Indian Journal of Clinical Practice february 2016 by IJCP

Indexed with IndMED

ISSN 0971-0876

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Volume 26, Number 9

February 2016, Pages 801â&#x20AC;&#x201C;900

Peer Reviewed Journal

yy American Family Physician yy Cardiology yy Community Medicine yy Dermatology yy Diabetology yy Endocrinology yy Internal Medicine yy Obstetrics and Gynecology

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

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IJCP Editorial Board Obstetrics and Gynaecology Dr Alka Kriplani Dr Thankam Verma, Dr Kamala Selvaraj Cardiology Dr Praveen Chandra, Dr SK Parashar Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses, Dr Sidhartha Das Dr A Ramachandran, Dr Samith A Shetty ENT Dr Jasveer Singh Dr Chanchal Pal Dentistry Dr KMK Masthan Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar Dr Rajiv Khosla Dermatology Dr Hasmukh J Shroff Dr Pasricha Dr Koushik Lahiri Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan Dr Vineet Suri Journal of Applied Medicine & Surgery Dr SM Rajendran, Dr Jayakar Thomas Orthopedics Dr J Maheshwari

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Volume 26, Number 9, February 2016 FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF

805 Protection of Children from Sexual Offences Act

AMERICAN FAMILY PHYSICIAN

807 Diagnosis and Management of Foodborne Ιllness

Timothy L. Switaj, Kelly J. Winter, Scott R. Christensen

813 Practice Guidelines 815 Photo Quiz CARDIOLOGY

819 Prescribing Pattern of Antihypertensive Drugs in a Tertiary Care Teaching Hospital in Lucknow Region

Vijay K Yadav, Shyam Sunder Keshari, Krishna Pandey

COMMUNITY MEDICINE

822 Study of Prevalence of Severe Acute Malnutrition in Children Under 5 Years in Chatra Area of Serampore Municipality Under the State of West Bengal

Pradip Kumar Das

DERMATOLOGY

827 Clinical Survey with Dermatologists on Benefits and Safety of Minoxidil 10%

Sujeet N Charugulla, Amisha Ahuja

DIABETOLOGY

832 Diabetic Ketoacidosis: Clinical Characteristics and Precipitating Factors in a Tertiary Care Hospital, Bareilly, Uttar Pradesh

Amit Varshney, Rohit Singh, Tanvi Sood, P Nigam

ENDOCRINOLOGY

836 Thyroid, Obesity and Thyromimetic Compounds

Pragati Kapoor, Pankaj Kumar, AK Kapoor

INTERNAL MEDICINE

846 Detection of Pulmonary Nocardiosis Mimicking Tuberculosis: Role of Sputum Microscopy

Shashi Chopra, Shaveta Dhiman, Gomty Mahajan, Silky Mahajan

853 Self-injected “Harpic” Poisoning: A Case Report

Mantu Jain, Ritesh Runu, Manish Kumar, Santosh Kumar

856 Can Snake Bite Present as Jaundice - It Can!

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

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KK Aggarwal

Manish N Mehta, Hemanth K Acharya, AC Tanna, Jemima Bhaskar, Pratik M Vora

OBSTETRICS AND GYNECOLOGY

858 Enlarged Ovaries Following IVF/ICSI as an Etiology of Obstructive Uropathy Resulting in Acute Renal Failure: A Case Report

Pratibha Vishwakarma, Priya Mohan, Kundavi Shankar, Thangam R Varma

OBSTETRICS AND GYNECOLOGY

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

861 Neurocysticercosis - A Cause of Convulsions During Pregnancy: A Case Report

Jaya Kundan Gedam, Minal Bhalerao

ONCOLOGY

864 Malignant Peripheral Nerve Sheath Tumor Arising in a Neurofibroma: A Case Report

Printed at New Edge Communications Pvt. Ltd., New Delhi E-mail: edgecommunication@gmail.com

Monica Kumbhat M, Leena Dennis Joseph, Archana B, Arulappan

PEDIATRICS

867 Chromosome 3p Duplication: A Rare Chromosomal Anomaly

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.

Braja Kishore Behera, Rishav Raj, Sailabala Shaw, Mitali Mahapatra

870 Vital Nutritional Requirements in the Growing Years

Shweta Pathak

EXPERT VIEW

Editorial Policies

875 Are Î˛-blockers Contraindicated in Patients with Congestive Heart Failure?

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MEDILAW

877 Medical Negligence and Internationally Accepted Never Events

KK Aggarwal

CONFERENCE UPDATE

880 53rd Annual Conference of Indian Academy of Pediatrics (PEDICON 2016) 883 46th Annual Conference of The Indian Society of Nephrology (ISNCON 2015) 886 56th Annual Conference of Indian Society of Gastroenterology (ISGCON 2015) AROUND THE GLOBE

889 News and Views INSPIRATIONAL STORY

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894 Determination and Persistence LIGHTER READING

895 Lighter Side of Medicine

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FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF

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Protection of Children from Sexual Offences Act ÂÂ

Child means any one below the age of 18 years.

ÂÂ

The act applies to all cases of sexual assault to a child.

ÂÂ

Any sexual activity with a child (boy or girl) is a crime.

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The act defines sexual offences against children and prescribes the punishment for the same.

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Sexual offences can be penetrative sexual assault (Sec 3), sexual assault (nonpenetrative - Sec 7), sexual harassment (Sec 11), and use of a child for pornography (Sec 13).

ÂÂ

A person commits penetrative sexual assault of a child below 18 years if he inserts his penis or any other object into the vagina, anus, urethra or any part of the body of the child, or causes any other person to do so to the child, or applies his mouth to any such part of the body of the child.

ÂÂ

Penetrative sexual assault of a child below 18 years is punishable with imprisonment of a minimum of 7 years, up to imprisonment for life and is also liable to fine.

ÂÂ

If a person touches the penis, vagina, anus, breast or any other part of the body of a child below 18 years of age with sexual intent, or causes any other person to do so, or causes the child to do so to him or any other person, he is said to commit (non-penetrative) sexual assault.

ÂÂ

Nonpenetrative sexual assault of a child below 18 years is punishable with imprisonment for 3-5 years and is also liable to fine.

ÂÂ

Sexual assault and penetrative sexual assault of a child below 18 years of age are considered to be aggravated when committed by a person in a position of trust or authority such as police/ army/security personnel, public servants or family member, persons in management or staff of educational, medical or religious institution or persons in management or staff of jail, remand

home, protection home observation home, or any other place of custody or care and protection. ÂÂ

Aggravated penetrative sexual assault of a child below 18 years is punishable with rigorous imprisonment of a minimum of 10 years, up to imprisonment for life and is also liable to fine.

ÂÂ

Aggravated sexual assault of a child below 18 years is punishable with imprisonment for 5-7 years and is also liable to fine.

ÂÂ

A person commits sexual harassment when, with sexual intent, in respect of child below 18 years of age, he utters a word or makes a sound or a gesture or exhibits a part of his body or any other object or makes the child exhibit a part of his body, or shows an object or any form of media to the child for pornographic purposes, or repeatedly follows the child or watches him directly or through digital, electronic or other means, or threatens to use any part of the body of the child or the involvement of the child in a sexual act in any form of media, or entices the child for pornographic purposes or gives the child gratification for this.

ÂÂ

Sexual harassment of a child below 18 years of age is punishable with imprisonment of 3 years and is also liable to fine.

ÂÂ

A person commits the offence of pornography if he uses a child below 18 years of age in any form of media for sexual gratification. This includes the representation of the sexual organs of the child, images showing the child in real or simulated sexual acts, or the indecent or obscene representation of the child.

ÂÂ

Use of a child below 18 years of age for pornographic purposes is punishable with imprisonment of 5 years and is also liable to fine.

