG Central obesity

30

26.2

IGT

35

Figure 4. Percentage of individual components of metabolic syndrome and T2DM in first-degree relatives of diabetic patients.

Age group

40

30-39 40-49 50-59 60-69

38.75

35 30 25 20 15 10 5 0

18.75 11.25 7.5 6.25 3.75

MS3

13.75 6.25 1.25

MS4

10 6.25

2.5

MS5

7.5 3.75 1.25

1.25

Total MS

IGT/T2DM

NGT

Table 6. Regression Analysis of Impaired Glucose Tolerance with Reference to FBS, Hip Measure, S. HDL R2

Standardized coefficient

p value

0.566

0.752

0.0001

FBS

0.703

0.0001

Hip measure

-0.320

0.005

FBS

0.723

0.0001

Hip measure

â&#x20AC;&#x201C;0.256

0.021

S. HDL

â&#x20AC;&#x201C;0.214

0.048

Dependent variable Model 1 FBS

Model 3

T2DM

45

10

Model 2

40 30

45.65

p = 0.023

29

Figure 6. Prevalence of metabolic syndrome in first-degree relatives with IGT/T2DM and NGT.

39.13

Percentage

Prevalence

40

48.75

MS

21

60

0

8.69

61

20

20

13.75

MS4

0 10 20 30 40 50 60 70

Prevalence

80 Percentage

No. of components of MS

Total Female Male

Metabolic syndrome absent Metabolic syndrome present

100

Figure 2. Percentage of diabetic patients with 4, 5 components of metabolic syndrome.

6.25

Total

No MS

Figure 5. Age-wise prevalence of metabolic syndrome in first-degree relatives of T2DM patients.

0.666

0.707

a. predictors: (constant), FBS b. predictors: (constant), FBS, HIP c. predictors: (constant), FBS, HIP, s. HDL d. dependent variable: 2 hour glycemia

In the diabetic patients, 90% were hypertensive and 85% had low HDL, which forms the commonest criteria for metabolic syndrome. Central obesity was more common in females (55% average, 30% males and 80% females); 40% had high TG level.

Eighty-five percent of diabetic patient had metabolic syndrome (90% males and 80% females); 40% of

Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

525

diabetology diabetic patient had four components of metabolic syndrome (60% males and 20% females) and 25% had five criteria satisfying metabolic syndrome (10% males and 40% females).

Among first-degree relatives of diabetic patients, 48.75% had metabolic syndrome (39.13% males and 61% females); 13.75% had four criteria and 6.25% had five criteria satisfying metabolic syndrome. There was no significant difference in prevalence of metabolic syndrome in males and females (p = 0.4).

Among asymptomatic first-degree relatives of T2DM subjects, hypertension, low HDL, central obesity, IGT, T2DM were present in 52.5%, 68.7%, 48.7%, 26.2%, 35%, respectively.

Among first-degree relatives of diabetic patients prevalence, the prevalence of metabolic syndrome was at age 31-39 years: 10%, at 40-49 years: 13.75%, at 50-59 years: 18.75% and at >60 years: 6.25%. Thus, the prevalence of metabolic syndrome was highest in age group 50-59 years (Table 3).

According to ADA, first-degree relatives were classified as NGT, IGT or DM after OGTT (Table 4).

Forty-nine out of 80 subjects displayed an abnormal glucose level either as IGT (26.2%) or as DM (35%) (Table 4).

T2DM subjects were significantly older than IGT (IGT vs DM; p = 0.01) and NGT (NGT vs DM; p = 0.03) subjects. Thus age was a contributing factor for DM. BMI (p = 0.029) was significantly higher in both pathological groups.

When blood pressure was considered, diastolic values were higher in abnormal OGTT compared to NGT. No difference in terms of sex distribution was found in any category.

In subjects with abnormal glucose level (n = 49), 59.18% subjects and in subjects with normal glucose level (n = 31), 32.25% met the criteria for metabolic syndrome (Table 5).

So, prevalence of metabolic syndrome was significantly increased if the subject had glucose intolerance (p = 0.023).

FBS, hip measure and serum HDL independently determined two hours glycemia value in OGTT (R2 = 0.707, p = 0.001). FBS, Hip measure and serum HDL together explains 70% of variation in data of two hours glycemia control (Table 6).

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Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

Table 7. Comparisons between Botnia study with our Study Components

Botnia Study

Our Study

Male (%)

Female (%)

Male (%)

Female (%)

92

78

90

80

93.33

79

30

80

Dyslipidemia

57

57.3

65

60

Hypertension

32

55.6

100

80

Metabolic syndrome Obesity

DISCUSSION Until 1970, the prevalence of T2DM was considered to be low in India. The projection from the World Health Organization (WHO) in the year 1998 has highlighted that India would lead the world in the prevalence of diabetes. Studies done in Western countries have confirmed that the prevalence of diabetes among migrant Indians is significantly higher than the host populations. This might be explained by a higher genetic susceptibility to the development of diabetes among Asian Indians or stronger environmental factors (e.g., decreased physical activities, eating habits, etc).

Studies on native Indian population during the last 30 years have shown rising trends in the prevalence of diabetes. The prevalence of metabolic syndrome has also increased in the world.

Metabolic Syndrome in Diabetic Patients In our study, 85% of the diabetic patients (n = 20), aged >40 years (female: 80% and male: 90%) met the criteria for diagnosis of metabolic syndrome as per ATP III guidelines.

In Botnia study 2001 (in Finland and Sweden), the prevalence of metabolic syndrome according to WHO criteria in T2DM among males and females was 84% and 78%, respectively. Cardiovascular mortality was markedly increased in subjects with metabolic syndrome (12%; p < 0.001).

The percentage of T2DM patients with age >40 years with metabolic syndrome in both the studies are comparable. Obesity in Botnia study was classified using BMI or Waist-hip ratios. This may explain a higher prevalence of obesity in Botnia study as compared to our study, where we used the ATP III criteria for central obesity (i.e., waist circumference >88 cm in females and >102 cm in males). The

diabetology cut-off for hypertension in Botnia study was higher; 160 mmHg systolic or 90 mmHg diastolic blood pressure, whereas in our study, hypertension was considered as per ATP III guidelines (normal levels were taken as 130/85 mmHg). Difference in cut-off value may explain higher percentage of study population having hypertension in present study. However, other racial, environmental and personal factors cannot be ruled out in both instances.

In our study, 40% diabetic patients had four components satisfying criteria for metabolic syndrome. Twenty percent had three criteria and 25% had five criteria. It has been suggested by Cruz et al that number of criteria for metabolic syndrome may be inversely proportional to insulin sensitivity.

The NCEP ATP III has recently recognized the metabolic syndrome as an important risk factor for IHD among men and women. It has been estimated, on the bases of the results of Third National Health and Nutrition Examination Survey (NHANES) that >1 in five adults in USA have metabolic syndrome with almost a doubling prevalence (43%) among people >60 years of age. The prevalence of unstable angina and myocardial infarction were highest among patients with five insulin-resistant syndrome features as defined

by NCEPIII. Hence, for individuals with established DM, risk factor management must be intensified to diminish their higher risk for CVD. Among first-degree relatives of patients with T2DM, 48.75% aged >30 years (males 39.1% and among females 61%) met the criteria for metabolic syndrome. One-third of the first-degree relatives with metabolic syndrome belonged to the age group 50-59 years. Hypertension and low HDL have contributed maximum among the components of metabolic syndrome.

These data shows high prevalence of metabolic syndrome among the Indian population. The Deepa study in Chennai 2002 used the EGIR criteria to compute the prevalence of metabolic syndrome in random population with age group of 20-75 years and hence a lower occurrence of metabolic syndrome is seen in this study. Gupta et al held at Jaipur, 2003 was carried out on random population with age >20 years while the present study was carried out on first-degree relatives of age >30 years. This may explain a high percentage of subjects having metabolic syndrome. Ramachandra et al observed a prevalence of 41% and the Strong Heart Study on American Indians observed a prevalence of 55.2%. The above studies had been done on random population, whereas our study was carried out on first-degree relatives. This explains higher percentage

of study population having metabolic syndrome in the present study.

Because of the documented high relatives risk of AV, CVD events and T2DM, the metabolic syndrome undoubtedly carries a relatively high lifetime risk for these disorders even when shorter term (10 years) risk is in low moderate range. The prime emphasis in management of metabolic syndrome per se is to mitigate the modifiable, underlying risk factor (obesity, physical inactivity and atherogenic diet) through lifestyle changes. Its absolute risk is high enough, therapeutic interventions like metformin, statins, etc. may be incorporated to the regimes.

More than 61.25% (49 out of 80) of first-degree relatives of diabetic patient with NIDDM displayed abnormal glucose tolerance either as IGT (26.25%) or NIDDM (35%).

The Catalonia study and Aragon study were done on general population and hence showed a lesser prevalence of abnormal glucose tolerance than our study. However, the Catalonia study done on firstdegree relatives with age >20 years shows a much higher prevalence of 30% for abnormal glucose tolerance than in general population (20%). Racial difference would explain the higher prevalence of abnormal glucose tolerance in our study. Further Indian studies are required to support our data.

Individuals with a parent with T2DM have increased risk of DM and if both parents have T2DM it approaches 40%. Insulin resistance as demonstrated by decreased glucose utilization in skeletal muscle is present in many nondiabetic first-degree relative of T2DM. Annually, IGT carries 1-10% rate of progression to frank T2DM. Thus, all patients in whom diabetes develops probably go through stage IGT and this condition confirms a non-negligible risk in terms of CVDs as well as its progression to NIDDM. Thus by identifying this cluster of individuals at high-risk for metabolic syndrome, we can delay the emergence of DM, CVD, dyslipidemia, stroke and obesity by pharmacological and nonpharmacology measure.

The Diabetes Prevention Program (DPP) demonstrated that intense lifestyle changes (diet and exercise for 30 mins/d) in individuals with IGT prevented or delayed development of T2DM by 58%. By lifestyle intervention, IGT lost 5.7% of body weight in three years. The use of metformin in IGT prevented DM by 31%.

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diabetology When subjects with abnormal glucose tolerance were analyzed, they displayed a higher BMI, blood pressure, triglyceride level, central obesity and lower HDL levels, than NGT groups, all well-recognized features of metabolic syndrome. NIDDM subjects were significantly older than IGT (IGT vs DM; p < 0.01) and NGT (NGT vs DM; p < 0.03) subjects.

BMI was significantly higher in both pathological groups (p < 0.0294). When blood pressure was considered, diastolic values were higher in abnormal OGTT compared to NGT. No difference in terms of sex distribution was found in any category.

CONCLUSION

Our study dealt with the identification of factors, which determine plasma glucose concentration after two hours in OGTT. A step-wise multiple linear regression was applied using SPSS to all first-degree relatives to assess the independent contribution of IGT to separate components of metabolic syndrome; which demonstrated that FBG, hip circumference and low HDL levels were independent determined two hours glycemia value in OGTT (R2 = 0.70; p < 0.00%) of oral glucose tolerance. So IGT, increased hip circumference and low HDL levels can be considered as risk factors for glucose intolerance.

Acknowledgment

This piece of information can be further used with support from a larger Indian study in setting up criteria for precocious screening for IGT and DM in first-degree relatives. This would minimize the number of OGTT and thereby reduce the cost of screening for the given family. Our study shows a high prevalence of metabolic syndrome and IGT in a selected native Indian population. The study also demonstrates that impaired fasting glucose, increased hip circumference and low HDL levels were associated with glucose intolerance.

Furthermore, synergistic effect on increasing the risk for diabetes by lifestyle factors and family history of diabetes was observed in this study.

These populations with family history of DM have increased risk for both cardiovascular disease and T2DM. ÂÂ

ÂÂ

528

Metabolic syndrome being a cardiovascular risk factor according to ATP III lifestyle modification, timely therapeutic intervention is crucial in the prevention of both T2DM and premature CVD in a risk population.

With high degree of heritability and increased urbanization, diabetes could become a major health hazard in India and this underscores the fact that prevention of diabetes must be one of the important health targets for the nation in this century.

Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

ÂÂ

In T2DM and their asymptomatic first-degree relatives, hypertension and low HDL were commonest components of metabolic syndrome, females were more obese.

ÂÂ

Glucose intolerance was significantly associated with other components of metabolic syndrome.

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Impaired fasting glucose, increased hip circumference and low HDL levels were independently associated with, so were the risk factors for glucose intolerance.

We sincerely acknowledge our medical institute VS General Hospital, their staff, our teachers and also the all patients and their relatives without whom this study can’t be possible.

SUGGESTED READING 1. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive summary publication no.

01-3670. Bethesda, National Institutes of Health, 2001.

2. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey.

JAMA 2002;287(3):356-9.

3. Granner DK, O’Brien RM. Molecular physiology and genetics of NIDDM. Importance of metabolic staging.

Diabetes Care 1992;15(3):369-95.

4. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37(12):1595-607.

5. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications.

Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15(7):539-53.

6. Balkau B, Charles MA, Drivsholm T, Borch-Johnsen K, Wareham N, Yudkin JS, et al; European Group For The Study Of Insulin Resistance (EGIR). Frequency of the WHO metabolic syndrome in European cohorts, and an alternative definition of an insulin resistance syndrome.

Diabetes Metab 2002;28(5):364-76.

7. Assmann G, Nofer JR, Schulte H. Cardiovascular risk assessment in metabolic syndrome: view from PROCAM. Endocrinol Metab Clin North Am 2004;33(2):377-92.

8. Harrison’s Principles of medicine 18th Edition, 1995:p.95.

9. Einhorn D, Reaven GM, Cobin RH, Ford E, Ganda OP, Handelsman Y, et al. American College of Endocrinology position statement on the insulin resistance syndrome.

Endocr Pract 2003;9(3):237-52.

diabetology 10. Shah T, Jonnalagadda SS, Kicklighter JR, Diwan S, Hopkins BL. Prevalence of metabolic syndrome risk factors among young adult Asian Indians. J Immigr Health 2005;7(2):11726.

15. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR Groop L. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24(4):683-9.

11. International Diabetes Federation. Worldwide definition of the metabolic syndrome. Available at: http://www.idf. org/webdata/docs/IDF_Meta_def_final.pdf.

16. Cruz ML, Weigensberg MJ, Huang TT, Ball G, Shaibi GQ, Goran MI. The metabolic syndrome in overweight Hispanic youth and the role of insulin sensitivity. J Clin Endocrinol Metab 2004;89(1):108-13.