Indian Journal of Clinical Practice, Vol. 26, No. 9, February 2016

805

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AMERICAN FAMILY PHYSICIAN

Diagnosis and Management of Foodborne Ιllness TIMOTHY L. SWITAJ, KELLY J. WINTER, SCOTT R. CHRISTENSEN

ABSTRACT The Centers for Disease Control and Prevention estimates that each year, one in six Americans will experience a foodborne illness. The most common causes in the United States are viruses, such as norovirus; bacteria, such as Salmonella, Escherichia coli, Campylobacter, and Listeria; and parasites, such as Toxoplasma gondii and Giardia. Resources are available to educate consumers on food recalls and proper handling, storage, and cooking of foods. Diagnosis and management of a foodborne illness are based on the history and physical examination. Common symptoms of foodborne illnesses include vomiting, diarrhea (with or without blood), fever, abdominal cramping, headache, dehydration, myalgia, and arthralgias. Definitive diagnosis can be made only through stool culture or more advanced laboratory testing. However, these results should not delay empiric treatment if a foodborne illness is suspected. Empiric treatment should focus on symptom management, rehydration if the patient is clinically dehydrated, and antibiotic therapy. Foodborne illnesses should be reported to local and state health agencies; reporting requirements vary among states.

Keywords: Centers for Disease Control and Prevention, foodborne illness, diagnosis, empiric treatment, symptom management, rehydration

oodborne illness can be caused by a multitude of microorganisms such as viruses, bacteria, and parasites. Foodborne illness is a worldwide problem, and U.S. outbreaks often garner media attention and result in food recalls. Foodborne illnesses are becoming a greater challenge because of new and emerging microorganisms and toxins, the growth of antibiotic resistance, increasing food contamination caused by new environments and methods of food production, and an increase in multistate outbreaks.1 There are more than 250 identified pathogens that cause foodborne illness.

The Centers for Disease Control and Prevention (CDC) esti mates that one in six Americans (approxi mately 48 million) will become sick from a foodborne pathogen each year, resulting in 128,000 hospitalizations and 3,000 deaths.2 Most foodborne illnesses, hospitalizations, and deaths are caused by one of eight com mon pathogens: norovirus, nontyphoidal Salmonella, Clostridium perfringens, Campy lobacter, Staphylococcus aureus, Toxoplasma gondii, Listeria monocytogenes, and

TIMOTHY L. SWITAJ, MD, is deputy commander for clinical services at Reynolds Army Community Hospital, Fort Sill, Okla. KELLY J. WINTER, DO, is a staff family physician at William Beaumont Army Medical Center, Fort Bliss, Tex. SCOTT R. CHRISTENSEN, MD, is officer-in-charge at the family medicine clinic #1 at Reynolds Army Community Hospital. Source: Adapted from Am Fam Physician. 2015;92(5):358-365.

Shiga toxin—producing Escherichia coli2 (Table 13). E. coli is commonly divided into two broad types, Shiga toxin–producing—of which E. coli O157:H7 is the best studied—and non-Shiga toxin—producing, which includes enteropathogenic, enteroinvasive, enteroaggregative, and diffusely adherent E. coli. New pathogens emerge constantly, whereas others decrease in significance or disappear altogether. Predicting the emergence or disappearance of specific pathogens—other than in the setting of an identified outbreak—is difficult and has not significantly prevented or limited foodborne illnesses. PREVENTION Prevention is the first step in combatting foodborne illnesses. Consumer informa tion on food safety is available from the CDC at http:// www.cdc.gov/foodsafety/facts.html or from the U.S. Food and Drug Administration at http:// www.fda. gov/Food/FoodborneIllnessContaminants/ FoodborneIllnessesNeedToKnow/default.htm or http:// www.foodsafety.gov, or by calling (888) SAFEFOOD ([888] 723-3366). Guidelines for safely handling and preparing food should be followed regardless of the setting in which food is consumed. Although these recommendations have been shown to reduce the risk of foodborne illness in the United States, the risk increases with travel.

Indian Journal of Clinical Practice, Vol. 26, No. 9, February 2016

807

AMERICAN FAMILY PHYSICIAN DIAGNOSIS

History Foodborne illness can have various presentations, rang ing from clinically mild illness that requires only outpa tient care to severe illness that requires hospitalization. Most foodborne illnesses are associated with vomiting or diarrhea (more than three loose stools in 24 hours). Other common symptoms include fever, bloody diarrhea, abdominal cramping, headache, dehydration, myalgia, and arthralgias.4 Patients may have several symptoms or only one. The history is the most important step in evaluating a patient with diarrheal illness (Table 2).5 None of the symptoms of foodborne illness is specific, so the clinician must consider the history, epidemiologic features, and objective findings to make an accurate diagnosis. Symptoms and time of onset can narrow the differential diagnosis (Table 3) and help identify a likely pathogen.4 Early onset of vomiting and diarrhea results from ingestion of preformed toxins, most often S. aureus or Bacillus cereus. Diarrhea within 24 hours of ingestion is most likely caused by C. perfringens or B. cereus. Diarrhea within 24 to 48 hours of ingestion is most often caused by Campylobacter jejuni in individual

cases or Salmonella in outbreaks.4 Foodborne illnesses commonly associated with fever are caused by Vibrio cholerae non-O1, Shigella, and C. jejuni (Table 4). Enterotoxins in the small bowel caused by E. coli, C. perfringens, and viruses produce excessive secretions of fluids and electrolytes that overwhelm the large bowel; therefore, they are typically associated with watery diarrhea. Bloody diarrhea with abdominal pain should prompt consideration of inflammatory damage to the intestinal mucosa or an infection (e.g., C. jejuni, Salmonella enteritidis, enteroinvasive E. coli) affecting the large bowel.

Physical Examination The physical examination can help narrow the differential diagnosis, and vital signs can help determine the severity of volume depletion. Orthostatic pulse and blood pressure changes should be noted, and a basic general physical examination should be performed, with assessment of skin turgor, the abdomen, mucous membranes, and mental status.5

Ancillary Testing Watchful waiting is often the most appropriate option in the initial diagnosis and management of foodborne illness; ancillary testing is usually not necessary.

Table 2. Clues to the Differential Diagnosis of Diarrhea Findings from patient history

Comment

Acute abdominal pain, fever, and vomiting

Together, these symptoms raise suspicion for infectious diarrhea

Dietary factors

Recent changes in diet and ingestion of foods included in recent recalls or undercooked foods should raise suspicion for foodborne illness

Duration of symptoms

Longer duration raises concern for dehydration

Employment history

Persons who work at child care centers or in close contact with others are at risk of viral diarrhea

Exposure to other persons with diarrhea

Cross-contamination and transmission of pathogens are possible; may help narrow differential if cause is known in the other person

Hospitalization or nursing home admission

Raises suspicion for Clostridium difficile infection

Immunocompromise

Raises suspicion for atypical causes of diarrhea

Medical history

Can help determine possible comorbidities that suggest a cause

Recent antibiotic use

Raises suspicion for C. difficile infection

Stool characteristics (bloody, foul smelling, watery)

Bloody diarrhea raises suspicion for Salmonella, Shigella, or enterohemorrhagic Escherichia coli infection (or mesenteric ischemia in at risk populations) Foul-smelling stools in patients with recent hospitalization or antibiotic use raise suspicion for C. difficile or Giardia infection Watery stools raise suspicion for viral cause or Giardia infection

Travel history

Travel to foreign countries, especially non-Western countries, should raise suspicion for infectious diarrhea

Information from reference 5.

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Indian Journal of Clinical Practice, Vol. 26, No. 9, February 2016

AMERICAN FAMILY PHYSICIAN Table 3. Differential Diagnosis of Foodborne Ιllness Diagnosis

Common presenting symptoms

Diagnostic studies

Acute cholecystitis

Decreased appetite, fever, jaundice, CBC, C-reactive protein level, liver function testing, right uppernausea, right upper-quadrant abdominal quadrant ultrasonography pain, vomiting

Acute hepatitis

Abdominal pain, arthralgias, arthritis, fever, Ammonia levels, hepatitis panel, liver biopsy, liver function testing, jaundice, malaise, nausea, vomiting ultrasonography

Diverticular disease

Fever, left lower-quadrant abdominal pain

Inflammatory bowel disease

Abdominal pain, chronic diarrhea, occasional Colonoscopy with tissue biopsy, negative stool culture bloody diarrhea, weight loss

Mesenteric ischemia

Abdominal pain, diarrhea, hematochezia, Abdominal CT, arterial blood gas levels, blood chemistry panel, melena, weight loss CBC, colonoscopy, electrocardiography, lactate levels, magnetic resonance angiography

Viral syndromes

Abdominal pain, anorexia, diarrhea, fever, Diagnosis is generally clinical; may be confirmed by antigennausea, vomiting detecting enzyme immunoassay, immunofluorescence assay, microscopy, polymerase chain reaction testing, serology, or viral culture (although routine use of these tests is not necessary)

Abdominal CT, CBC; contrast enema and colonoscopy may be considered

CBC = Complete blood count; CT = Computed tomography.

Table 4. Foodborne Pathogens Associated with Fever and Vomiting Fever

Vomiting

Characteristically associated

Campylobacter jejuni Shigella Vibrio cholerae non-O1 Often associated Norwalk virus Salmonella Vibrio parahaemolyticus

Bacillus cereus (emetic syndrome) Norwalk virus Staphylococcus aureus Often associated Clostridium botulinum V. cholerae O1 V. parahaemolyticus

If testing is performed, stool culture can provide a definitive diagnosis of infectious diarrhea and is useful for outbreak identification. In most outpatients who have self-limiting gastroenteritis, a stool culture does not affect management.4 Bacteria are the most common cause of non–self-limiting foodborne illness; however, stool cultures are positive in less than 40% of cases.4,5 Newer techniques such as polymerase chain reaction testing have become readily available and provide more rapid, reliable determination of specific pathogens. An organism-specific diagnosis can help clinicians to narrow treatment recommendations, aid public health professionals, and prevent unnecessary procedures. Other tests that can be considered include serum chemistry (including albumin levels), C-reactive

protein levels, complete blood count, blood cultures, urinalysis, abdominal radiography, anoscopy, and endoscopy, if warranted by the severity and pattern of symptoms.5 In severe cases of infectious diarrhea, toxic megacolon should be considered, which can be identified on plain abdominal radiography.4 Severe inflammatory changes can also be seen on computed tomography. It may be reasonable to obtain blood cultures in patients with fever and diarrhea (with or without blood), because up to 1% of cases of nontyphoidal Salmonella infections are associated with bacteremia.4,5 Sigmoidoscopy or colonoscopy may be useful in hospitalized patients with bloody diarrhea to obtain tissue and histology, which could aid in the diagnosis. Stool microscopy is rarely diagnostic, but the presence of red and white blood cells may signal a colonic source.4 Its primary use is identification of ova, cysts, and parasites, although antigen testing is more sensitive and specific for Giardia. Microscopic evaluation for fecal polymorphonuclear leukocytes or lactoferrin measurements may be useful if an inflammatory etiology is suspected. A positive stool culture is more likely when analysis indicates an inflammatory process. Compared with leukocyte examinations, lactoferrin measurements are more sensitive but more expensive, have a higher false-positive rate, and require a freshcup sample examined by an experienced microscopist.5

Indian Journal of Clinical Practice, Vol. 26, No. 9, February 2016

809

AMERICAN FAMILY PHYSICIAN MANAGEMENT

Symptomatic Treatment Use of antidiarrheal medications, including antimotility agents, anticholinergics, and adsorbents, is not recommended in children, especially those younger than two years, and is discouraged if infection with Shiga toxin–producing E. coli is suspected.6-8 Symptomatic treatment with loperamide and bismuth subsalicylate is effective and may be considered in adults with uncomplicated acute or traveler’s diarrhea.9-11 Although loperamide is more effective than bismuth subsalicylate, it is not recommended for patients with hematochezia and systemic symptoms because it may increase the risk of invasive disease.10 In patients with clinically significant vomiting, antiemetics can alleviate symptoms and reduce the need for hospitalization and intravenous fluid administration. Multiple studies support the use of a single dose of ondansetron in children with gastroenteritis-related vomiting.12-14 The use of antiemetics in adults with gastroenteritis is reasonable, but data about adverse effects are lacking.

Dehydration Many physicians are reluctant to use oral rehydration therapy, despite its proven effectiveness in the manage ment of diarrhea-associated dehydration.6,15 It has been proven to prevent and treat dehydration in patients of all ages.5,16-19 Guidelines that recommend the use of oral rehydration therapy for mild to moderate dehydration in infants and children have been published by the World Health Organization, the American Academy of Pediatrics, and the CDC.6,7,20 Oral rehydration solutions contain a blend of electrolytes, as well as carbohydrates. Sports drinks and soft drinks have a high carbohydrate-to-sodium ratio and total osmolality, and can exacerbate diarrhea.19 Clinical assessment should be used to guide rehydration therapy. Children—especially infants—are predisposed to dehydration and require more diligence in determining hydration status. CDC guidelines recom mend the initial use of oral rehydration therapy with replacement of continuing fluid losses in children with mild to moderate dehydration. Children with severe dehydration should be hospitalized and given intravenous fluids.6,7 When oral rehydration therapy or intravenous fluid administration is used in infants, care should be taken to minimize interruptions in breastfeeding or formula feeding.6,7

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Empiric Antibiotics Most cases of acute infectious diarrhea are viral, and improper use of empiric antibiotics is associated with increased morbidity caused by adverse effects and Clostridium difficile colitis. Empiric antibiotics should be considered in cases of suspected foodborne illness only if the patient is febrile and has signs of invasive disease (e.g., gross hematochezia, leukocytes on fecal smear), if symptoms have persisted for more than one week or are severe (i.e., more than eight liquid stools per day), or if hospitalization fluoroquinolone may be required.10,16,17,19 A (or trimethoprim/sulfamethoxazole in children) is generally recommended for empiric antibiotic therapy.5 Stool testing should still be performed. Empiric antibiotic therapy decreases the duration of symptoms in patients with traveler’s diarrhea.5,9 Enterotoxigenic E. coli is the most common cause of traveler’s diarrhea worldwide and is generally susceptible to ciprofloxacin, but azithromycin is equally effective and a better choice in areas where fluoroquinolone-resistant C. jejuni is present.9,21 Patients with diarrhea of more than 10 days’ duration that is associated with fatty or foul-smelling stools, cramps, bloating, and weight loss can be treated empirically for Giardia infection.22 Because of an increased risk of hemolytic uremic syndrome, patients receiving empiric antibiotic therapy should be monitored closely if Shiga toxin–producing E. coli infection is suspected.4,23

Targeted Antibiotics If empiric treatment has not been initiated, antibiotic therapy may be indicated once stool culture, bacterial toxin, or microscopy results are available. Antibiotic therapy can shorten the duration of symptoms and may prevent bacteremia in older adults, newborns, and immunocompromised patients.4 Recommended treat ment regimens for foodborne pathogens are outlined in Table 5.8,18,19,21-24 Ciprofloxacin is no longer recommended for treatment of Campylobacter infection; a macrolide, such as erythromycin, is recommended instead.24 OUTBREAK SURVEILLANCE AND REPORTING Although reporting requirements vary, most states require physicians to report cases of hepatitis A and botulism, and Salmonella, Shiga toxin–producing E. coli, Listeria, Shigella, and Vibrio infections. A definitive diagnosis is not necessary to report a suspected foodborne illness. Outbreaks can be declared by local,