12. Grundy SM, Brewer HB, Cleeman JI, Smith SC, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Arterioscler Thromb Vasc Biol 2004;24(2):e13-8.

13. Ramachandran A, Snehalatha C, Satyavani K, Sivasankari S, Vijay V. Metabolic syndrome in urban Asian Indian adults--a population study using modified ATP III criteria. Diabetes Res Clin Pract 2003;60(3): 199-204.

14. Nyholm B, Nielsen MF, Kristensen K, Nielsen S, Ostergard T, Pedersen SB, et al. Evidence of increased visceral obesity and reduced physical fitness in healthy insulin-resistant first-degree relatives of type 2 diabetic patients. Eur J Endocrinol 2004;150(2):207-14.

17. Shen BJ, Todaro JF, Niaura R, McCaffery JM, Zhang J, Spiro A 3rd, et al. Are metabolic risk factors one unified syndrome? Modeling the structure of the metabolic syndrome X. Am J Epidemiol 2003;157(8):701-11.

18. Diabetes & Obesity: Time to Act. International Diabetes Federation 2004 19. Klein S, Sheard NF, Pi-Sunyer X, Daly A, WylieRosett J, Kulkarni K Clark NG. Weight management through lifestyle modification for the prevention and management of type 2 diabetes: rationale and strategies: a statement of the American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition. Diabetes Care 2004;27(8):2067-73.

■■■■

Black Race, Diabetes with Complications CRVO Risk Factors Black race and diabetes mellitus (DM) with complications are two previously unrecognized risk factors for central retinal vein occlusion (CRVO), according to a large study of healthcare claims. The data also confirm that hypertension (HTN), which accelerates stiffening of arteries, and vascular disease are significant risk factors for CRVO. (Source: Medscape)

Sugar is Nobody’s Sweetheart any More The intake of free sugars or sugar-sweetened beverages is a determinant of body weight according to a systematic review and meta-analysis conducted for the World Health Organization (WHO).

The findings are intended to support new WHO guidelines on dietary intake of sugar, which currently urge that it be kept to less than 10% of total energy.

Gestational Diabetes Screening Based on Risk Misses too Many Selective screening of pregnant women for gestational diabetes by risk factors misses about a third of women who have the condition and who are at increased risk for adverse pregnancy outcomes, a large retrospective analysis shows. (Source: Medscape)

Little Help from Lucentis for Diabetic Eyes Patients with vitreous hemorrhage related to diabetic retinopathy derived no short-term benefits from treatment with the angiogenesis inhibitor ranibizumab (Lucentis), results of a randomized trial showed.

(Source: Medpage Today)

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ENT

Common Superficial Tongue Lesions Anuradha Sunil*, Jacob Kurien**, Archana Mukunda†, Ashik Bin Basheer‡, Deepthi#

Abstract The tongue is an important structure in the oral cavity and the strongest muscular organ in the body involved in critical functions of taste, speaking, chewing and swallowing. The basic anatomy of tongue is such that unless scrupulous dental hygiene is followed it may lead to pathological lesions. Since the earliest days of medicine, the tongue has been considered a good reflection of systemic diseases. Assessment of the tongue has historically been an important part of a clinical medical examination as many pathological lesions are seen exclusively on the tongue. Lesions occurring on the tongue are vast and range from developmental disorders to infections to idiopathic lesions to malignancies; some lesions may be clues to the underlying systemic illness. General practitioners/physicians and dentists regularly come across such lesions on tongue in their day-to-day practice. A basic and through knowledge of the commonly occurring lesions on the tongue may enlighten the general practitioner in regards to the diagnosis and thereby help in the most effective management of the patients. Uniform diagnostic criteria may heighten the level of clinical diagnosis. Most lesions occurring on tongue heal fast owing to the rich blood supply and if a lesion fails to heal within 10-14 days it must be biopsied and/or further evaluation is necessary for an appropriate diagnosis.

Keywords: General practitioner, superficial tongue lesions, squamous cell carcinoma of tongue, pyogenic

granuloma of tongue, tuberculous ulcers on tongue, aphthous ulcers, pemphigus vulgaris lesions on tongue, lichenoid lesions on tongue

O

ral health highlights the relationship between oral and overall health, emphasizing that oral health involves more than dentition. Oral lesions have long been considered the first signs of many systemic disorders and a plethora of oral diseases.

Hippocrates, Galen and others considered the tongue to be a barometer of health, emphasizing its diagnostic and prognostic importance. Most tongue disorders are short-lived and resolve spontaneously or with simple treatment, while others may cause long-term difficulties, requiring uptodate medical management.

Recognition and diagnosis require taking a thorough history and performing a complete oral examination.

Knowledge of clinical characteristics such as size, location, surface morphology, color, pain and duration is helpful in establishing a diagnosis.1,2 Though, the lesions occurring on tongue are enormous, this present review however, highlights only the most commonly encountered superficial lesions on the tongue. To serve this purpose of ours, we have formulated a working classification based on the incidence of occurrence.

Working classification of common superficial tongue lesions ÂÂ

Injury zz

ÂÂ

*Professor and Head Dept. of Oral and Maxillofacial Pathology Royal Dental College (KUHS), Chalissery, Kerala **Professor and Head Dept. of Oral and Maxillofacial Pathology St. Gregarious Dental College (KUHS), Chalissery, Kerala †Reader ‡Senior Lecturer #Senior Lecturer Dept. of Oral and Maxillofacial Pathology Royal Dental College (KUHS), Chalissery, Kerala Address for correspondence Dr Anuradha Sunil Professor and Head Dept. of Oral and Maxillofacial Pathology Royal Dental College (KUHS), Chalissery, Kerala E-mail: anuradhasunil@hotmail.com

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ÂÂ

Physical, chemical and thermal

Infections zz

Bacterial: Tuberculosis and Scarlet fever

zz

Viral: Human immunodeficiency virus (HIV) and hairy leukoplakia

zz

Fungal: Candidiasis

Developmental disturbances zz

Macroglossia

zz

Geographic tongue

zz

Fissured tongue

zz

Median rhomboid glossitis

zz

Hairy tongue

ENT ÂÂ

ÂÂ

ÂÂ

Nutritional deficiency zz

Iron deficiency anemia

The lesions of tongue heal well and resolve by themselves within 10-14 days.

zz

Pernicious anemia

BACTERIAL INFECTIONS

zz

Vitamin deficiency

Premalignant zz

Leukoplakia

zz

Oral submucous fibrosis

Tumors zz

ÂÂ

ÂÂ

Squamous cell carcinoma

Immunological zz

Recurrent aphthous

zz

Pemphigus

zz

Lichen planus

Miscellaneous zz

Lichenoid reaction

zz

Pyogenic granuloma

Injuries Injuries to the tongue are seen as lacerations or ulcerations and are caused by physical, chemical and thermal injury, the most common causes being physical. Injuries may result from accidental biting while talking, sleeping, secondary to mastication, self-induced by patients or secondary to seizures.

In addition to these causes, fractured, carious, malposed or malformed teeth and premature eruption of teeth, poorly maintained and ill, fitting dental prosthetic appliances may cause trauma (Fig. 1). Ulceration can occur on the lateral borders of tongue can impair taste sensation when there is damage to the taste buds located in the papilla.3 Thermal injuries can result due to intake of very hot soup or tea or pizza/samosas, etc.

It may involve the dorsal surface of tongue along with labial, buccal and palatal mucosa. Chemical injuries of the tongue can be noted due to accidental contact of caustic and dangerous chemicals and some drugs like aspirin.4 Ulcers of thermal and chemical injury tend to be more painful than physical injury.

Treatment is largely based on the withdrawal of agents causing the injury, trimming sharp teeth, correcting the prosthetic appliance, stopping intake of caustic chemicals or drugs. A soft diet should be advised along with appropriate analgesics and topical anesthetics.

Sipping ice cold water every few minutes will reduce the thermal injury. Soft mouth guard may be given to the patients. Oral hygiene should be maintained using saline mouthwashes to prevent secondary infections.

Tuberculosis (TB) is a bacterial infection caused by Mycobacterium tuberculosis that usually occurs in the lungs but it can also affect the oral cavity. Oral lesions are secondary to pulmonary infection and seldom a primary infection. The integrity of oral epithelium normally resists direct penetration by tubercle bacilli.

Thus, bacilli can be inoculated either when there is a break in continuity of epithelium or by hematogeneous seeding. Local predisposing factors like infections, local trauma, poor oral hygiene and systemic predisposing factors like immunosuppression and nutritional deficiency also play a major role in occurrence of oral TB. Tuberculous ulcers of the tongue occur on the tip, lateral borders, dorsum, towards the midline and base (Fig. 2). They are irregular, pale, shallow, oval, indolent painful ulcers with undermined margins, with granulations in the floor and sometimes with a thin slough. Remission of tuberculous ulceration of the tongue takes place along with lung lesions after adequate antitubercular therapy with isoniazid, ethambutol, pyrazinamide and rifampicin.1,5 Scarlet fever is a highly contagious bacterial infection, occurring predominantly in children caused by β-hemolytic Streptococcus pyogenes producing exotoxin, which causes rashes on the skin and mucous membrane.

Initially, the tongue appears broad, thick, dirty with pasty white coating with edematous and hyperemic fungiform papilla protruding as small red knobs, described as ‘strawberry tongue’ or ‘white strawberry tongue’ (Fig. 3). The white coating is lost starting from tip to margin and the tongue appears red glistening smooth with hyperemic edematous fungiform papilla.

This gives the appearance of a ‘raspberry tongue’ or ‘red strawberry tongue’. This infection is treated with systemic or topical application of penicillin, dicloxacillin and cephalexin.6 Syphilis is a venereal disease caused by Treponema pallidium bacteria. It was thought to be virulent and fatal and its incidence decreased after the invention of penicillin. However, in the past few years the incidence of syphilis has increased related to HIV diseases.

Syphilis is classified as congenital or acquired (primary, secondary and tertiary forms). Syphilitic lesions in any stage can be seen in the oral cavity due to increase in the incidence of oral sex. Primary syphilitic lesion called chancre occurs 1-2 weeks later at the site of exposure, which starts as a macule, progresses into papule and

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ENT later on ulcerates. In the oral cavity, it is seen on the dorsum of the tongue as a painless, solitary, indurated ulcer with irregular raised borders, hyperplastic foliate papilla and regional nontender lymphadenopathy.

Oral lesions in secondary syphilis are multiple (Fig. 4) and painful associated with fever and sore throat. The lesions occur on the lateral border of the tongue as irregular fissures or deep ulcers with erythematous border with overlying grey or silver white membranous exudates known as lues maligna.

Tertiary syphilitic lesions known as gumma are seen on the palate or dorsal surface of the tongue as atrophic, fissured, lobulated or leukoplakic plaque.7 VIRAL INFECTIONS Recurrent herpes is a painful viral infection caused by human herpes virus 1 and occurs in approximately one-third of patients who have experienced primary herpetic gingivostomatitis. Unlike primary herpes, it is a more limited disease and occurs on keratinized mucosa of lips, gingiva, hard palate and dorsal aspect of the tongue (Fig. 5). The lesion presents as vesicles in a discrete area, typically the same site every time in any given patient. Vesicles rupture easily in the oral cavity; hence generally an ulcer can be seen.

Triggers for recurrence may include trauma from a dental procedure emotional stress and systemic illness.

Recurrent herpes in immunosuppressed individuals is severe and may occur on any oral mucosal surface, including nonkeratinized sites or solely as lesions on the dorsal aspect of the tongue presenting as red or white nodules or painful nonvesicular ulcerations or fissures and rarely also as a tongue mass.8 Human herpes virus 4, Epstein-Barr virus causes hairy leukoplakia, which occurs primarily in adults who are immunosuppressed. It manifests as asymptomatic white lesions on the lateral border of the tongue, often bilaterally and may extend on the adjacent dorsal or ventral surface of the tongue. The lesions have a corrugated, linear appearance and may appear granular or nodular or may have hair like projections (Fig. 6).

Hairy leukoplakia may be the first manifestation of immunosuppression and may prompt the clinician to test the patient’s HIV status. The presence of hairy leukoplakia is significantly associated with an HIV infection.8 These viral lesions are treated with antiviral drugs like acyclovir.

FUNGAL INFECTION Oral candidiasis is an opportunistic fungal infection caused by Candida albicans seen in the elderly with

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systemic illnesses and immunocompromised patients.

It presents clinically as acute and chronic candidiasis.

Acute pseudomembranous candidiasis occurs as thick white plaque, which can be wiped off to reveal a raw bleeding base whereas acute atrophic candidiasis appears bright red on the dorsal surface of the tongue (Fig. 7). Chronic hyperplastic candidiasis is seen on the lateral border of the tongue as speckled or homogenous white lesion, whereas chronic atrophic form appears as flat red depapillated area on the dorsal surface of tongue.9 Median rhomboid glossitis is a central papillary atrophy of the tongue occurring in the midline.

Nowadays it is thought to be an infection by C. albicans.

It is seen as a well-delineated, rhomboidal, erythematous zone of atrophic filiform papilla located anterior to the circumvallate papillae on dorsal surface (Fig. 8).10 Candidal infections are effectively treated with new specific antifungal like nystatin either systemically or locally. Other drugs like clotrimazole, amphotericin B and iconazole are also used.

DEVELOPMENTAL DISTURBANCES Macroglossia is the presence of excessively large tongue which protrudes between the alveolar ridges.

It can be congenital due to muscular hypertrophy or may be due to secondary causes like tumor, hemangioma, etc. This condition causes problems in feeding, breathing, swallowing, normal jaw development. It interferes with teeth positioning and causes malocclusion and hence the lateral borders of the tongue show scalloping corresponding to the spaces between teeth and gingiva.11 Geographic tongue: It is a common, painless lesion seen on the dorsal surface of the tongue. It is also called as ‘wandering rash of the tongue’ or ‘benign migratory glossitis’. It affects the dorsal surface of the tongue and is seen as well-defined red depapillated areas surrounded by serpiginous white or yellow white lines (Fig. 9). This condition is associated with spontaneous remission and recurrences. No treatment is usually required; symptomatic lesions may be treated with topical corticosteroids.11 Fissured or scrotal tongue is commonly seen in the general population affecting the dorsum of tongue and extending to the lateral borders. It is asymptomatic, characterized by grooves that vary in depth and noted usually on routine examination (Fig. 10). The grooves may be upto 6 mm deep and may at times be

ENT

Figure 1. A large roughly oval shaped ulcer seen on the lateral border of the tongue due to traumatic injury by a sharp tooth.