AMERICAN FAMILY PHYSICIAN Table 5. Recommended Treatment Regimens for Foodborne Pathogens Pathogen

Recommended regimen for adults

Recommended regimen for children

Erythromycin, 500 mg 2 times per day for 5 days

Azithromycin, 10 mg per kg per day for 3 to 7 days

Bacteria Campylobacter

or Azithromycin, 500 mg on day 1, then 250 mg on days 2 through 5 Escherichia coli (non-Shiga toxin–producing)

Ciprofloxacin, 500 mg 2 times per day for 3 days

TMP-SMX, 5/25 mg per kg 2 times per day for 3 days*

TMP/SMX, 160/800 mg 2 times per day for 3 to 7 days*

Azithromycin, 10 mg per kg per day for 3 to 7 days

or Azithromycin, 500 mg on day 1, then 250 mg on days 2 through 5 E. coli (Shiga toxin–producing)

Not recommended

Salmonella (nontyphoidal)

Generally not recommended†

If indicated:

Ciprofloxacin, 500 mg 2 times per day for 5 to 7 days

TMP-SMX, 5/25 mg per kg 2 times per day for 5 to 7 days*

Azithromycin, 500 mg on day 1, then 250 mg on days 2 through 5‡

Azithromycin, 10 mg per kg per day for 3 to 7 days

Ceftriaxone, 1 to 2 g per day intramuscularly or intravenously for 5 to 7 days

Ceftriaxone, 50 to 100 mg per kg per day intramuscularly or intravenously for 5 to 7 days

Ciprofloxacin, 500 mg 2 times per day for 3 days

TMP-SMX, 5/25 mg per kg 2 times per day for 3 days†

Azithromycin, 500 mg on day 1, then 250 mg on days 2 through 5

Azithromycin, 10 mg per kg per day for 3 to 7 days

Cryptosporidium

Generally not recommended§

Entamoeba histolytica

Metronidazole, 750 mg 3 times per day for 5 to 10 days

Metronidazole, 30 to 50 mg per kg per day in 3 divided doses for 7 to 10 days

Shigella

Parasites

Giardia

plus Paromomycin, 500 mg 3 times per day for 7 days, or iodoquinol, 650 mg 3 times per day for 7 days

plus

Metronidazole, 250 to 750 mg 3 times per day for 7 to 10 days

Metronidazole, 30 to 50 mg per kg per day in 3 divided doses for 7 to 10 days

Paromomycin, 25 to 35 mg per kg per day in 3 divided doses for 5 to 10 days

TMP/SMX = Trimethoprim/Sulfamethoxazole. *If susceptible. †Antibiotic

therapy is not recommended except in severe infections, patients younger than 6 months or older than 50 years, immunocompromised patients, and patients with prostheses, valvular heart disease, severe atherosclerosis, malignancy, or decreased renal function.

‡Alternative

dosing regimen for azithromycin in adults with salmonellosis: 1,000 mg on day 1, then 500 mg per day for 2 to 6 days.

§Treatment

for cryptosporidiosis is generally not recommended in immunocompetent patients. For persistent symptoms, some clinicians prescribe nitazoxanide, although it has not been approved for this use and has not been proven superior to placebo. Dosing for adults and children 12 years and older is 500 mg orally every 12 hours for 3 days. Dosing for children 4 to 11 years of age is 200 mg of oral suspension every 12 hours for 3 days. Dosing for children 1 to 3 years of age is 100 mg of oral suspension every 12 hours for 3 days. Information from references 8, 18, 19, and 21 through 24.

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AMERICAN FAMILY PHYSICIAN county, state, or national agencies; reporting outbreaks to the CDC is left to the discretion of the agency. Physicians should avoid attributing cases of foodborne illness to specific food sources without definitive testing and reporting. In cases of suspected foodborne illness or in the setting of an outbreak, stool and vomitus samples should be sent for testing. All reports of outbreaks are entered into the CDC’s Foodborne Disease Outbreak Surveillance System, after which the data are analyzed to monitor and identify the root cause of the outbreak. Once an outbreak has occurred, prevention strategies should focus on educating the public through the news media and correcting the underlying cause, such as through food product recalls. Information on outbreaks, outbreak surveillance, and identified trends can be found at http://www.cdc.gov/foodsafety/fdoss/ index.html or by calling the CDC at (800) CDC-INFO ([800] 232-4636). Note: For complete article visit: www.aafp.org/afp. REFERENCES

Travel Medicine. 3rd ed. Philadelphia, Pa.: Elsevier/ Saunders; 2012. 10. Steffen R. Worldwide efficacy of bismuth subsalicylate in the treatment of travelers’ diarrhea. Rev Infect Dis. 1990;12(suppl 1):S80-S86. 11. DuPont HL, Flores Sanchez J, Ericsson CD, et al. Comparative efficacy of loperamide hydrochloride and bismuth subsalicylate in the management of acute diarrhea. Am J Med. 1990;88(6A):15S-19S. 12. DeCamp LR, Byerley JS, Doshi N, Steiner MJ. Use of antiemetic agents in acute gastroenteritis: a systematic review and meta-analysis. Arch Pediatr Adolesc Med. 2008;162(9):858-865. 13. Levine DA. Antiemetics for acute gastroenteritis in children. Curr Opin Pediatr. 2009;21(3):294-298. 14. Ramsook C, Sahagun-Carreon I, Kozinetz CA, MoroSutherland D. A randomized clinical trial comparing oral ondansetron with placebo in children with vomiting from acute gastroenteritis. Ann Emerg Med. 2002;39(4):397-403. 15. Snyder JD. Use and misuse of oral therapy for diarrhea: comparison of US practices with American Academy of Pediatrics recommendations. Pediatrics. 1991;87(1):28-33.

1. Centers for Disease Control and Prevention. CDC and food safety. http://www.cdc.gov/foodsafety/cdc-andfood-safety.html. Accessed May 15, 2014.

16. Santosham M, Daum RS, Dillman L, et al. Oral rehydration therapy of infantile diarrhea: a controlled study of wellnourished children hospitalized in the United States and Panama. N Engl J Med. 1982; 306(18):1070-1076.

2. Centers for Disease Control and Prevention. Food safety: foodborne illness, foodborne disease, (sometimes called “food poisoning”). http:// www.cdc.gov/foodsafety/facts. html. Accessed May 15, 2014.

17. Santosham M, Burns B, Nadkarni V, et al. Oral rehydration therapy for acute diarrhea in ambulatory children in the United States: a double-blind comparison of four different solutions. Pediatrics. 1985;76(2):159-166.

3. U.S. Food and Drug Administration. Foodborne illnesses: what you need to know. http://www.fda.gov/food/ resourcesforyou/consumers/ucm103263.htm. Accessed May 7, 2015.

18. Tamer AM, Friedman LB, Maxwell SR, Cynamon HA, Perez HN, Cleveland WW. Oral rehydration of infants in a large urban U.S. medical center [published correction appears in J Pediatr. 1986;108(1):160]. J Pediatr. 1985;107(1):14-19.