Figure 4. Secondary syphilitic lesions seen as multiple ulcers on the dorsum of the tongue.

Figure 2. Tuberculous ulcer seen as an irregular ulcer in the midline on dorsum of tongue with undermined margins

Figure 5. Herpetic lesions seen as multiple ulcers on the dorsal surface of the tongue along with lesion on the lip.

Figure 3. Strawberry tongue seen as white coating on the dorsal surface of the tongue with edematous, hyperemic fungiform papilla protruding as small red knobs

Figure 6. Hairy leukoplakia seen on the lateral border of the tongue with a corrugated or hairy like surface.

interconnected appearing like lobules seen associated with Melkersson’s Rosenthal syndrome and Down syndrome. No definitive treatment or medication is required. The grooves have to be maintained clean to avoid secondary infection.11

Hairy tongue or black ‘hairy tongue’ or ‘lingua villosa’ is a common condition, where there is defective desquamation of filiform papilla due to variety of precipitating factors and overuse of broad spectrum antibiotics. On the dorsal surface filiform papilla

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ENT

Figure 7. Dorsal surface of the tongue showing pseudomembranous candidiasis as thick white plaques interspersed with bright red areas of atrophic candidiasis.

Figure 8. Median rhomboid glossitis appearing as rhomboidal, erythematous zone of atrophic filiform papilla located anterior to the circumvallate papillae on dorsal surface.

Figure 9. Geographic tongue seen as well defined, red depapillated areas surrounded by serpiginous white or yellow white lines seen on the dorsal surface of the tongue.

Figure 10. Scrotal tongue showing numerous grooves of varying depths on the dorsal surface of the tongue.

Figure 11. Hairy tongue presenting as hypertrophic filiform papilla with black pigmentation seen on the dorsal surface of the tongue.

Figure 12. Hunterâ&#x20AC;&#x2122;s glossitis appearing as beefy red, smooth or bald tongue with atrophy of papilla.

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ENT are hypertrophic with elongation upto 15 mm in length (normally it is 1 mm), there is lack of normal desquamation and the tongue appears pigmented [pink, white, black, brown, green] (Fig. 11). It is seen frequently in tobacco users and heavy coffee or tea drinkers. It is reported with greater frequency in males with HIV. The elongated papilla rubs against the soft palate causing tickling or gagging sensation. Food entrapment between the papilla gives rise to halitosis.

It is treated by simply brushing the tongue with tooth brush or tongue scraper. Severe complicated cases are treated by surgical excision of papilla by electrodissection, carbon dioxide laser or even scissors.2,12 NUTRITIONAL DEFICIENCIES Iron and vitamin deficiency is one of the most common deficiencies that affect the oral cavity including the tongue. Chronic iron deficiency is associated with Plummer Vinson syndrome where tongue is very painful with burning sensation. The tongue is inflamed and beefy red, smooth or bald due to atrophy of papilla, hence called as Hunterâ&#x20AC;&#x2122;s glossitis (Fig. 12). Vitamin B12 deficiency associated with pernicious anemia results in inflammation of the tongue with beefy red, atrophy of papilla and soreness resulting in smooth tongue. The tongue is severely affected by other vitamin deficiencies like niacin deficiency (pellagra) results in black tongue and riboflavin deficiency causes magenta tongue.

The treatment should comprise of first identifying the underlying cause of the deficiency and then the appropriate supplement should be given.13 PREMALIGNANT LESIONS Leukoplakia (leuko = white; plakia = patch) term was first used by Schwimmer in 1877, to describe a white lesion of the tongue, which probably represented a syphilitic glossitis. It is a clinical diagnosis of exclusion and not histopathological diagnosis as it does not show any specific microscopic features. It usually involves all intraoral sites and when the tongue is involved, it affects the lateral borders more commonly followed by the dorsum. Leukoplakia occurring on tongue along with floor of the mouth and lip are considered as highrisk sites as they show dysplastic features or squamous cell carcinoma. It presents clinically as a homogenous thick white or grey patch which cannot be wiped away (Fig. 13), or ulcerated and nodular or speckled forms where red nodules are seen projecting above the white patch.14 Oral submucous fibrosis is a chronic debilitating disease, premalignant condition of the oral mucosa

first described by Schwartz 1952. It is characterized by inflammation and progressive fibrosis of the submucosal tissues, well recognized for its malignant potential and is particularly associated with use of areca nut in various forms. It is usually seen with prodromal symptoms like burning sensation associated with blisters or ulcers on buccal mucosa and palate and as petechiae on the tongue. This leads to juxtaepithelial inflammatory reaction followed by progressive hyalinization of the lamina propria. As a result the oral mucosa becomes blanched and slightly opaque with palpable white fibrous bands. Impairment of tongue movements and atrophy of papilla on tongue are seen in advanced cases (Fig. 14).15 NEOPLASM Squamous cell carcinoma of the tongue is the most common malignant tumor of the oral cavity in patients younger than 40 years and is more common in men than women.16 It is regarded as a biologically different entity compared to cancer affecting other oral sites.

It is more aggressive and generally associated with a higher rate of metastasis. It commonly involves the mobile tongue i.e., anterior two-thirds of the tongue, lateral borders followed by dorsum. It may arise de novo or from an existing leukoplakia or irritation from a sharp tooth or prosthesis. It is clinically silent as there is laxity of the tissue planes separating the intrinsic tongue musculature, which helps cancer cells to spread easily and becomes symptomatic only when tumor size interferes with tongue mobility. Despite, the ease of inspecting the tongue by both patient and physician, they often present late, as they are usually painless and often ignored by the patient. Eventually, they present as a nonhealing ulcer which, demonstrates growth over time usually >2 cm at presentation, with the lateral border being the most common site (Fig. 15). The patient may develop speech and swallowing dysfunction and pain occurs when the tumor involves the lingual nerve, and this pain may also be referred to the ear.17 IMMUNOLOGICAL DISORDERS Recurrent aphthous stomatitis, also called as canker sores, is an inflammatory lesion of unknown etiology, thought to be an immunological disorder. It is seen as painful ulcers affecting both keratinized and nonkeratinized mucosa. There are three clinical forms: aphthous minor, major and herpetiform ulcers. They present clinically as single or multiple, round or oval ulcers, which generally last for 7-14 days and heal

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ENT without scarring. Floor of the ulcer is yellowish initially then becomes grayish as epithelialization occurs. Minor aphthae are 2-4 cm, usually seen on the nonkeratinizing mucosa on ventrum of tongue and rare on palate and dorsal surface of tongue. Major aphthae are ≥1 cm or more, seen on keratinized mucosa like palate and dorsum of tongue (Fig. 16). Herpetiform ulcers occur in any site of oral cavity. Aphthous ulcer recurs after 1- to 4-month interval.

Aphthous ulcers are treated effectively with topical steroid triamcinolone acetonide 0.1% in oral base applied four times daily on to the ulcers and/or 2.5 mg hydrocortisone hemisuccinate lozenges dissolved slowly in the mouth four times daily. Herpetiform ulcers respond to tetracycline 250 mg dissolved in 10-15 ml of water and used as mouthwash held in the mouth for 3-5 minutes and then expectorated. Systemic steroids, cauterization, antibiotics, mouth rinses, active enzymes, laser treatments and combination therapy are also available. Treatment reduces pain, number and size of ulcers and hastens healing time.18 Pemphigus is a chronic autoimmune disorder, which affects skin and mucous membrane, where antibodies are produced against desmoglein 3 between keratinocytes resulting in loss of cellular adhesion. In most cases (70-90%) oral lesions are the first and sole presentation of the disease. It is of four major types namely vulgaris, vegetans, foliaceous and erythematosus. of these, the last two manifest only on skin and are rarely seen orally. Oral lesions start as bulla which easily ruptures due to friction to form ulcers with slight or absent erythematous halo around, and are covered with yellow white pseudomembrane (Fig. 17). In contrast to traumatic ulcers and aphthous ulcers, the base is not concave and so is less painful and can be secondarily infected. Several ulcers in the mouth can interfere with eating and drinking leading to nutritional deficiency.19 Pemphigus vegetans is a common form of pemphigus lesion, which resembles vulgaris in all aspects except that papillomatous hyperplasia is observed following rupture of vesicles seen as vegetations and is known as ‘cerebriform tongue’.20 A mild case of pemphigus is treated by topical or intralesional corticosteroid therapy along with dapsone or tetracycline. For more diffuse disease, steroids along with an immunosuppressant like cyclophosphamide, methotrexate, chlorambucil may be required.

Oral lichen planus is a chronic inflammatory disease characterized by remission and recurrences. It is referred to as isolated oral lichen planus as it is not associated with cutaneous lesions. The etiology is not known and psychological problems or immune disorder is currently favored. Women are more commonly

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affected than males. The lesion commonly presents bilaterally as reticular, erosive, plaque and ulcerative type with atrophic and bullous types being rare.

Erosive and ulcerative types are associated with pain, burning or itching sensation. Lesions on the tongue may show keratotic plaques more commonly than the typical reticular form with Wickham’s striae (Fig. 18).

Asymptomatic patients do not require any treatment.

For symptomatic lesions, topical steroids can be given as mouth rinses and gels along with antioxidants and multivitamin. Patient should be periodically followed up.21 MISCELLANEOUS Lichenoid reactions occurring on the oral mucosa and skin resemble lichen planus clinically and microscopically. It differs in the etiology and is caused by contact with specific agents like metallic restorations, resins, drugs and flavoring agents. Lind in 1986 employed the term lichenoid reaction referring to clinical lesions resulting with amalgam restoration.

Tissue alteration seen is caused by the antigen fixation in the keratinocytes, which are recognized and destroyed by cells of the immune system. Majority of lesions are located in the molar and retromolar areas of buccal mucosa and lateral border of tongue (Fig. 19). They appear clinically as white or red patches, erythema, erosions and ulcerations associated with pain and soreness. They may at times be bilateral and may also show white streaks resembling Wickham’s striae of lichen planus. The clinical and histopathological criteria must be included in order to establish a final diagnosis of lichenoid reaction.22 Pyogenic granuloma is a nonneoplastic, inflammatory hyperplastic response to various stimuli like lowgrade infection, injury, trauma or hormonal factors.

It commonly affects females in the second decade. It is seen commonly on skin and oral mucosa as smooth or lobulated exophytic hemorrhagic and compressible lesion, which is usually pedunculated but sometimes sessile. The lesion is usually asymptomatic, may grow rapidly in size and may vary in size from few millimeters to centimeters. The surface is usually friable and ulcerated as it is composed of hyperplastic granulation tissue with pronounced vascularity. Gingiva is the commonest site for occurrence of pyogenic granulomas with lateral borders of tongue (Fig. 20), buccal mucosa and lips being the next common site. These lesions are treated successfully with removal of local irritants and conservative surgical excision.23 Latest techniques like laser, cryosurgery and electro-dissection cause less bleeding and are well-tolerated by patients with no adverse effects.24

ENT

Figure 13. Leukoplakia occurring on the lateral border of the tongue as a large homogeneous thick white plaque, which cannot be wiped.

Figure 14. Oral submucous fibrosis causing atrophy of papilla and impaired movements of tongue.

Figure 15. Squamous cell carcinoma presenting on the lateral border of the tongue as a large, non healing ulcer covered with slough.

Figure 16. Recurrent aphthous major seen as three small ulcers on the dorsal surface of the tongue.

Figure 17. Pemphigus vulgaris manifesting on the tongue as numerous ulcers covered with yellow white pseudomembrane, with slight or absent erythematous halo.

Figure 18. Lichen planus seen as reticular lesions on the lateral border of the tongue.

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ENT

Figure 19. Lichenoid reaction seen typically on the lateral border of the tongue in the molar retromolar area resembling reticular pattern with Wickham’s striae.

Figure 20. Pyogenic granuloma seen on the dorsum of the tongue as a smooth, sessile hemorrhagic lesion.

Summary

12. Sambandan T. Review on oral manifestations of blood diseases. JIADS 2010;1(4):41-3.

Among the broad-spectrum of lesions that occur on the tongue a few tongue lesions present more commonly.

The most important thing to remember is that most tongue lesions will resolve spontaneously or with simple therapy within a week, if they do not, then the lesions will have to be biopsied to rule out malignancies or serious disorders. Diagnosing such common tongue lesions will help in the best interest of the patient which is achieved by both general practitioner and dentists.

References 1. Hodgson TA, Porter SR. Diagnosing common tongue lesions. Practitioner 2001;245(1621):340-6.

2. Lent GS. Complex tongue laceration. Available at: http:// emedicine.medscape.com/article/83275-overview.

3. Cox RD. Chemical burns in emergency medicine. Available at: http://emedicine.medscape.com/article/769336-overview.

4. Bhat P, Mehndiratta A, D’Costa L, Mesquita AM, Nadkarni N. Tuberculosis of tongue: A case report. Ind J Tub 1997;44:31-3.

5. Scarlet fever. In: Shafer WG, Hine MA, Levy BM. A textbook of oral pathology. 5th Edition, Elsevier 2006:p.435-436.

6. Gordon SC. Viral infections of the mouth. Available at: http://emedicine.medscape.com/article/1079920-overview.

7. Leão JC, Gueiros LA, Porter SR. Oral manifestations of syphilis. Clinics (Sao Paulo) 2006;61(2):161-6.

8. Akpan A, Morgan R. Oral candidiasis. Postgrad Med J 2002;78(922):455-9.

9. Goregen M, Miloglu O, Buyukkurt MC, Caglayan F, Aktas AE. Median rhomboid glossitis: a clinical and microbiological study. Eur J Dent 2011;5(4):367-72.

10. Development disturbances of tongue. In: Shafer WG, Hine MA, Levy BM. A textbook of oral pathology. 5th Edition, Elsevier 2006:p.36-42.

11. Vañó-Galván S, Jaén P. Black hairy tongue. Cleve Clin J Med 2008;75(12):847-8.

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13. Neville BW, Day TA. Oral cancer and precancerous lesions. CA Cancer J Clin 2002;52(4):195-215.

14. Rajendran R. Oral submucous fibrosis: etiology, pathogenesis, and future research. Bull World Health Organ 1994;72(6):985-96.

15. Mathew Iype E, Pandey M, Mathew A, Thomas G, Sebastian P, Krishnan Nair M. Squamous cell carcinoma of the tongue among young Indian adults. Neoplasia 2001;3(4):273-7.

16. Ye H, Yu T, Temam S, Ziober BL, Wang J, Schwartz JL, Mao L, et al. Transcriptomic dissection of tongue squamous cell carcinoma. BMC Genomics 2008;9:69.

17. Fernandes R, Tuckey T, Lam P, Allidina S, Sharifi S, Nia D. The best treatment for aphthous ulcers an evidence based study of the literature. Available at: http://www. utoronto.ca/dentistry/newsresources/evidence_based/ aphthousulcers.pdf.

18. Dagistan S, Goregen M, Miloglu O, Cakur B. Oral pemphigus vulgaris: a case report with review of the literature. J Oral Sci 2008;50(3):359-62.

19. Bhargava P, Kuldeep CM, Mathur NK. Isolated pemphigus vegetans of the tongue. Indian J Dermatol Venereol Leprol 2001;67(5):267.

20. van der Waal I. Oral lichen planus and oral lichenoid lesions; a critical appraisal with emphasis on the diagnostic aspects. Med Oral Patol Oral Cir Bucal 2009;14(7):E310-4.

21. Do Prado RF, Marocchio LS, Felipini RC. Oral lichen planus versus oral lichenoid reaction: difficulties in the diagnosis. Indian J Dent Res 2009;20(3):361-4.

22. Issa Y, Duxbury AJ, Macfarlane TV, Brunton PA. Oral lichenoid lesions related to dental restorative materials.

Br Dent J 2005;198(6):361-6; discussion 549; quiz 372 23. Jafarzadeh H, Sanatkhani M, Mohtasham N. Oral pyogenic granuloma: a review. J Oral Sci 2006;48(4):167-75 24. Saghafi S, Zare-Mahmoodabadi R, Danesh-Sani SA, Mahmoodi P, Esmaili M. Oral pyogenic granuloma: a retrospective analysis of 151 cases in an Iranian population. Int J Oral Maxillofac Pathol 2011;2(3):3-6.

Obstetrics and Gynecology

Comparative Study of Sublingual versus Vaginal Misoprostol on Preoperative Cervical Priming in First Trimester Abortion Parneet Kaur*, Manjeet Kaur*, Balwinder Kaur**, Manjit Kaur Mohi†; Khushpreet Kaur‡, Preeti Jindal¶

Abstract Objective: To compare the effect of sublingual versus vaginal misoprostol on preoperative cervical priming in first trimester abortion. Material and methods: One hundred women seeking first trimester abortion were randomized into either sublingual or vaginal groups of 50 each. They were given 400 µg misoprostol via sublingual or vaginal route for cervical priming three hours before the procedure. The outcome measures assessed were cervical dilatation before surgery, duration of procedure, intraoperative blood loss and preoperative side effects. Results: Subjects in the sublingual group achieved significantly higher mean cervical dilatation compared to vaginal group (8.34 ± 0.62 mm vs 7.60 ± 0.67 mm, p = 0.0001). The mean duration of procedure for sublingual group was significantly lower compared to the vaginal group (2.62 ± 0.64 minutes vs 3.17 ± 0.71 minutes, p = 0.0001). The mean intraoperative blood loss was found to be more in sublingual group as compared to vaginal group (34.90 ± 10.90 ml vs 32.90 ± 7.42 ml), but the difference was not significant (p = 0.286). The sublingual group experienced more preoperative side effects such as pain, bleeding, nausea and shivering as compared to vaginal group.

Conclusion: Sublingual misoprostol is more effective and convenient route than vaginal misoprostol for preoperative cervical priming in first trimester abortion.

Keywords: Misoprostol, sublingual, vaginal, cervical priming

A

n abortion is termination of a pregnancy either spontaneously or intentionally, before the fetus develops sufficiently to survive independently.

The traditional method for termination of early pregnancy has been priming of the cervix followed by evacuation by suction aspiration performed under anesthesia or sedation.1 Cervical priming can be achieved with the use of prostaglandins or hydrophilic dilators.2 Various prostaglandin E1 (PGE1) analogs can be used, but misoprostol (15-deoxy-16-hydroxy16methyl-PGE1) is cheap, easily stored and associated with fewer side effects,3 so, it is most commonly used

worldwide. The sublingual route appears as effective as vaginal administration and requires less time for priming, but is associated with more side effects.4 In order to dilate the cervix preoperatively, the subject must receive the agent at least 3-4 hours prior to the procedure.5 Objective The present study was undertaken to compare the effect of 400 µg sublingual and 400 µg vaginal misoprostol on preoperative cervical priming in first trimester abortion.

Material and methods

*Associate Professor **Assistant Professor †Professor and Head ‡Professor and Unit Head ¶Junior Resident Dept. of Obstetrics and Gynecology Government Medical College and Hospital, Patiala, Punjab Address for correspondence Dr Parneet Kaur H. No.: 151, Punjabi Bagh Near Klair Orthopedic Centre, Patiala, Punjab - 147 001 E-mail: parneetkd@yahoo.co.in

The present study was conducted in the Dept. of Obstetrics and Gynecology, Government Medical College and Hospital, Patiala, Punjab. One hundred women seeking first trimester abortion were randomized into either sublingual (Group A) or vaginal group (Group B) of 50 each. They were given 400 µg misoprostol via sublingual or vaginal route for cervical priming three hours before the procedure. The inclusion criterion was young healthy women with period of gestation

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Obstetrics and Gynecology upto 12 weeks. Gestational age was estimated clinically and was confirmed by ultrasonography in case of any doubt. Subjects with history of previous uterine surgery, allergy or contraindications to prostaglandins, hemoglobin <9 g/dl, pelvic inflammatory diseases, ectopic pregnancy, multiple pregnancy and uterine anomalies were excluded. Detailed history was taken and a complete physical and obstetrical examination was done. Routine investigations including hemoglobin, urine analysis and blood group were done.

The women were admitted on the morning of the procedure and misoprostol was administered either vaginally or sublingually by doctors other than surgeons assessing the treatment outcome. Their pulse, blood pressure, temperature and other side effects associated with misoprostol including pain, nausea, vomiting, diarrhea, fever, shivering and bleeding per vaginum were recorded. The severity of preoperative abdominal pain experienced by the subject was assessed as Score 1 - no pain, Score 2 - mild pain and Score 3 - severe pain requiring analgesics. Similarly, preoperative vaginal bleeding was measured as: Score 1 - Spotting or minimal bleeding, Score 2 - bleeding amount similar to menstrual flow and Score 3 - heavy bleeding with clots.

The abortion was carried out by suction evacuation under general anesthesia. After three hours, outcome measures assessed were cervical dilatation, duration of procedure, intraoperative blood loss and preoperative side effects. The degree of cervical dilatation before vacuum aspiration was measured by passing Hegar’s dilators. Duration of procedure was measured from the start of dilatation of cervical os until end of curettage and intraoperative blood loss was measured with a measuring cylinder.

Following the procedure, the subjects were kept in hospital for four hours for observation. The final outcome regarding efficacy, side effects and acceptability of treatment was assessed.

Results Table 1 summarizes the characteristics of subjects recruited in each group. There was no significant difference with respect to age, gravida, parity and gestational age between the two groups.

Mean cervical dilatation achieved in sublingual group was significantly higher compared to vaginal group (8.34 ± 0.62 mm vs 7.60 ± 0.67 mm, p = 0.0001) (Table 2).

The mean duration of procedure for sublingual group was significantly lower compared to vaginal group (2.62 ± 0.64 minutes vs 3.17 ± 0.71 minutes, p = 0.0001).

(Table 3)

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Table 1. Subject Characteristics Parameters

Sublingual group (Group A)

Vaginal group (Group B)

p value

Results

Age

29.78 ± 4.03

29.84 ± 3.61

0.93 (>0.05)

NS

Gravida

3.50 ± 0.86

3.46 ± 0.71

0.80 (>0.05)

NS

Parity

2.36 ± 0.80

2.32 ± 0.68

0.78 (>0.05)

NS

Gestational age

7.76 ± 1.37

7.60 ± 1.27

0.60 (>0.05)

NS

The values are expressed as mean ± SD.

Table 2. Showing Comparison of Cervical Dilatation in Group A and B Cervical dilatation (Hegar's dilator) (mm)

Sublingual group (Group A)

Vaginal group (Group B)

No.

%

No.

%

6

-

-

2

4

7

2

4

19

38

8

31

62

26

52

9

15

30

3

6

10

2

4

-

-

Total

50

100

50

Range Mean ± SD

100

7-10

6-9

8.34 ± 0.62 mm

7.60 ± 0.67 mm

‘t’ and ‘p’ value

5.732; <0.05

Significance

S

Table 3. Showing Comparative duration of Procedure in Group A and B Duration of procedure (Minutes)

Sublingual group (Group A)

Vaginal group (Group B)

No.

%

No.

%

1-2

6

12

2

4

2-3

35

70

19

38

3-4

6

12

24

48

4-5

3

6

5

10

Total

50

100

50

100

Range Mean ± SD ‘t’ and ‘p’ value Significance

1-5

1-5

2.62 ± 0.64

3.17 ± 0.71

4.068; <0.05 S

Obstetrics and Gynecology Table 4. Showing Comparison of Intra-operative Blood Loss in Group A and B Blood loss (ml)

Sublingual group (Group A)

Vaginal group (Group B)

No.

%

No.

%

<20

3

6

2

4

21-40

37

74

42

84

41-60

10

20

6

12

Total

50

100

50

100

Mean ± SD

34.90 ± 10.90

‘t’ and ‘p’ value

32.90 ± 7.42

1.072; >0.05

Significance

NS

Table 5. Showing Comparison of Side Effects in Group A and B Side effects

Sublingual group (Group A)

Vaginal group (Group B)

‘p’ value

Results (S/NS)

Pain

18

16

0.715 (>0.05)

NS

Bleeding

14

12

0.814 (>0.05)

NS

Nausea

7

2

0.081 (>0.05)

NS

Shivering

7

3

0.183 (>0.05)

NS

Vomiting

-

-

-

-

Fever

-

-

-

-

Diarrhea

-

-

-

-

The mean intraoperative blood loss was found to be more in sublingual group as compared to vaginal group (34.90 ± 10.90 ml vs 32.90 ± 7.42 ml), but difference was not significant (p = 0.286) (Table 4).

In the present study, subjects in sublingual group experienced more preoperative side effects as compared to vaginal group such as pain (18 vs 16, p = 0715), bleeding (14 vs 12, p = 0.814), nausea (7 vs 2, p = 0.081) and shivering (7 vs 3, p = 0.183). None of the subjects in present study experienced fever, diarrhea or vomiting. But, the difference of side effects in both the groups was not statistically significant (Table 5).

No complication occurred in either of the two groups during surgery or in the period of observation. Out of a total of 50 subjects in vaginal group, in 11 (22%) subjects, tablet was only partially absorbed, while in sublingual group, drug was absorbed completely in

5-10 minutes in all the subjects. Sublingual route was more acceptable to the subjects than vaginal route and none of the subjects in sublingual group complained of any unpleasant taste.

Discussion First trimester abortion by surgical methods has been widely used in modern obstetrics. Vacuum aspiration is a commonly used method for first trimester abortion and is one of the most common surgical procedures performed worldwide.6 Cervical dilatation is the most critical step in vacuum aspiration as most cervical and uterine injuries are due to forceful dilatation of cervix.

Adequate dilatation decreases pain and duration of surgery and increases operative ease. Previously, laminaria tent, gemeprost and PGE2 gel have been used for cervical ripening.7 These days misoprostol, a synthetic PGE1 analog, has become popular for its effectiveness and for its other advantages like less cervical injuries, minimal intraoperative blood loss, reduced requirement of general anesthetics and availability in different dosage forms. It can be given by oral, intravaginal, sublingual or intrarectal route.

The present study observed that the cervical dilatation achieved with misoprostol was favorable among the sublingual group compared to the vaginal group. The observed difference can be attributed to the different absorption kinetics and subsequent more systemic bioavailability with the sublingual and vaginal routes.

Similar results were found by Saxena et al,8 Parveen et al9 and Vimala et al.10 The duration of procedure was less in the sublingual group. This can be explained on the basis of the more cervical ripening and dilatation achieved in this group.

Saxena et al,8 Parveen et al,9 Vimala et al10 and Carbonell et al11 have also reported similar findings.

The mean intraoperative blood loss was found to be slightly more in sublingual group as compared to vaginal group, which is same as reported by Parveen et al9 and Tang et al,12 which was not significant.

In the present study, subjects in sublingual group experienced more preoperative side effects as compared to vaginal group, the most common being the pain (18 vs 16, p = 0715). Other side effects like bleeding (14 vs 12, p = 0.814), nausea (7 vs 2, p = 0.081) and shivering (7 vs 3, p = 0.183) were also seen slightly more frequently in sublingual group. This increased frequency of side effects may be explained by the

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Obstetrics and Gynecology higher bioavailability of sublingual misoprostol. None of the subjects in the present study experienced fever, diarrhea or vomiting. But, the difference of side effects in both the groups was not significant.

Conclusion It is concluded from the present study that sublingual misoprostol is better than vaginal misoprostol for preoperative cervical priming in first trimester abortion.

The operative time is also decreased with sublingual route and it has good patient acceptability rate and no significant difference in side effects experienced by the subjects.

References 1. Saxena P, Salhan S, Sarda N. Comparison between the sublingual and oral route of misoprostol for pre-abortion cervical priming in first trimester abortions. Hum Reprod 2004;19(1):77-80.

2. Fong YF, Singh K, Prasad RN. A comparative study using two dose regimens (200 microg or 400 microg) of vaginal misoprostol for pre-operative cervical dilatation in first trimester nulliparae. Br J Obstet Gynaecol 1998;105(4): 413-7.

3. el-Refaey H, Calder L, Wheatley DN, Templeton A. Cervical priming with prostaglandin E1 analogues, misoprostol and gemeprost. Lancet 1994;343(8907):1207-9.

4. Saxena P, Salhan S, Sarda N. Role of sublingual misoprostol for cervical ripening prior to vacuum aspiration in first trimester interruption of pregnancy. Contraception 2003;67(3):213-7.

5. Allen RH, Goldberg AB; Board of Society of Family Planning. Cervical dilation before first-trimester surgical

abortion (<14 weeks’ gestation). SFP Guideline 20071.