4. Conlon C. Food-borne diarrheal illness. In: Cohen J, ed. Infectious Diseases. 3rd ed. St. Louis, Mo.: Mosby; 2010. 5. Guerrant RL, Van Gilder T, Steiner TS, et al.; Infectious Diseases Society of America. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis. 2001;32(3):331-351. 6. Duggan C, Santosham M, Glass RI; Centers for Disease Control and Prevention. The management of acute diarrhea in children: oral rehydration, maintenance, and nutritional therapy. MMWR Recomm Rep. 1992;41 (RR-16):1-20. 7. American Academy of Pediatrics, Provisional Committee on Quality Improvement, Subcommittee on Acute Gastroenteritis. Practice param eter: the management of acute gastroenteritis in young children. Pedi atrics. 1996;97(3):424-435. 8. Cimolai N, Carter JE, Morrison BJ, Anderson JD. Risk factors for the pro gression of Escherichia coli O157:H7 enteritis to hemolytic-uremic syn drome [published correction appears in J Pediatr. 1990;116(6):1008]. J Pediatr. 1990;116(4):589-592. 9. Löscher T, Alberer M. Clinical presentation and management of travelers’ diarrhea. In: Keystone JS, ed.

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19. Avery ME, Snyder JD. Oral therapy for acute diarrhea. The underused simple solution. N Engl J Med. 1990;323(13):891-894. 20. World Health Organization; UNICEF. Clinical management of acute diarrhoea: WHO/UNICEF joint statement. http://www.who.int/iris/ handle/10665/68627. Accessed July 7, 2015. 21. Adachi JA, Ericsson CD, Jiang ZD, et al. Azithromycin found to be comparable to levofloxacin for the treatment of US travelers with acute diarrhea acquired in Mexico. Clin Infect Dis. 2003;37(9):1165-1171. 22. DuPont HL; Practice Parameters Committee of the American College of Gastroenterology. Guidelines on acute infectious diarrhea in adults. Am J Gastroenterol. 1997;92(11):1962-1975. 23. Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med. 2000;342(26):1930-1936. 24. Smith KE, Besser JM, Hedberg CW, et al.; Investigation Team. Quinolone-resistant Campylobacter jejuni infections in Minnesota, 1992-1998. N Engl J Med. 1999;340(20):1525-1532.

AMERICAN FAMILY PHYSICIAN

Practice Guidelines

Anterior cruciate ligament (ACL) injuries, which are usually related to sports, have an incidence of approximately 252,000 yearly, with women two to eight times more likely to have an ACL injury vs. men. Persons who experience ACL injuries have an increased risk of arthritis. The American Academy of Orthopaedic Surgeons (AAOS) has provided guidance in determining the best options for treating an ACL injury.

tendon autografts, and should use a single- or doublebundle approach when performing intra-articular ACL reconstruction. Results of stability testing, patient satisfaction, knee function scores, and rates of failure have been shown to be similar between these two types of grafts, and there is no statistically significant difference in outcomes, including postoperative pain and knee function scores, between the single- and double-bundle approaches. It should be noted that the rate of postoperative pain while kneeling has been shown to be greater in persons receiving the bone-patellar tendon-bone graft.

Recommendations

Based on Moderate Evidence

Based on Strong Evidence

Prevention. Neuromuscular training programs may reduce or prevent ACL injuries, with several studies supporting this training; one analysis suggests 109 athletes would need to participate to prevent one injury.

MANAGEMENT OF ACL INJURIES: CLINICAL PRACTICE GUIDELINE FROM THE AAOS

Diagnosis. Because of their effectiveness in diagnosing ACL injuries, a history (e.g., mechanism of injury, presence of a popping sensation, locking, or catching; weight-bearing ability; ability to return to play; previous knee injuries; area of pain) should be obtained and musculoskeletal examination of the lower extremities (e.g., distal perfusion and tibial/peroneal nerve function; joint line tenderness or obvious stepoff/deformity; effusion; varus and valgus laxity at 0 and 30 degrees of extension; anteroposterior and rotational laxity) should be performed. The presence of a popping sensation in combination with swelling is a significant predictor of an ACL injury, as are positive findings on the Lachman test. Magnetic resonance imaging has a high sensitivity and specificity for confirming an ACL injury. It also can help determine if other conditions are present, such as a meniscal injury; however, the sensitivity and specificity for this use are lower. Treatment. Physicians performing ACL reconstruction should use autograft or allograft tissue that is processed correctly. Studies have found that the clinical outcomes are similar between the two; however, how the allograft is prepared (e.g., procurement, processing, storage, implantation) may cause some differences. Physicians should use bone-patellar tendon-bone or hamstring-

Source: Adapted from Am Fam Physician. 2015;92(3):232-234.

Treatment. Surgery can be appropriate in persons with an ACL tear who are 18 to 35 years of age and active, because it has been shown to decrease pathologic laxity, instances of instability, and additional injuries. Reconstructive surgery should be per formed in the five months following injury; this is to protect the articular cartilage and menisci. Performing reconstruction within three to five months vs. after three to five months has been shown to improve stability, allow a higher level of activity and greater function, and reduce meniscus tears. When performing an intra-articular ACL reconstruction, a tibial independent or trans tibial technique can be used for femoral tunnel placement; there appear to be no consistent differences between the techniques with regard to objective metrics, results reported by patients, or knee function scores. Because of the lack of evidence of benefit regarding function or laxity, routinely using functional knee braces (e.g., neoprene brace) after ACL reconstruction is not recommended. Early accelerated (19 weeks) and non-accelerated (32 weeks) rehabilitation programs may be beneficial after ACL reconstruction, with studies showing that, two years after undergoing reconstruction, patients in both types of programs had similar outcomes (e.g., knee laxity, satisfaction, level of activity, function).

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AMERICAN FAMILY PHYSICIAN Based on Limited Evidence Prevention. Physicians may not recommend knee bracing as a preventive measure for ACL injuries, because risk of injury does not appear to be lower when bracing is used. Two studies of low and moderate strength found that the rate of injury was not reduced in football play ers at high school and college levels. Treatment. Limited evidence supports that rather than providing nonsurgical management, physicians may opt to perform recon struction because it decreases pathologic knee laxity. If a patient has a meniscus tear in addition to an ACL injury, physicians may repair the meniscus when performing reconstruction. Despite limited evidence, physicians may still perform ACL reconstruction in persons who are skeletally immature, because it appears to provide significant benefit vs. nonsurgical management with regard to stability, function, and activity. Evidence is limited to support nonsurgical treatment for persons who are less active and have less laxity, or performing reconstruction of an ACL tear combined

with treating medial collateral ligament tears without surgery. Additionally, having to reach a particular functional milestone or waiting a certain amount of time after injury or surgery before returning to play or activity is not recommended. Based on Consensus Opinion Diagnosis. When first assessing persons with a knee injury, anteroposterior and lateral knee radiography should be performed to determine if there are possible injuries that may necessitate emergency care (e.g., fracture, dislocation, neoplasm, foreign body); making a diagnosis early in these cases can be beneficial in reducing morbidity. However, if magnetic resonance imaging or computed tomography is an imaging option, other radiography may not be needed. Treatment. Immediate treatment is rec ommended in persons with a torn ACL and a locked knee from a displaced meniscus tear, which can lead to fixed flexion contracture. Promptly unlocking the knee can help prevent this from occurring. If the meniscus is reduced earlier, then the tear may be more easily repaired.

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AMERICAN FAMILY PHYSICIAN

Photo Quiz A BUMP ON THE KNEE A 13-year-old girl presented with a painless bump on her left medial knee that had been present for about two weeks. She did not report any trauma or injury, and the bump was not interfering with her daily activities. Her personal and family histories were unremarkable. Physical examination revealed no ecchymosis or knee joint effusion. On palpation, there was a nontender bony prominence in the medial distal left femur. There was no palpable inguinal lymphadenopathy, and her knee range of motion was normal. Plain radiography was performed (Figure 1).

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

Figure 1.

A. Enchondroma.

D. Osteochondroma.

B. Fibrous dysplasia.

E. Osteoid osteoma.

C. Nonossifying fibroma.

SEE THE FOLLOWING PAGE FOR DISCUSSION.