Contraception 2007;76(2):139-56.

6. Ngai SW, Yeung KC, Lao T, Ho PC. Oral misoprostol versus vaginal gemeprost for cervical dilatation prior to vacuum aspiration in women in the sixth to twelfth week of gestation. Contraception 1995;51(6):347-50.

7. el-Refaey H, Templeton A. Early induction of abortion by a combination of oral mifepristone and misoprostol administered by the vaginal route. Contraception 1994;49(2):111-4.

8. Saxena P, Sarda N, Salhan S, Nandan D. A randomised comparison between sublingual, oral and vaginal route of misoprostol for pre-abortion cervical ripening in firsttrimester pregnancy termination under local anaesthesia.

Aust N Z J Obstet Gynaecol 2008;48(1):101-6.

9. Parveen S, Khateeb ZA, Mufti SM, Shah MA, Tandon VR, Hakak S, et al. Comparison of sublingual, vaginal, and oral misoprostol in cervical ripening for first trimester abortion. Indian J Pharmacol 2011;43(2):172-5.

10. Vimala N, Mittal S, Kumar S, Dadhwal V, Sharma Y. A randomized comparison of sublingual and vaginal misoprostol for cervical priming before suction termination of first-trimester pregnancy. Contraception 2004;70(2):117-20.

11. Carbonell Esteve JL, Marí JM, Valero F, Llorente M, Salvador I, Varela L, et al. Sublingual versus vaginal misoprostol (400 microg) for cervical priming in firsttrimester abortion: a randomized trial. Contraception 2006;74(4):328-33.

12. Tang OS, Mok KH, Ho PC. A randomized study comparing the use of sublingual to vaginal misoprostol for pre-operative cervical priming prior to surgical termination of pregnancy in the first trimester. Hum Reprod 2004;19(5):1101-4.

■■■■

Subtle Cognitive Declines follow Menopause The year after a woman’s final menstrual period - a phase classified as early postmenopause - is a time in which subtle changes in cognition occur, researchers found. Compared with women in an earlier stage of menopause known as the late menopausal transition phase, those in early postmenopause scored worse on tests of verbal learning (B = –0.93, p < 0.01) and verbal memory (B = –0.80, p = 0.01), according to Miriam T Weber, PhD, of the University of Rochester in New York, and colleagues. In addition, women in early postmenopause fared worse on measures of fine motor skills (B = -0.70, p = 0.0) and attention/working memory (B = –0.55, p = 0.04), the researchers reported online in Menopause.

Source: Medpage Today

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Obstetrics and Gynecology

Sequential Bilateral Torsion of a Normal Ovary at 31 Weeks of Gestation and 12 Months Following Delivery B Poornima R Bhat*, Aruna Kamath

Abstract Torsion of a normal ovary should be considered in the differential diagnosis of acute abdominal pain in the third trimester.

Accurate diagnosis and early surgical intervention is essential to avoid fetal and maternal morbidity and mortality. We herein report a case of torsion of a normal ovary alone at 31 weeks of gestation following a spontaneous conception and again torsion of right normal ovary 14 months later. We had to do oophorectomy in both instances since the ovaries were gangrenous.

Keywords: Normal ovary, torsion, third trimester, oophorectomy

A

dnexal torsion during pregnancy is a rare condition, more common in the first and early second trimesters and exceptional during the third trimester. Torsion of normal ovary alone is exceptional but torsion of the normal fallopian tube with or without ovary is not rare. Preoperative diagnosis based on symptoms, physical findings or imaging modalities during pregnancy is often difficult.

Since this condition is uncommon in third trimester, a high index of suspicion is required to diagnose.

Delay in surgical intervention can lead to irreversible damage to the ovary. Torsion is most frequently unilateral and commonly involves the right side. The first case of bilateral adnexal torsion reported was

by Warnek in 1895. Since then few cases have been described. The first case of bilateral asynchronous torsion was reported by Baron in 1934. Mostly all these were in children and adolescents where the adnexa is hypermobile.

*Associate Professor Dept. of Obstetrics and Gynecology Father Muller Medical College Mangalore, Karnataka Address for correspondence Dr B Poornima R Bhat Dept. of Obstetrics and Gynecology Father Muller Medical College Mangalore - 565 002, Karnataka E-mail: bprbhat@rediffmail.com

Case report A 30-year-old woman third gravida with previous two abortions reported at 31 weeks with a history of severe abdominal pain on the left side since two days.

There was no history of fever, vomiting, bladder or bowel disturbances, bleeding or leaking per vagina.

Patient was treated as urinary tract infection (UTI) by a local doctor. There was no improvement, so she came to our hospital. She had been married for 12 years and investigated for infertility for which she had taken treatment irregularly. The present conception was spontaneous after stopping all medications six months back. She had regular antenatal care (ANC); the pregnancy was uneventful so far.

Her vital signs were stable. Systemic examination was normal. Per abdominal examination revealed uterus of 32 weeks size, relaxed, head in the lower pole, fetal heart rate (FHR) regular; severe tenderness was present in the left lumber region. Transabdominal USG showed single intrauterine gestation of 31-32 weeks, partial torsion of left ovary 8 x 5 cm in size with increased stromal echogenicity and multiple small peripheral cystic spaces. No was detectable color/power flow on Doppler. Routine investigations like Hb, TLC, DLC, ESR and urine analysis were normal. Since, the patient did not give consent for immediate surgery, laparotomy and left sided oophorectomy was done on next day.

Intraoperative findings were enlarged left ovary 7 x 4 cm,

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Obstetrics and Gynecology

Figure 1A. Left ovary.

Figure 2. Right ovary.

done since the ovary had twisted twice and undergone gangrenous change (Fig. 2). Histopathology confirmed the torsion of normal ovary. Patient was advised hormone replacement therapy.

Discussion Figure 1B. Cut section of the left ovary.

twisted thrice in its pedicle and had gangrenous change (Figs. 1A and 1B). Postoperative period was uneventful.

Histopathological report showed ovarian cortex with areas of hemorrhage within, suggestive of ovarian torsion. Pregnancy continued till term. She delivered vaginally a live male baby of weight 3 kg by vaccum.

Patient had similar pain on right side of abdomen 10 months after the first episode. USG abdomen showed right hemorrhagic cyst of 4 x 3 cm with no torsion. Patient was advised oral contraceptive (OC) pills for two months.

Again the patient presented with sudden-onset of severe pain in the right side of abdomen two months later. USG and Doppler showed torsion of right ovary.

Laparotomy was done and right oophorectomy was

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Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

Adnexal torsion is an uncommon cause of surgical emergency. Most of the cases are secondary to adnexal pathology or develop as a complication of ovarian hyperstimulation syndrome and ovarian stimulation for in vitro fertilization (IVF). The symptoms are nonspecific and can be confused with other acute abdominal conditions such as appendicitis, ureteral or bowel obstruction. If the diagnosis is delayed hemorrhagic infarction of the involved ovary may be followed by infection leading to peritonitis and in some cases, death.

Combination of magnetic resonance imaging (MRI) and color Doppler helps in accurate diagnosis. Therapy of adnexal torsion remains controversial. Although laparoscopic approach combined with simple detorsion has been described in the third trimester, laparotomy and salpingo-oophorectomy may sometimes be necessary. It depends upon the degree of ischemia and necrosis. Detorsion of ovary, bi-sections of the necrotic tissue and pexis of any residual ovarian tissue without

Obstetrics and Gynecology oophorectomy should be performed in children and young adults to conserve ovaries.

Conclusion Normal ovary torsion should be considered in the differential diagnosis of acute abdominal pain in the third trimester. Accurate diagnosis and early surgical intervention is essential to avoid fetal and maternal morbidity and mortality. We had to do oophorectomy in both instances since the ovaries were gangrenous.

Suggested reading 1. Prefumo F, Ciravolo G. Adnexal torsion in late pregnancy. Arch Gynecol Obstet 2009;280(3):473-4.

2. Tindall VR. Jeffcoated’s Principles of Gynaecology.

5th edition, Oxford: London, 1997.

3. Koroglu M, Yalcin M, Baykal B, Yildiz H, Yesildag A, Oyar O. MRI in the diagnosis of ovarian torsion in a pregnant patient. S.D.U. Tip Fak Derg 2005;12(3):39-42.

4. Varras M, Akrivis C, Demou A, Antoniou N. Asynchronous bilateral adnexal torsion in a 13-year-old

adolescent: our experience of a rare case with review of the literature. J Adolesc Health 2005;37(3):244-7.

5. Bisharah M, Tulandi T. Laparoscopic surgery in pregnancy. Clin Obstet Gynecol 2003;46(1):92-7.

6. Nagayama M, Watanabe Y, Okumura A, Amoh Y, Nakashita S, Dodo Y. Fast MR imaging in obstetrics.

Radiographics 2002;22(3):563-80; discussion 580-2.

7. Dohke M, Watanabe Y, Okumura A, Amoh Y, Hayashi T, Yoshizako T, et al. Comprehensive MR imaging of acute gynecologic diseases. Radiographics 2000;20(6):1551-66.

8. Ribic-Pucelj M, Kobal B, Peternelj-Marinsek S. Surgical treatment of adnexal masses in pregnancy: indications, surgical approach and pregnancy outcome. J Reprod Med 2007;52(4):273-9.

9. Born C, Wirth S, Stäbler A, Reiser M. Diagnosis of adnexal torsion in the third trimester of pregnancy: a case report. Abdom Imaging 2004;29(1):123-7.

10. Bassil S, Steinhart U, Donnez J. Successful laparoscopic management of adnexal torsion during week 25 of a twin pregnancy. Hum Reprod 1999;14(3):855-7.

11. Rackow BW, Patrizio P. Successful pregnancy complicated by early and late adnexal torsion after in vitro fertilization. Fertil Steril 2007;87(3):697.e9-12.

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How can Assisted Reproductive Techniques Help Couples Diagnosed with Endometriosis?

According to western figures, couples diagnosed with endometriosis have success rates with assisted reproductive technology (ART) procedures such as in vitro fertilization and embryo transfer (IVF–ET) that are similar to those for couples with other causes of infertility. Success rates for ART procedures vary greatly depending on a woman’s age. Nationally, live birth rates for IVF-ET are approximately 30-35% for women under age 35, 25% from ages 35 to 37, 15–20% from ages 38 to 40, and about 10% between 41 and 42. IVF-ET is the most effective treatment for moderate or severe endometriosis, particularly if surgery fails to restore fertility.

What is Hyperprolactinemia?

Hyperprolactinemia is a condition in which too much prolactin is present in the blood of women who are not pregnant and in men. In women, this causes a decline in the body’s production of progesterone after ovulation which, in turn, can lead to irregular ovulation and infrequent menstruation, cause you to stop menstruating altogether, or cause your breasts to start producing milk, a condition called galactorrhea. Men also can experience galactorrhea. High prolactin levels in men can also lead to impotence, reduced libido and infertility.

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Gastroenterology

Acute Fatty Liver of Pregnancy Jitesh Mafatlal Shah*, Meghana Narendrabhai Mehta**, Hiral Babubhai Viradiya†

Abstract Acute fatty liver of pregnancy (AFLP) is a rare life-threatening complication of pregnancy. It usually occurs in late third trimester.

There is usually severe liver dysfunction with hypofibrinogenemia, hypoalbuminemia, hypocholesterolemia and prolonged clotting times. The most critical component of caring for a woman with AFLP is the delivery of her fetus.

Keywords: Acute fatty liver of pregnancy, jaundice in pregnancy

A

cute fatty liver of pregnancy (AFLP) is a rare life-threatening complication of pregnancy that affects one in 7,000 to one in 16,000 deliveries.1-3

Case report Twenty-six years old Mrs. XYZ was admitted in labor room at 9.30 pm on 19/2/2011 with nine months of amenorrhea and jaundice. She had complaints of yellow-colored sclera and urine since eight days and vomiting since three days. Her last menstrual period (LMP) was 13/5/2010. So, her estimated due date (EDD) was 20/2/2011. She had taken regular antenatal care from private hospital. She was 2nd gravida with previous male child of two years old, delivered by lower segment cesarean section (LSCS) for premature rupture of membranes and failed induction. There was no significant past history.

On examination, she was conscious, co-operative and well-oriented. Temperature was normal, pulse 88/min, blood pressure (BP) -120/80 mmHg, sclera was yellow and respiratory and cardiovascular systems were normal. On abdominal examination, uterus was term size, cephalic presentation, fetal heart sounds normal, uterus was relaxed and no scar tenderness.

On per vaginum, cervix was closed. *Associate Professor **Assistant Professor †Resident Dept. of Obstetrics and Gynecology Surat Municipal Institute of Medical Education and Research (SMIMER) Address for correspondence Dr Jitesh M Shah D- 503, Citizen Heights, Opp. Nanavati Motors Punagam Road, Magob, Surat - 395 010 E-mail: drjiteshshah@gmail.com

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On laboratory test, hemoglobin (Hb) 10.4 g/dl, B+ve, bile salts and pigment were present in urine, serum bilirubin 5.9 mg/dl, prothrombin time (PT) and activated partial thromboplastin time (aPTT) were markedly raised, low serum fibrinogen, elevated fibrin degradation products (FDP), blood sugar 20 mg/dl, raised liver enzymes, markers of hepatitis A, B, C, E normal.

Clinical diagnosis of AFLP was suspected and pregnancy was terminated by LSCS by keeping ready packed cell infusion, fresh frozen plasma (FFP) and cryoprecipitate. Live male child of 2.6 kg was delivered.

Heyman’s stitches were taken to control portpartum hemorrhage (PPH). Abdominal drain was kept. She was shifted to ICU and managed by Critical Care Specialist, Gynecologist, Gastroenterologist and Anesthetist.

On Day 2, abdominal ultrasound showed fatty changes with bright echo texture in liver; ascites was present.

Total eight FFP, 5 cryoprecipitate and six packed cells were infused. She was shifted to ward on 10th day and discharged on Day 16. Mother and baby were normal on follow-up on Day 30.

Discussion Jaundice during pregnancy has many causes such as cholestasis, cholelithiasis, viral hepatitis, pre-eclampsia with or without HELLP syndrome and AFLP. Acute liver failure during pregnancy may be caused by fulminant viral hepatitis, drug-induced hepatic toxicity or AFLP. “Acute yellow atrophy of the liver”, a rare and fatal complication of pregnancy, was first described by Stander and Cadden in 1934.1,2 Later it is termed as

Gastroenterology AFLP of pregnancy. Fatty liver is more common in nulliparas with a male fetus and in 15% of cases there is a multifetal gestation.2 It usually occurs in late third trimester, rare cases have been reported as early as 23 and 26 weeks.1 It is characterized by microvesicular steatosis in the liver.