Source: Adapted from Am Fam Physician. 2015;92(2):149-150.

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AMERICAN FAMILY PHYSICIAN DISCUSSION

Summary Table

The answer is D: osteochondroma. Osteochondromas are the most common benign bone tumors. They usually affect adolescents and children, but occur in up to 3% of the general population and account for up to 30% of all bone tumors.1 Osteochondromas are generally asymptomatic and found incidentally on imaging, but they occasionally present as painless masses.1,2 They rarely present as painful lesions due to irritation of the surrounding soft tissue.1,3 Solitary osteochondromas generally are found in the metaphysis of long bones, including the femur or tibia, but can be found in any bone.1-3 Osteochondromas usually communicate with the intramedullary bone canal.

Condition

Characteristics

Enchondroma

Benign appearance with irregular calcification (“popcorn” or “stippled” lesion); most common in the metaphysis or diaphysis of the hand, distal femur, proximal humerus, and tibia; may be painful because of irritation of the overlying soft tissue

On radiography, osteochondromas appear as bony outgrowths in continuity of the cortex and should not have cystic lesions, surrounding edema, or periostitis.1,3 Magnetic resonance imaging may be indicated for further evaluation in symptomatic cases.2 Osteochondromas usually have a cap of hyaline cartilage that is seen best on magnetic resonance imaging.2 They rarely transform into malignant lesions.1-3 Treatment is not indicated unless there is inflammation of the overlying soft tissue, risk of fracture because of the size of the osteochondroma, or mechanical joint restriction.1,3 Enchondromas are common benign bone tumors affecting all age groups and are usually found incidentally on radiography.3 They are typically asymptomatic but may be painful because of irritation of the overlying soft tissue.2,3 Enchondromas are intramedullary lesions, typically more centrally than eccentrically located, and are usually found in the metaphysis or diaphysis of long bones.2,3 On radiography, they appear benign with irregular calcification (“popcorn” or “stippled” lesion).3 Fibrous dysplasia is an uncommon benign develop mental anomaly of bone formation with replacement of normal bone by a matrix of fibrous tissue and small woven spicules of bone.3,4 Fibrous dysplasias are usually localized to the metaphysis of the femur and tibia, are asymptomatic, and occur before 30 years of age.3,4 There is an increased risk of a pathologic fracture in the long bones because of bowing.3,4 Radiography shows a centrally located lesion with a ground-glass appearance of the matrix, with sharp and well-defined sclerotic margin.4 Nonossifying fibromas are common benign bone lesions found incidentally on radiography in patients younger than 30 years.5 They are most often located in the long bones, predominantly the femur and tibia.3,5 They are cortically based eccentric lesions found in the medullary cavity of long bones without periosteal reaction, irregular borders, or surrounding edema.2,3,5

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Fibrous dysplasia Ground-glass appearance of the matrix with sharp and well-defined sclerotic margin; most common in the metaphysis of the femur and tibia; bowing deformity and pathologic fracture may occur Nonossifying fibroma

Geographic appearing, cortically based eccentric lesions found in the medullary cavity of long bones; usually asymptomatic and can occur before 30 years of age; more common in children and adolescents

Osteochondroma

Bony outgrowths that usually communicate with the intramedullary bone canal; usually occur in the metaphysis of long bones of children and adolescents

Osteoid osteoma

Well-circumscribed, 1- to 2-cm lesion with osteoblastic nidus and a surrounding sclerotic border; most common in male adolescents; usually located in the distal femur or proximal tibia; often causes pain at night overlying a hard mass

Osteoid osteomas often present with pain at night overlying a hard mass, usually in male adolescents.3,5,6 Radiography shows a well-circumscribed, 1- to 2-cm lesion with a sclerotic border surrounding an osteoblas tic nidus.3,6 They are usually located in the distal femur or proximal tibia.3,5,6 REFERENCES 1. Kitsoulis P, Galani V, Stefanaki K, et al. Osteochondromas: review of the clinical, radiological and pathological features. In Vivo. 2008;22(5):633-646. 2. Subhas N, Bui KL, Sundaram M, Ilaslan H, Recht MP. Incidental tumor and tumor-like lesions around the knee. Semin Musculoskelet Radiol. 2009;13(4):353-370. 3. Heck RK, Toy PC. Benign bone tumors and nonneoplastic conditions simulating bone tumors. In: Campbell WC, et al., ed. Campbell’s Operative Orthopaedics. Philadelphia, Pa.: Elsevier/Mosby; 2013. 4. Gould CF, Ly JQ, Lattin GE Jr, Beall DP, Sutcliffe JB 3rd. Bone tumor mimics: avoiding misdiagnosis. Curr Probl Diagn Radiol. 2007;36(3):124-141. 5. Khodaee M, Bartkus R. Knee pain following a ski injury. Asian J Sports Med. 2012;3(3):214-215. 6. Kujawski EJ, Morgan RL. Lateral knee pain in a male college student. Am Fam Physician. 2012;85(5):509-510.

2016

CARDIOLOGY

Prescribing Pattern of Antihypertensive Drugs in a Tertiary Care Teaching Hospital in Lucknow Region VIJAY K YADAV*, SHYAM SUNDER KESHARI†, KRISHNA PANDEY‡

ABSTRACT Aims and objectives: To evaluate the prescribing pattern of antihypertensive drugs in a tertiary care teaching hospital in Lucknow region. Material and methods: A cross-sectional study was carried out at Outpatient Department in a tertiary care teaching hospital in Barabanki to evaluate the prescribing pattern of antihypertensive drugs during August 2013 to July 2015. Results: In present study, 68.5% patients received monotherapy while 31.5% received combination therapy. In monotherapy, angiotensin-converting enzyme inhibitor (ACEI) (25.7%) was the most commonly prescribed while angiotensin receptor blockers (ARBs) + diuretics (11.9%) were most commonly prescribed combination therapy. Conclusion: In present study, it was found that ACEIs were the most commonly prescribed antihypertensive drug followed by ARBs and calcium channel blockers (CCBs) in monotherapy. Combination therapy was given according to associated risk factors and comorbid conditions.

Keywords: Prescribing pattern, monotherapy, ARB, ACEI, CCB

ypertension is a major health problem in our country. There are several factors which are responsible for hypertension like age, ethnic background, family history of hypertension, obesity, sedentary lifestyle, food habits, smoking, alcoholism, stress and some chronic pathological conditions like diabetes, renal disease, etc. The estimated total number of adults with hypertension in 2000 was 972 million; 333 million in economically developed countries and 639 million in economically developing countries. The number of adults with hypertension in 2025 was predicted to increase by about 60% to a total of 1.56 billion (1.54-1.58 billion). Worldwide data for the global burden of hypertension reveal that 20.6% of Indian men and 20.9% of Indian women were suffering from hypertension in 2005.1 It has been estimated that by the year 2030, 23 million cardiovascular deaths are projected to be due to hypertension, of which about 85% cases will be from low-resource settings and developing nations.2

*Assistant Professor †Professor ‡Tutor Dept. of Pharmacology Mayo Institute of Medical Sciences, Barabanki, Uttar Pradesh Address for correspondence

Dr Shyam Sunder Keshari Professor, Dept. of Pharmacology Mayo Institute of Medical Sciences, Gadia, Barabanki - 225 001, Uttar Pradesh E-mail: drsskeshari@gmail.com

Recent studies from India have shown the prevalence of hypertension to be 25% in urban and 10% in rural people in India.3-4 The poor control of hypertension leads to further progressive cardiovascular complications like ischemic heart disease, heart failure, stroke and chronic renal insufficiency.5 Awareness and adequate control of hypertension in India is poor, only 69% people suffering with hypertension are aware that they have the disease, among them only 54% receive treatment and only 27.4% achieve adequate blood pressure control.6 Treatment of hypertension with monotherapy or combination therapy is updated time to time according to Joint National Committee (JNC) I-VIII guidelines. The blood pressure stages in the JNC-VIII definition/ classification are: Categories of Systolic blood Diastolic blood hypertension pressure (mmHg) pressure (mmHg) Normal <120 <80 Prehypertension 120-139 80-89 Stage I hypertension 140-159 90-99 Stage II hypertension >160 >100

MATERIAL AND METHODS A cross-sectional study was carried out at Outpatient Department of Medicine in Mayo Institute of Medical Sciences (MIMS), Barabanki, Uttar Pradesh during August 2013 to July 2015. Samples of 453 prescriptions were screened and written consent was taken.