The precise etiology of AFLP is not known. It is thought to be due to a mitochondrial dysfunction in the oxidation of fatty acids leading to an accumulation in hepatocytes. The infiltration of fatty acids causes acute liver insufficiency. Some, if not all, cases of maternal fatty liver are due to recessively inherited mitochondrial abnormalities of fatty acid oxidation. These defects were first studied in children with Reye-like syndromes and were later found to be associated with microvesicular liver disease in pregnancy. Hallmarks of the disease includes jaundice, coagulopathy and encephalopathy.

Women who develop AFLP are more likely to have a heterozygous long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency.1-4 LCHAD is found on the mitochondrial membrane and is involved in the beta oxidation of long-chain fatty acids. This gene mutation is recessive; therefore, outside of pregnancy under normal physiological conditions, women have normal fatty acid oxidation. However, if the fetus is homozygous for this mutation, it will be unable to oxidize fatty acids. These acids are passed to the mother, who, because of diminished enzyme function, cannot metabolize the additional fatty acids.

Fatty liver is characterized by accumulation of microvesicular fat that literally â&#x20AC;&#x2DC;crowds outâ&#x20AC;&#x2122; normal hepatocytic function. Gross examination shows a small, soft, yellow and greasy liver. Prominent histological abnormalities are swollen hepatocytes with central nuclei and cytoplasm filled with microvesicular fat, periportal sparing, and minimal hepatocellular necrosis. Although the diagnosis of AFLP can be made by liver biopsy, today the diagnosis is usually made clinically. Ultrasound and computed tomography have been used but the sensitivity and specificity of these imaging studies are insufficient to make a definitive diagnosis and false negative results are common.3,5 Symptoms usually develop over several days to weeks and include malaise, anorexia, nausea and vomiting, epigastric pain and progressive jaundice.

In many women, persistent vomiting in late pregnancy is the major symptom. There is usually severe liver dysfunction with hypofibrinogenemia,

hypoalbuminemia, hypocholesterolemia and prolonged clotting time. Hyperbilirubinemia usually is <10 mg/dl and there are modestly elevated serum transaminase levels. Endothelial cell activation and exudation cause hemoconcentration, leukocytosis and thrombocytopenia. Markedly reduced antithrombin III levels have also been described.6 The syndrome continues to progressively worsen. Marked hypoglycemia is common and obvious hepatic encephalopathy, severe coagulopathy and renal failure can occur.7 Fetal death is common with severe disease. Fortunately, delivery arrests rapid deterioration of liver function.

During recovery, over the next week to 10 days, evidence of transient diabetes insipidus is common and presumably due to elevated vasopressinase concentrations. When acute pancreatitis develops, the prognosis is more ominous. Ascites is almost universal.

Coagulopathy can be a dramatic component of fatty liver of pregnancy. Primarily caused by diminished hepatic synthesis, there is also increased procoagulant consumption.

Prior to the 1970s, maternal and fetal mortality rates were reported to be as high as 75 and 85%, respectively.8 However, recent reports suggest maternal mortality 0-10% and fetal mortality 8-25%.1,4 Maternal deaths usually occurs due to coagulopathy, aspiration, renal failure, liver failure and sepsis. Women surviving from AFLP usually recover without any sequele.1,2,4 LCHAD deficient infants are at subsequent risk for hepatic steatosis, hypoglycemia, coagulopathy, coma and death, all of which can be prevented with the use of a special diet and frequent regular feeding. Infants of all women who were affected by AFLP should undergo molecular analysis for LCHAD gene mutations.1 The most critical component of caring for a woman with AFLP is the delivery of her fetus. There is no clear benefit to immediate cesarean delivery versus induction of labor and vaginal delivery with meticulous supportive care. Significant procrastination in effecting delivery may increase the maternal risk of coma, hypoglycemia, renal failure, worsening acidosis and severe hemorrhage. It is preferable to begin a trial of labor induction with close fetal surveillance. Other clinicians recommend cesarean delivery to hasten hepatic healing. With a severe coagulopathy, however, this increases maternal risk. Transfusions with variable amounts of FFP, cryoprecipitate, whole blood, packed red cells and platelets are usually necessary if surgery is performed or if lacerations complicate vaginal delivery Hepatic dysfunction begins to resolve postpartum.

Liver function usually normalizes within a week,

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Gastroenterology and in the interim, intensive medical support may be required. Only rarely is liver transplantation necessary.

AFLP can recur in subsequent pregnancy in a small number of cases.

Conclusion AFLP is an uncommon, life-threatening complication of third trimester with variable presentation. While the natural history of the disease is improvement within 24-48 hours of delivery, it is recommended that patients who are critically ill at the time of presentation, who develop complications, or who continue to deteriorate despite emergency delivery, should be managed in the intensive care unit.

References 1. McNulty J. Acute fatty liver of pregnancy. In: Obst Intensive Care Manual. Tata McGraw-Hill: New Delhi 2005:p.207-15.

2. Bhat RA, Kumar PN, Vyas NM. Liver diseases complicating pregnancy. Obs Gynae Today 2006;XI(8):437-40.

3. Vora KS, Shah VR, Parikh GP. Acute fatty liver of pregnancy: a case report of an uncommon disease. Indian J Crit Care Med 2009;13(1):34-6.

4. Mackillop L, Williamson C. Liver disease in pregnancy.

Postgrad Med J 2010;86(1013):160-4.

5. Usta IM, Barton JR, Amon EA, Gonzalez A, Sibai BM. Acute fatty liver of pregnancy: an experience in the diagnosis and management of fourteen cases. Am J Obstet Gynecol 1994;171(5):1342-7.

6. Castro MA, Goodwin TM, Shaw KJ, Ouzounian JG, McGehee WG. Disseminated intravascular coagulation and antithrombin III depression in acute fatty liver of pregnancy. Am J Obstet Gynecol 1996;174(1 Pt 1): 211-6.

7. Koroshi A, Babameto A. Acute renal failure during acute fatty liver of pregnancy. Nephrol Dial Transplant 2002;17(6):1110-12.

8. Pilego Periz AR, Zavala Soto JO, Rodriguez Ballesteros R. Fatty liver of pregnancy. A report of two cases and medical literature review. Ginecol Obstet Mex 2006;74(3):164-9.

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GI Bleed Survival Higher with Few Transfusions A restrictive transfusion strategy in patients with acute upper gastrointestinal bleeding improved outcomes compared with a liberal approach, results of a randomized trial indicated.

Source: Medpage Today

GI Bleeds: Withholding Transfusions Boosts Survival Withholding transfusions until hemoglobin levels are lower than 7%, rather than 9%, improves overall survival by 45% in patients with acute upper gastrointestinal (GI) bleeding, according to a study published in the January 3 issue of the New England Journal of Medicine.

Source: Medscape

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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 diffculties 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 Arsava

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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.

■■■■

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)

Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

559

Pediatrics

Urinary Iodine Excretion in Urine Samples Among Children in Dahod District, Gujarat JR Damor*, NG Padhiyar**, GL Ninama†

Abstract Aim: To measure urinary iodine excretion level and to assess the iodine level in salt sample. Study design: Cross-sectional study done in 30 randomly selected wards/villages of Dahod district. Materials and method: The IDD survey at the Dahod district was conducted by population proportionate to size (PPS) cluster sampling. A sample of 90 children (45 boys and 45 girls) of age group of 6-12 years from the school was taken. In each cluster, seven urine samples of boys and seven samples of girls were collected and sent to the public health laboratories. From each cluster, salt samples were collected from a minimum of 10 houses and tested with the use of spot salt testing kit for the presence of iodine. Results: The median urinary iodine level was 115 μg/dl. Age-wise distribution of urinary iodine showed that the proportion of children with urinary iodine excretion <100 μg/dl was lowest in the 6-year age group, whereas the highest proportion was in the 10-year age group. Out of 300 salt samples, 207 samples (69%) had >15 ppm (parts per million) iodine; four samples (1.3%) had <15 ppm iodine. This means that the use of iodized salt was 70.3%. Conclusion: The lowest urinary iodine excretion was seen in age group of six years whereas highest urinary iodine excretion was seen in age group of 10 years. In 69%, salt samples had >15 ppm iodine present and in 1.3%, samples had <15 ppm iodine present. Thirty percent of salt samples were noniodized.

Keywords: Iodine deficiency disorders, salt samples, urinary iodine excretion

I

odine is an essential micronutrient with an average daily requirement of 100-150 µg for normal human growth and mental development. Inadequate or poor intake of iodine can result in physical and mental retardation. It affects people of all ages, both sexes and of different socioeconomic backgrounds.

The disorders caused due to deficiency of nutritional iodine in the food or diet are called iodine deficiency disorders (IDDs).1

According to Public Health Standards, an area is declared to be iodine deficient, if 5% or more of schoolgoing children suffer from goiter (enlargement of the thyroid gland situated in the neck). From this point of view, several districts in the state of Gujarat have the problem of iodine deficiency. *Associate Professor **Assistant Professor Dept. of Community Medicine †Assistant Professor Dept. of Microbiology Medical College and SSG Hospital, Vadodara Address for correspondence Dr JR Damor D-27, Akanksha Duplex Opposite Laxmikunj Society Laxmipura Road, Gorwa Vadodara - 390 016, Gujarat E-mail: jivrajdamor@yahoo.co.in

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Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

Major activities of National Iodine Deficiency Disorders Control Programme (NIDDCP) are to conduct surveys to assess the magnitude of the IDDs, monitoring of iodized salt consumption, laboratory monitoring of iodized salt, urinary iodine salt concentration and health education and publicity.1 It is a well-established fact that with the exception of certain types of goiter, IDDs are permanent and incurable. But, these disorders can be easily prevented.

The simplest method to prevent the broad-spectrum of IDDs is to consume iodized salt daily. This is the most effective and inexpensive mode to prevent these disorders. Iodized salt should ensure availability of not <150 µg of iodine per person per day. Since salt is consumed by all every day, the supply of iodized salt will ensure the availability of iodine for normal body function. The average consumption of iodized salt per person per day is about 10 grams. This consumption is in moderate amounts.

The Central Government had issued a notification banning the sale of noniodized salt for direct human consumption in the entire country with effect from 17th May, 2006 under the Prevention of Food Adulteration Act 1954.

Starting with Bharuch district in 1982, the State Government brought the entire state under IDD Control

Pediatrics Programme in a phased manner by the year 1994.

Surveys conducted by the Preventive and Social Medicine (PSM) Dept. of the Govt. Medical Colleges in the state show that IDDs continue to be a health problem in several districts of the state. The high prevalence rate was found in Dangs, Bharuch and Valsad districts.2 The geographical difference reflects the difference in iodine content in drinking water and to some extent in milk.3

PPS systematic sampling. A sample of 90 children (45 boys and 45 Girls) of age group of 6-12 years from the school and in each cluster, seven urine samples of boys and seven samples of girls were collected and sent to the public health laboratories. From each cluster, salt samples were collected from a minimum of 10 houses and tested with the use of spot salt testing kit for the presence of iodine.

Aims and Objectives

Limitations: As it is a cross-sectional study, children who were not present in school at the time of study could not be examined.

ÂÂ

To determine median urinary iodine excretion in samples of school children.

ÂÂ

To assess iodine level in salt samples in households and at retail shops.

ÂÂ

To assess the availability of iodized salt and information, education and communication (IEC) material at public distribution system shop.

Results and Review of Literature The median urinary iodine level is 115 μg/dl. The proportion of samples with urinary iodine <50 μg/dl was found to be 15.6%, which is <20% (Table 1). Thus, this corresponds to the category of adequate iodine nutrition as per WHO guidelines for monitoring for IDDs. The age-wise distribution of urinary iodine showed that the proportion of children with urinary iodine excretion <100 μg/dl was lowest in the 6-year age group, whereas the highest proportion was found in the 10-year age group (Fig. 1, Table 2).

The gender-wise distribution of urinary iodine excretion showed that the proportion of children with urinary iodine excretion >100 μg/dl was almost similar among both the genders (Fig. 2, Table 3). A population based cross-sectional study evaluated the iodine status among

Materials and Method The survey for IDDs at Dahod district was conducted by population proportionate to size (PPS) cluster sampling. Selection of villages/wards by PPS was done from list of villages/wards along with the population from the latest census. The data are available for all districts of the country on CD from Registrar General Office. A sample of 30 villages/wards had to be selected from the district. The method of sampling used was

<100 µg/dl

>100 µg/dl

100% 90% 80%

Percentage

70%

63.2

55.9

53.4

56.7

52.5

60.3

57.6

57.1

36.8

44.1

46.6

43.3

47.5

39.7

42.4

42.9

8

9

10

11

12

Total

60% 50% 40% 30% 20% 10% 0%

6

7

Age (years)

Figure 1. Age-wise distribution of urinary iodine.

Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

561

Pediatrics

Boys

3%

8%

15%

57%

Girls

4%

30%

58%

25%

<20 µg/dl

50-99 µg/dl

<20 µg/dl

50-99 µg/dl

20-49 µg/dl

≥100 µg/dl

20-49 µg/dl

≥100 µg/dl

Figure 2. Gender-wise distribution of urinary iodine excretion.