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CARDIOLOGY Inclusion criterion for the selection of prescriptions was hypertensive patients according to JNC-VIII guidelines. Fifty-three prescriptions having lifestyle modification and nonpharmacological measures were excluded from our study. The results are based upon the data obtained from 400 participants. Data were analyzed using MS Excel 2007 and summarized as counts and percentages.

Inclusion Criteria ÂÂ Patients with age groups more than 18 years. ÂÂ Hypertensive patients with and without comorbid conditions i.e., cardiovascular disease, diabetes mellitus and chronic kidney disease. ÂÂ Patients on monotherapy and combination therapy. ÂÂ Patients with addiction or nonaddiction to alcohol or nicotine.

by angiotensin receptor blockers (ARBs) (22.7%) and calcium channel blockers (CCBs) (15%) (Table 2). Among combination therapy, 27% patients received two drugs combination therapy and the most commonly prescribed combination was ARB + diuretics (11.9%), followed by CCB + β-blockers (4%). Three drug combinations were received by 3% patients. Among three drug combinations, ARB + β-blocker + diuretics and ACEI + β-blocker + diuretics were used in 1.7% and 1.2% patients, respectively. Four drug combinations were received by only 1.5% patients. Equal number of patients (0.7%) received ARB + β-blocker + diuretic + CCB and ACEI + β-blocker + diuretic + CCB combinations (Table 3).

Exclusion Criteria ÂÂ Patients with age group less than 18 years. ÂÂ Prescriptions having lifestyle modifications and nonpharmacological measures.

Table 2. Prescribing Pattern of Monotherapy Antihypertensive Drugs

RESULTS AND OBSERVATION In present study, 55.7% hypertensives were male while 44.2% were female. Out of 400 prescriptions, 68.5% patients received monotherapy and 31.5% received combination therapy. Most of the hypertensives patients were in the age group of 50-59 years (28.2%) followed by 60-69 years (26.7%) (Table 1). Out of 274 monotherapy, angiotensin-converting enzyme inhibitors (ACEIs) (25.7%) were the most commonly prescribed, followed Table 1. Demographic Characteristics of Hypertensive Patients (n = 400) Variables

Antihypertensive drugs

No. of prescriptions (274) Male (n = 144) No. (%)

Female (n = 130) No. (%)

ACEIs

52 (13)

51(12.7)

ARBs

41 (10.2)

50 (12.5)

β-blockers

4 (1)

CCBs

36 (9)

24 (6)

11 (2.7)

1 (0.2)

Diuretics

Table 3. Prescribing Pattern of Combination Therapy Antihypertensive Drugs Antihypertensive drugs ARB + Diuretics

No. of prescriptions (126) Male (n = 76) No. (%)

Female (n = 50) No. (%)

27 (6.7)

21 (5.2)

12 (3)

4 (1)

Male (n = 223) No. (%)

Female (n = 177) No. (%)

223 (55.7)

177 (44.2)

ARB + CCBs

10 (2.5)

6 (1.5%)

ACEI + Diuretics

5 (1.2)

3 (0.7)

Monotherapy

144 (36)

130 (32.5)

ARB + β-blockers

6 (1.5)

2 (0.5)

Combination therapy

76 (19)

50 (12.5)

ACEI + β-blockers

4 (1)

ARB+ β-blocker + Diuretics

4 (1)

3 (0.7)

ACEI + β-blocker + Diuretics

3 (0.7)

2 (0.5)

α-blocker + CCBs

1 (0.2)

3 (0.7)

ARB+ β-blocker + Diuretics + CCBs

2 (0.5)

1 (0.2)

ACEI + β-blocker + Diuretics + CCBs

2 (0.5)

1 (0.2)

Antihypertensive prescriptions

Age (in years) 20-29

4 (1.8)

2 (1.1)

30-39

30 (13.4)

23 (13.0)

40-49

43 (19.3)

36 (20.3)

50-59

51 (22.9)

62 (35.0)

60-69

67 (30.0)

40 (22.6)

70-79

14 (5.3)

9 (5.1)

80-89

8 (3.6)

5 (2.8)

820

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CCB + β-blockers

CARDIOLOGY DISCUSSION

REFERENCES

Reduction of systolic as well as diastolic blood pressure reduces the cardiovascular events. At ages 40-69 years, each difference of 20 mmHg systolic or 10 mmHg diastolic blood pressure was associated with more than a two-fold difference in the stroke death rate, and with two-fold differences in the death rates from coronary heart disease and other vascular causes.7 In the present study, it was found that the prevalence of hypertension was more in male patients (55.7%) as compared to females (44.2%), so male are affected more than female, which correlates with the previous study done by Farang et al.8 The maximum number of patients (74.7%) fall in the age group of 40-69 years. This indicates that risk of hypertension increases as the age advances. A previous study revealed that increasing age, body mass index, smoking, diabetes and extra salt intake are common risk factors for hypertension.9 Present study shows monotherapy (68.5%) is more common than combination therapy (31.5%). These results were in accordance with previous study done by Kuchake et al.10 The combination therapy is given to those patients who are not controlled by monotherapy. In present study, ACEIs (25.7%) were the most commonly prescribed drug in monotherapy followed by ARBs. These results were in accordance with the work of Pandey et al.11 Combination therapy in hypertensives, adequately controlled the blood pressure.12 Combination therapy also reduces the cardiovascular complications thus reduces mortality.13 In our study, CCBs were preferred in elderly patients which is in accordance to the guidelines of National Institute for Health and Care Excellence (NICE).14 ARBs were preferred in the patients of age less than 50 years of age. Diuretics were most preferred drugs in combination therapy with ARB, ACEI and CCB which was in accordance with the study done by Johnson et al.15 It is essential to combine diuretics with these drugs for reduction of blood volume, peripheral vascular resistance. Use of ACEI/ARB was higher in patients with nephropathy.

1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365(9455):217-23.

CONCLUSION

12. Hansson L, Dahlöf B, Gudbrandsson T, Hellsing T, Kullman S, Kuylenstierna J, et al. Antihypertensive effect of felodipine or hydralazine when added to beta-blocker therapy. J Cardiovasc Pharmacol. 1988;12(1):94-101.

In the present study, it was found that ACEIs were the most commonly prescribed drug followed by ARBs and CCBs in monotherapy. In ACEIs, ramipril was the most commonly prescribed drug while telmisartan was the most common in ARBs. Amlodipine was most commonly prescribed drug in CCBs. Combination therapy was given according to associated risk factors and comorbid conditions. We feel that there is need of further studies from time to time to evaluate and improve the prescribing pattern of hypertension.