The gender-wise distribution of urinary iodine excretion shows that the proportion of children with urinary iodine excretion >100 μg/dl was almost similar among both the genders.

primary school children of Dhankuta and Dharan in eastern Nepal. The median urinary iodine excretion in primary school children of Dhankuta and Dharan in eastern Nepal were 157.1 μg/dl and 180.3 μg/dl, respectively. The percentage of salt samples containing iodine >15 ppm (parts per million) was 81.3% in Dhankuta and 89.6% in Dharan.4 Horton et al observed that median urinary iodine excretion was significantly and positively related to household availability of iodized salt for developing countries.5

Table 1. Distribution of Urinary Iodine (n = 400) Urinary iodine level

Number

%

<20 μg/dl

16

3.9%

20-49 μg/dl

48

11.7%

50-99 μg/dl

112

27.3%

<100 μg/dl

176

42.9%

≥100 μg/dl

234

57.1%

Total

410

100%

Table 2. Age-wise Distribution of Urinary Iodine Age (years)

Samples collected

<20 μg/dl

20-49 μg/dl

50-99 μg/dl

<100 µg/dl

≥100 μg/dl

6

57

No. 2

% 3.5

No. 5

% 8.8

No. 14

% 24.6

No. 21

% 36.8

No. 36

% 63.2

7

59

2

3.4

7

11.9

17

28.8

26

44.1

33

55.9

8

58

2

3.4

10

17.2

15

25.9

27

46.6

31

53.4

9

60

1

1.7

5

8.3

20

33.3

26

43.3

34

56.7

10

59

3

5.1

4

6.8

21

35.6

28

47.5

31

52.5

11

58

3

5.2

8

13.8

12

20.7

23

39.7

35

60.3

12

59

3

5.1

9

15.3

13

22.0

25

42.4

34

57.6

Total

410

16

3.9

48

11.7

112

27.3

176

42.9

234

57.1

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Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

Pediatrics Table 3. Gender-wise Distribution of Urinary Iodine Excretion Gender

Samples collected

<20 μg/dl

20-49 μg/dl

50-99 μg/dl

<100 μg/dl

≥100 μg/dl

No.

%

No.

%

No.

%

No.

%

No.

%

Male

207

7

3.4

32

15.5

51

24.6

90

43.5

117

56.5

Female

203

9

4.4

16

7.9

61

30

86

42.3

117

57.6

Total

410

16

3.9

48

11.7

112

27.3

176

42.9

234

57.1

Table 4. Taluka-wise Urinary Iodine Excretion Taluka

Total samples taken

Median urinary iodine excretion (20 μg/dl)

<20 μg/dl

20-49 μg/dl

50-99 μg/dl

≥100 μg/dl

No.

%

No.

%

No.

%

No.

%

Dahod

83

195

0

0

2

2.4

9

10.8

72

86.7

Devgadhbaria

48

150

1

2.1

2

4.2

12

25

33

68.8

Dhanpur

28

70

1

3.6

5

17.9

18

64.3

4

14.3

Fatehpura

55

95

3

5.5

8

14.5

22

40

22

40

Garbada

42

222.5

0

0

0

0

4

9.5

38

90.5

Jhalod

84

85

2

2.4

17

20.2

32

38.1

33

39.3

Limkheda

70

75

9

12.9

14

20

15

21.4

32

45.7

Total

410

115

16

3.9

48

11.7

112

27.3

234

57.1

The median urinary iodine excretion is <100 µg/dl for Dhanpur, Jhalod, Fatehpura and Limkheda and it is >100 µg/dl for the rest of the Talukas.

In a study of more than 2000 school children aged 6-12 years from Rajkot district, India, the median urinary iodine excretion was 110 μg/dl. Iodine level >15 ppm was found in 81% of salt samples tested at household level.6 Urinary iodine excretion level was <100 μg/dl in 42.9% talukas and >100 μg/dl in 57.1% talukas (Table 4). Out of 300 salt samples, 207 samples (69%) had >15 ppm iodine present (Table 5). Iodized salt was available in majority of private shops (88.8%) in the villages (Table 6).

the 6-year age group, whereas the highest proportion was found in the 10-year age group.

Sixty-nine percent contained >15 ppm iodine; 30% of the salt samples were noniodized. There was no genderwise difference in urinary iodine excretion. More than 50% talukas had urinary iodine excretion levels >100 μg/dl.

Recommendations ÂÂ

In Dahod district, Gujarat, 30% salt samples were found to be noniodized; hence, there is a need to create awareness among community people and school children about iodized salt by using IEC materials.

ÂÂ

To make available iodized salt in all public distribution shops.

ÂÂ

Ten percent of private shops had noniodized salts, so there should be a strict implementation of ban on selling of noniodized salt.

Conclusion The proportion of samples with urinary iodine <50 μg/dl was found to be 15.6%, which is <20%.

Thus, this corresponds to the category of adequate iodine nutrition as per WHO guidelines for monitoring for IDDs. The age-wise distribution of urinary iodine showed that the proportion of children with urinary iodine excretion <100 μg/dl was lowest in

Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

563

Pediatrics Table 5. Use of Iodized Salt at Household Level Cluster No.

0 ppm

<15 ppm

≥15 ppm

Total samples

1

2

0

8

10

2

4

0

6

10

3

3

0

7

10

4

8

0

2

10

5

9

1

0

10

6

3

0

7

10

7

10

0

0

10

8

4

0

6

10

9

0

0

10

10

10

10

0

0

10

11

4

0

6

10

12

5

0

5

10

13

0

0

10

10

14

0

0

10

10

15

6

1

3

10

16

0

0

10

10

17

2

0

8

10

18

0

1

9

10

19

5

0

5

10

20

0

1

9

10

21

0

0

10

10

22

0

0

10

10

23

3

0

7

10

24

2

0

8

10

25

0

0

10

10

26

0

0

10

10

27

4

0

6

10

28

0

0

10

10

29

3

0

7

10

30

2

0

8

10

89 (29.7%)

4 (1.3%)

207 (69%)

300

Total

Table 6. Distribution of Private Shop with Respect to Salt Iodization Status Name of Taluka Iodized

Noniodized

Fatehpura

1

0

1

Jhalod

1

0

1

Limkheda

0

1

1

Dahod

3

0

3

Devgadhbaria

1

0

1

Dhanpur

1

0

1

Garbada

1

0

1

Total

8

1

9

2. State Nutrition cell, Government of Gujarat Document on Iodine deficiency Disorders Control Programme: Gujarat, 2008.

3. Pedersen KM, Laurberg P, Nohr S, Jorgensen A, Anderson S. Iodine in drinking water varies by more than 100-fold in Denmark. Importance for iodine content of infant formulas. Eur J Endocrinol 1999;140(5): 400-3.

4. Gelal B, Chaudhri RK, Nepal AK, Sah GS, Lamsal M, Brodie DA, et al. Iodine deficiency disorders among primary school children in eastern Nepal. Indian J Pediatr 2011;78(1):45-8.

5. Horton S, Miloff A. Iodine status and availability of iodized salt: an across-country analysis. Food Nutr Bull 2010;31(2):214‑20.

6. Chudasama RK, Verma PB, Mahajan RG. Iodinenutritional status and goiter prevalence in 6-12 years primary school children of Saurashtra region, India.

World J Pediatr 2010;6(3):233-7.

7. Chudasama R, Patel UV, Patel RR, Verma PH. Iodine deficiency disorders in 6-12 years - old rural primary school children in Kutch District, Gujarat. Indian Pediatr 2010 Nov 30. pii: S097475590900853-1. [Epub ahead of print].

8. Misra S, Kantharia SL, Damor JR. Prevalence of goitre in 6 -12 years school-going children of Panchmahal district in Gujarat, India. Indian J Med Res 2007;126(5):475‑9.

Suggested Reading 1. Revised Policy Guidelines on National Iodine Deficiency Disorders Control Programme. National Rural Health Mission IDD & Nutrition Cell, Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India New Delhi, Revised Edition, October 2006.

9. Biswas AB, Chakraborty I, Das DK, Biswas S, Nandy S, Mitra J. Iodine deficiency disorders among school children of Malda, West Bengal, India. J Health Popul Nutr 2002;20(2):180-3.

10. Kapil U, Sharma TD, Singh P. Iodine status and goiter prevalence after 40 years of salt iodisation in the Kangra District, India. Indian J Pediatr 2007;74(2):135-7.

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Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

Total

Iodized salt was available in majority of private shops (88.8%) in the villages.

Out of 300 salt samples, 207 samples (69%) contained >15 ppm iodine.

564

Salt

orthopedics and rheumatology

What are the Drugs Used for the Treatment of Rheumatoid Arthritis?

VR Joshi

Five main classes of drugs are currently used for the treatment of rheumatoid arthritis (RA) Analgesics These include topical analgesics (e.g. capsaicin or diclofenac) and oral agents e.g. acetaminophen (paracetamol), propoxyphene, tramadol and more potent opioid agents (e.g., oxycodone, hydrocodone, etc.). These drugs provide only analgesia.

Nonsteroidal anti-inflammatory drugs Nonsteroidal anti-inflammatory drugs (NSAIDs) have both analgesic and anti-inflammatory properties and provide relief from pain and stiffness. But, they do not alter the disease course. Selective cyclooxygenase-2 (COX-2) inhibitors may be substituted for nonselective NSAIDs in patients who are at higher risk for adverse gastroduodenal effects events e.g. elderly, past history of peptic ulcer, etc. COX-2 inhibitors may be avoided in patients with or prone to cardiovascular disease.

Glucocorticoids Prednisolone is the most commonly used preparation.

Glucocorticoids suppress inflammation and retard joint damage if used in early RA. Prednisolone may be administered orally, intravenously or by intra-articular injection. Oral dose equivalent total of 7.5 mg/day of prednisolone or less is relatively safe and can be used for extended periods of time. Higher doses though more effective, carry a greater risk of side effects.1 Doses >7.5 mg/day should be used for the shortest time possible.

SAARDs or DMARDs This is a miscellaneous group of drugs termed slowacting antirheumatic drugs (SAARDs) or diseasemodifying antirheumatic drugs (DMARDs). They have the potential to reduce or prevent joint damage, preserve joint integrity and function, reduce health costs Director, Research Consultant Dept. of Rheumatology PD Hinduja National Hospital and Medical Research Centre, Mumbai

and maintain economic productivity.2 The commonly used DMARDs are chloroquine, hydroxychloroquine, sulfasalazine, methotrexate and leflunomide. Less often used are gold salts, D-penicillamine, azathioprine and cyclosporine. Tetracycline derivatives (e.g., doxycycline, minocycline) can inhibit activity of metalloproteinases involved in joint destruction, and can be used as adjunctive therapy in early disease. A 2008 systematic review of 23 head-to-head trials of synthetic or biologic (anticytokine and other) DMARDs concluded that none of the DMARDs was more effective or safer than another.3 These can be used as monotherapy or in combination.

Biologicals

Anticytokine Therapies Anticytokine agents were the first biologicals introduced to treat RA. Their use is based upon increasing understanding of the biology of RA. Presently available in India are anti-TNF-a agents etanercept, and infliximab, IL-6 blocker tocilizumab and the IL-1 receptor antagonist, anakinra.

Other Biologic Agents Examples of other biologic response modifiers include abatacept (CTLA4-Ig) and the b-cell depleting monoclonal antibody, rituximab. Most biologicals, while effective, carry an increased risk of opportunistic infections.

References 1. Gotzsche PC, Johansen HK. Short-term low-dose corticosteroids vs placebo and nonsteroidal antiinflammatory drugs in rheumatoid arthritis. Cochrane Database Syst Rev 2003;(1):CD000189.

2. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 Update.

Arthritis Rheum 2002;46(2):328-46.

3. Donahue KE, Gartlehner G, Jonas DE, et al. Systematic review: comparative effectiveness and harms of diseasemodifying medications for rheumatoid arthritis. Ann Intern Med 2008;148(2):124-34.

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565

Medilaw

Can a Cardiologist be Liable if the Patient Develops Intracranial Bleed after Angiography?

Dr KK Aggarwal

T

he Delhi Medical Council examined a complaint of PKD forwarded by Directorate of Health Services, Govt. of NCT of Delhi, alleging medical negligence on the part of a hospital Cardiologist in the treatment administered to complainantâ&#x20AC;&#x2122;s wife.

The Delhi Medical Council perused the complaint, reply of the hospital and medical records of the hospital.

The patient with complaints of chest heaviness and pain in left arm was admitted in the said hospital.

The patient had history of hypertension, had underwent primary angioplasty and coronary stenting for acute anterior myocardial infarction two years ago at some other hospital.

A drug-eluting stent was deployed in ostial, proximal left anterior descending (LAD) artery. Patient had sustained an intracranial hemorrhage (ICH) in Assam, confirmed by brain CT and for which she was managed conservatively over there. Patient underwent a check coronary angiography in the current admission (left femoral route) under informed consent, which revealed patent stent in ostial proximal LAD artery and no other coronary artery disease. Patient did not receive any antiplatelet drug immediately before, during or after the procedure.

Patient, however, developed an intracranial bleed soon after, which was confirmed by CT scan and necessitated neurosurgical intervention. CT head suggestive of post-fossa ICH with ventricular dilatation. Thereafter, immediate neurosurgical advice was taken. Post-fossa craniotomy for evacuation of cerebellar ICH was done.

Next day, under GA, left ventriculoperitonal (VP) shunt was done. There was gradual improvement in sensorium and overall condition of the patient during hospital stay and at the time of discharge, patient was hemodynamically stable. Patient was discharged with tracheostomy tube and Ryleâ&#x20AC;&#x2122;s tube subsequently.

The Delhi Medical Council observed that generally during angiography only low-dose heparin is given, which is mandatory and which generally does not cause intracranial bleed.

Patient may have suffered from intracranial bleed even if she had not undergone angiogram. It is further observed that the condition resulting from intracranial bleed was treated as per accepted professional practices in such cases.

Prima facie no case of medical negligence is made out against the doctors in the treatment administered to the patient.

Source: DMC/DC/F.14/Comp.823/2011/-

Senior Physician and Cardiologist Moolchand Medcity New Delhi

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Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

Medifinance

Asset Protection

A

sset protection is a field of law that deals with structuring asset and business ownership to make it either impossible or at least very expensive for a plaintiff to reach the assets of a defendant. If a doctor’s personal assets are impossible or too difficult to collect against, a plaintiff’s attorney will either not file the lawsuit in the first place, or will be a lot more willing to settle on terms favorable to the doctor.

Asset protection does not deal with secrecy or hiding assets because an intelligent and determined creditor will always be able to unearth hidden assets.

A properly structured asset protection plan would utilize commonly used structures such as trusts and limited liability companies in a manner that would legally, ethically and effectively shield a doctor’s assets from any lawsuit and any creditor. A doctor, who has an asset protection plan in place, will be able to sleep soundly, knowing that whether he is hit with a malpractice claim or is involved in an automobile accident, his assets will be safe and unreachable.

Once the plaintiff obtains a legal judgment against the doctor in a malpractice lawsuit, the plaintiff becomes a creditor of the doctor, and the doctor becomes a debtor.

The plaintiff can now use the judgment to collect and attach almost any and every personal and business asset of the doctor. Consequently, the purpose of all asset protection planning is to remove the debtor-doctor from legal ownership of his assets, while retaining the doctor’s control over and beneficial enjoyment of the assets.

There is no magical asset protection strategy. Depending on the assets owned by the doctor, the aggressiveness of the plaintiff and certain other factors different structures will be used to protect a doctor’s assets. The timing of the planning is important as well. While it is always possible to engage in asset protection planning, even after a lawsuit has been filed, the planning will be a lot more effective and simpler when implemented before a malpractice claim arises.

Personal Residence Personal residences represent the bulk of many people’s fortunes, and have great sentimental value.

A doctor’s personal residence is thus the most important asset which needs to be protected from creditor claims.

Creditors do not pursue the residence itself, but the equity in the residence that can be converted into money through a foreclosure sale of the residence.

There are two equity stripping techniques.

One way to strip out the equity is by obtaining a bank loan. Even if, we assume that a bank would lend an amount sufficient to eliminate 100% of the equity, the cost of this asset protection technique is staggering.

A ` 1 crore loan bearing a 10% interest rate, costs ` 10 lakhs/year. Another way to strip out the equity is to encumber the residence by recording a deed of trust in favor of a friend. This avoids the carrying costs of an actual bank loan. With this technique it is important to know the intelligence and the aggressiveness of the creditor. Some creditors may stop trying to collect when they realize that there is no equity in the residence.

Others may dig deeper, and if the debtor cannot substantiate the transaction as an actual loan, the deed of trust will be set aside by a court as a sham.

In addition to stripping out the equity, it is also possible to protect the residence by transferring ownership but retaining control and beneficial enjoyment. This can be done in a number of ways.

An arm’s-length cash sale is the best way to protect the residence (and the equity in the residence) because it is much easier to protect liquid assets than real estate.

While this technique affords the doctor, the best possible protection for his home, it is also the most radical and may result in additional income taxes. This technique is usually reserved for doctors facing very determined plaintiffs, or doctors facing government agencies.

An alternative to an outright sale is the sale and leaseback of the residence to a friendly third-party on a deferred installment note. This allows the doctor to transfer the ownership of the residence without having to move out. This structure works only so long as the doctor can establish the legitimacy and the arm’s-length nature of the sale.

The contribution of the residence to a limited liability company (LLC) or a limited partnership may be another way to protect the personal residence. The protection

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567

Medifinance afforded by LLCs and limited partnerships is derived from the concept of the charging order protection, addressed in more detail later. While the charging order protection is generally powerful, its usefulness may not extend to personal residences.

The final available alternative to protect a personal residence is by transferring the ownership of the residence to a trust commonly referred to as a personal residence trust (PRT). This is a trust established initially for the benefit of the doctor and the doctor’s spouse and later for the benefit of the doctor’s children or other beneficiaries. Because, the trust is irrevocable it is treated as the owner of the residence, although the doctor retains full control over his residence by appointing a friendly trustee. The trust allows the doctor to sell the existing home, buy a new home and refinance. In practice, PRTs have proven to be a simple and an extremely effective way of protecting a personal residence.

Rental Real Estate and Other Nonliquid Investments Some of the techniques discussed above may be used to protect rental real estate, businesses, intellectual property, collectibles or other valuable assets. These assets may be transferred into irrevocable trusts, sold for cash or on installment basis or encumbered.

However, for assets other than a personal residence there is a much better and simpler way to achieve as much or more protection.

Assets owned by a doctor through an LLC or a limited partnership are not deemed owned by the doctor because these legal entities have their own separate

legal existence. If a doctor transfers the ownership of his apartment building into an LLC, the doctor will no longer be treated as the owner of the apartment building. He will now be treated as the owner of a membership interest in the LLC. This means that a plaintiff suing the doctor will no longer be able to reach the apartment building directly, he would no have to pursue the doctor’s interest in the LLC. Forcing the plaintiff to pursue an ownership interest in an LLC or in a limited partnership is a lot more advantageous for the doctor because interests in LLCs and limited partnerships are not subject to attachment by a plaintiff. This is known as the charging order protection. The charging order protection limits a plaintiff’s remedy to a lien against the distributions from the legal entity, without conferring on the plaintiff any voting or management rights. Because, the doctor will remain in control of the entity and can defer distributions, the plaintiff will have no way of enforcing the judgment against the doctor’s LLC or limited partnership interests or the assets owned by these entities. As a practical matter, LLCs and limited partnerships create a formidable obstacle to the creditor’s collection efforts and usually force the creditor to drop his collection efforts or to settle.

These entities should be considered by doctors for all valuable assets with the exception of their personal residence.

Liquid Assets Liquid assets may be protected through many of the techniques described above, including LLCs, limited partnerships and irrevocable trusts.

■■■■

Some Useful Tips ÂÂ

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.

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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.

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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.

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

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Humor

Laugh-A-While

Chronic Laziness

The subtle truth

The man told his doctor that he wasn’t able to do all the things around the house that he used to do. When the examination was complete, he said, “Now, Doc, I can take it. Tell me in plain English what is wrong with me?” “Well, in plain English,” the doctor replied, “you’re just lazy.” “Okay,” said the man. “Now give me the medical term so I can tell my wife.”

“Is this a really healthy place?” asked a tourist to a local man.” Yes, of course, “the man replied.

“When I came here I couldn’t say a word. I had hardly any hair on my head, I didn’t have the strength to walk across a room, and I had to be lifted out of bed.” “Gosh, this is truly a healthy place. How long have you been here?” “I was born here“ replied the local man.

Mr. Wrong ……!!

Mary was shortsighted, to vain to wear glasses was determined to get married. She finally found herself a husband, and went off on a honeymoon with him. When Mary returned her mother gave a shriek, dashed to the telephone and rang up an oculist. “Doctor”, she gasped,“ You’ve got to come over here right away. It’s an emergency.

My daughter Mary has always refused to wear glasses and now she is back from her honeymoon and...” “Madam,” interrupted the doctor, “please control yourself. Ask your daughter to come and see me. No matter how bad her eyes are, it can’t be that much of an emergency.”

“Oh, no!“ said the mother. “Well, this fellow she’s got with isn’t the same one she went on the honeymoon with!”

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Forthcoming events

Forthcoming Events Website: www.ficecd.com

International Conference on Digestive Disorders

Organized by: Centre for Early Childhood Development and Research (CECDR), Jamia Millia Islamia, New Delhi

Date: 23-24 February. 2013 Venue: Hotel Bliss, Tirupathi, Andhra Pradesh, India E-mail: iapenmeet@gmail.com

Annual Conference of Indian Society of Electrocardiology

Website: www.iapen.co.in/iapen-conference.html

Date: 4-7 April, 2013 Venue: Gurgaon, India

2nd World Congress on Ga-68 (Generators and Novel Radiopharmaceuticals), Molecular Imaging (PET/CT), Targeted RadionuclideTherapy and Dosimetry: On the Way to Personalized Medicine Date: 28 February - 02 March, 2013 Venue: Bhargava Auditorium PGIMER Chandigarh, India Website: www.2ndworldcongress-ga-68.de

19th Annual Congress of the Indian Society of Critical Care Medicine and International Critical Care Congress 2013 Date: 1-6 March, 2013 Venue: Science City, Kolkata, India Email: secretariat@criticare2013kolkata.org Website: www.criticare2013kolkata.org

Website: www.iseindia.org

6th Study Camp on ‘Mind-Body Medicine and Beyond’ Sri Aurobindo Ashram - Delhi Branch will organize the 6th Study Camp on ‘Mind-Body Medicine and Beyond’ for doctors, medical students and other health professionals at its Nainital Centre (Van Nivas) from June 8-14, 2013. The camp, consisting of lectures, practice, and participatory and experiential sessions, will help the participants get better, feel better, and bring elements of mind-body medicine into their practice. The camp will be conducted by Prof. Ramesh Bijlani, M.D., former Professor, AIIMS, founder of the Mind-Body Medicine Clinic at AIIMS, and the author of Back to Health through Yoga, Eating Wisely and Well and Essays on Yoga. For more details, send an e-mail to the Ashram (aurobindo@vsnl.com) or to Dr. Bijlani (rambij@gmail.com).

First International Conference on Early Childhood Development

28th Congress and 49th Council meeting Confederation of Medical Associations of Asia and Oceania (CMAAO)

Date: 21-22 March, 2013

Date: 12th-14th September, 2013

Venue: New Delhi, India

Venue: Hotel Shangri-La, Ashok Road, New Delhi ■■■■

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eMedinewS Inspiration

Alexander The Great’s Last 3 Wishes Dr 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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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.

News of the month

Robotic Surgery Saves Life of Critically Ill Supersuper Obese Patient Vivek Bindal

B

ariatric surgery proves to be a boon for a critically ill 48-year-old female (on ventilator support for respiratory arrest because of super-super obesity) who underwent successful Robotic Bariatric Surgery at Institute of Minimal Access, Metabolic and Bariatric Surgery, Sir Ganga Ram Hospital.

She was planned for a Robotic Bariatric Surgery as robot helps access the inaccessible areas of abdomen.

Robot gives 3 dimensional high-definition vision, seven degrees of freedom (endowristed instruments), motion scaling and tremor filtration, which makes the surgery more precise with less blood loss.

The lady came to casualty of Sir Ganga Ram Hospital with severe dyspnea, obesity hypoventilation syndrome and was not able to maintain her oxygen saturation. She had a weight of 193 kg and a body mass index (BMI) of 84.64 kg/m2. Because of her super-super obesity, she had a severe hypoventilation and was not even able to breathe. She was immediately shifted to ICU, intubated and started on ventilator support. A team of Bariatric Surgeons led by Dr Parveen Bhatia, Anesthetists, Chest Physicians, Cardiologists, and Critical Care Physicians managed the patient and planned for bariatric surgery as that was the only life saving option available for the patient.

With the support of an excellent anesthesia team led

by Dr Jayashree Sood and Dr Anil Jain, the patient was taken up for Robotic Sleeve Gastrectomy. The patient underwent a successful surgery with minimal blood loss. The patient was taken off ventilator the day after the surgery and was discharged after a week in stable condition. She has lost 65 kgs in last three months and is leading an active lifestyle.

Bariatric surgery in such a patient was a very high-risk procedure because of very high BMI (85), very heavy liver with limited working space, anesthesia-related complications and the critically ill status.

In super obese patients, the challenge is a very limited working space because of heavy liver and lots of fat tissue/omentum. Robotic technology gives an advantage in these patients by giving better vision, more degrees of freedom (the endowrist) and the intuitive technology. We want to give the best clinical outcomes to our patients and thus advice robotic surgery.

Dr Vivek Bindal MRCS (Glas), MS (Surg), DNB (Surg), FNB (Minimal Access Surgery), FMAS, FRS, Consultant Laparoscopic, Bariatric and Robotic Surgeon Institute of Minimal Access, Metabolic and Bariatric Surgery (iMAS) and Institute of Robotic Surgery (IRS), Sir Ganga Ram Hospital Rajinder Nagar, New Delhi

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eMedi Quiz

Quiz Time Q1. Treatment with hemodialysis is ordered for a client and an external shunt is created. Which nursing action would be of highest priority with regard to the external shunt?

A. Heparinize it daily.

B. Avoid taking blood pressure measurements or blood samples from the affected arm.

C. Change the Silastic tube daily.

D. Instruct the client not to use the affected arm.

Q2. Roxy is admitted to the hospital with a possible diagnosis of appendicitis. On physical examination, the nurse should be looking for tenderness on palpation at McBurneyâ&#x20AC;&#x2122;s point, which is located in the A. Left lower quadrant B. Left upper quadrant

C. Telling him to resume his previous daily activities without limitations D. Recommending him to drink eight glasses of water daily Q4. The nurse applies mafenide acetate (Sulfamylon cream) to Clara, who has second and third degree burns on the right upper and lower extremities, as ordered by the physician. This medication will: A. Inhibit bacterial growth B. Relieve pain from the burn C. Prevent scar tissue formation D. Provide chemical debridement Q5. Clara, a burn client, receives a temporary heterograft (pig skin) on some of her burns. These grafts will:

C. Right lower quadrant D. Right upper quadrant Q3. Mr. has undergone surgical repair of his inguinal hernia. Discharge teaching should include A. Telling him to avoid heavy lifting for 4 to 6 weeks B. Instructing him to have a soft bland diet for two weeks

A. Debride necrotic epithelium B. Be sutured in place for better adherence C. Relieve pain and promote rapid epithelialization D. Frequently be used concurrently with topical antimicrobials.

Photo Quiz

1. What is the diagnosis?

2. What is the diagnosis?

Send your answers to the Editor-Indian Journal of Clinical Practice.

E-mail: editorial@ijcp.com The correct answers will be published in the next issue of IJCP.

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3. What is the name of this syndrome?

lighter reading

Lighter Side of Medicine Make Sure

Quote

During Medical Practice A patient on ACE inhibitor developed angioneurotic edema

“In Life, in every moment, something new happens; something that you never expected, something that you were waiting from a long while to happen and something you were expecting to happen.” −Dr GM Singh

Oh my God! Why was ACE inhibitor continued?

1. AALLLL 2. belt hitting 3. poFISHnd ©IJCP Academy

4. you cont ol r

Make sure that patients on ACE inhibitors are advised to watch for symptoms of urticaria and stop the drug immediately in case swelling of lip, face or tongue develops.

KK Aggarwal

Dr. Good & Dr. Bad evaluation.

©IJCP Academy

Go for Tissue Doppler Echo test

Doppler Echo Test for evaluation of diastolic functions.

Dr KK Aggarwal

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gegs gges

ILLUSION

Situation: A patient with heart failure came for cardiac

Lesson: A patient with heart failure must go for Tissue

segg

6. k k c c u u t t s s word word word word

Br J Clin Pharmacol 1999;48(6):861–5.

Go for Echo test

5. gesg

1. All in all. 2. Hitting below the belt. 3. Big fish in a little pond. 4. You are out of control. 5. Scrambled eggs.

6. Too stuck up for words.

Mind Trivia

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.

6. Suggestions for reviewers (name and postal address)

Articles in Books

2.____________ 2.________________

Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.

3.____________ 3.________________

4.____________ 4.________________

Tables –

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

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

–

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

Indian Journal of Clinical Practice, Vol. 23, No. 9 February 2013

Indian 1.____________Foreign 1.________________

7. All authors’ signatures________________________ 8.

Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________

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

Dr KK Aggarwal

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

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

Padma Shri & Dr BC Roy National Awardee

Dr SM Rajendran