2. World Health Organization. A global brief on hypertension: silent killer, global public health crisis. Geneva: WHO; 2013. (WHO/DCO/WHD/2013.2). 3. Thankappan KR, Sivasankaran S, Sarma PS, Mini G, Khader SA, Padmanabhan P, et al. Prevalence-correlates-awarenesstreatment and control of hypertension in Kumarakom, Kerala: baseline results of a community-based intervention program. Indian Heart J. 2006;58(1):28-33. 4. Das SK, Sanyal K, Basu A. Study of urban community survey in India: growing trend of high prevalence of hypertension in a developing country. Int J Med Sci. 2005;2(2):70-8. 5. Bhimaray SK, Sandeep A, Ramanath KV. Assessment of prescription pattern of antihypertensive in a tertiary care hospital of rural population. AJPSCR. 2011;1(3):5-12. 6. Shirley C, Nagavi BG. Impact of community pharmacy based patient education on the quality of life of hypertensive patients. Indian J Pharm Educ Res. 2007;41(2):164-9. 7. Gupta R, Guptha S. Strategies for initial management of hypertension. Indian J Med Res. 2010;132:531-42. 8. Farag YM, Mittal BV, Keithi-Reddy SR, Acharya VN, Almeida AF, C A, et al. Burden and predictors of hypertension in India: results of SEEK (Screening and Early Evaluation of Kidney Disease) study. BMC Nephrol. 2014;15:42. 9. Devi P, Rao M, Sigamani A, Faruqui A, Jose M, Gupta R, et al. Prevalence, risk factors and awareness of hypertension in India: a systematic review. J Hum Hypertens. 2013;27(5):281-7. 10. Kuchake VG, Maheshwari Od, Surana SJ, Patil PH, Dighore PN. Prescription pattern of antihypertensive drugs in uncomplicated hypertensive patients at teaching hospital. Indian J Pharm Pract. 2009;2(2):74-80. 11. Pandey V, Hoda U, Aqil M, Sharma M, Akhtar M, Khandewal R, et al. Evaluation of prescribing patterns in diabetic and hypertensive patients in a South Delhi Hospital. Int J Basic Clin Pharmacol. 2014;3(3):490-5.

13. Mancia G, Grassi G. Antihypertensive treatment: past, present and future. J Hypertens Suppl. 1998;16(1):S1-7. 14. National Clinical Guideline Centre. Hypertension. Clinical management of primary hypertension in adults. London (UK): National Institute for Health and Clinical Excellence (NICE); 2011 Aug. 36 p. (Clinical guideline; no. 127). 15. Johnson ML, Singh H. Patterns of antihypertensive therapy among patients with diabetes. J Gen Intern Med. 2005;20(9):842-6.

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COMMUNITY MEDICINE

Study of Prevalence of Severe Acute Malnutrition in Children Under 5 Years in Chatra Area of Serampore Municipality Under the State of West Bengal PRADIP KUMAR DAS

ABSTRACT Malnutrition in India has been cited as “The silent emergency” because the proportion of under nutrition among children and women in India figures at the topmost position in the world as depicted by increased incidence of anemia and wasting in addition to several other indicators of malnutrition. The main purpose of this study was to make a survey of severe acute malnutrition (SAM) in children under five in the Chatra area under Serampore Municipality for the identification of the societal factors that may contribute to SAM in children, to provide clinical management and reduce mortality among the children with SAM and to render appropriate health education for the mothers and other caregivers regarding the proper way of feeding and caring practices towards the infants and young children.

Keywords: Severe acute malnutrition, caregivers, health education

alnutrition in India has been cited as “The silent emergency” because the proportion of under nutrition among children and women in India figures at the topmost position in the world as depicted by increased incidence of anemia and wasting in addition to several other indicators of malnutrition (the Maternal and Child Health Sustainable Technical Assistance and Research [MCH-STAR]). It is evident from the study report of the National Nutrition Monitoring Bureau (NNMB) Rural Third Report survey that only 36% of infants in India were starting breastfeeding within 1 hour of birth. Moreover, the third National Family Health Survey (NFHS-3) report shows that 48% of under five children are stunted, 43% are underweight and 20% have wasting. It is also revealed from another survey report done by the HUNGaMA (Hunger and Malnutrition) in 2011 that 34% of children under five were stunted, 16.4% were underweight and 3.3% had wasting. According to UNICEF, a study report done by Black et al on 2013, globally the prevalence of

Secretary, Swasthya Bhabna Welfare Society, Principal Investigator, Consultant Physician and Dermatologist, Master Trainers and Supportive Supervisor in GFATM-Project -7 Address for correspondence

Dr Pradip Kumar Das 15/C, Raja KL Goswami Street, Serampore, Hooghly - 712 201, West Bengal E-mail: pradipdr2@gmail.com

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underweight children below 5 years is 16%, whereas in South Asia and Western Africa the figures are 30% and 20%, respectively. In Indian scenario, the picture is quite different. In Sikkim and Mizoram, the prevalence of underweight is 20%, whereas in Madhya Pradesh it reaches about 60%. In the state of Jharkhand and Bihar, the picture shows 50% and in Meghalaya, Chhattisgarh, Gujarat, Uttar Pradesh and in Odisha it is about 40%. The latest NNMB Rural Third Survey report done from 2011 to 2012 among the boys and girls under 5 years of age in 10 states of India, shows that the overall prevalence of underweight, stunting and wasting in boys are 42.1%, 44.3% and 22.5%, respectively, whereas in case of girls children these figures are 41.4%, 41.9% and 21.5%, respectively. METHODOLOGY Integrated Child Development Services (ICDS) centers in Chatra areas were selected. Proper permission was taken from the Child Development Project Ofﬁcer (CDPO) and concerned councillor of the Ward. After explaining the total procedure for our study to the mothers, verbal consent was taken from them regarding the check-up of their children and their interviews. A good rapport was built up with the ICDS workers. Vision and Mission of the present study was written

COMMUNITY MEDICINE

RESULTS It is evident from the study of 50 children including boys and girls under the age group below 5 years taken for the study when categorized as percentage of reference for weight-for-age for children (both boys and girls), 38 children (76%) belonged to the normal group, 11 children (22%) were grouped as mild malnutrition and 1 child (2%) fell under moderate malnutrition. It is good that no severe group of malnourished children was found in that center (Table 1 and Fig. 1). From the study, it was also revealed that out of 50 children when categorized as percentage of reference for height-for-age for children (both boys and girls), 44 (88%) categorized as normal children in respect of nutritional status, whereas 4 children (8%) belonged to mild malnutrition group, 1 children (2%) grouped as moderate malnutrition and 1 children (2%) as severe malnutrition (Table 2 and Fig. 2). Moreover, the study revealed that out of 50 children when categorized as percentage of reference for weight-for-height

Total no. of children taken for study works (50) Normal (90-110%)

Grade I: Mild malnutrition (75-89%)

Grade II: Moderate malnutrition (60-74%)

Grade III: Severe malnutrition (<60%)

50 Total no. of children

Whenever identified the children with SAM were transferred to Best Health Facility and Feeding-based care under the Sub Divisional Hospital and monitored. Referral children were properly monitored whenever they were admitted as inpatient in the Sub Divisional Hospital for their better care and treatment of medical complications. Enrollment register of the mothers and children linked to study was prepared for future reference. Patient care register and follow-up register were maintained. Group counseling register for the provision of health education towards the mothers was also maintained.

Table 1. Percentage of Reference Weight-for-age for Girls and Boys (0-5 Years)

30 20 11

10 0

01 Normal (90-110%)

Grade I: Mild malnutrition (75-89%)

Grade II: Moderate malnutrition (60-74%)

Grade III: Severe malnutrition (<60%)

Figure 1. Percentage of reference weight-for-age for boys and girls (under 5).

Table 2. Percentage of Reference for Height-for-age for Girls and Boys (0-5 Years) Total no. of children taken for study works (50) Normal (>95%)

Grade I: Mild malnutrition (90-95%)

Grade II: Moderate malnutrition (85-90%)

Grade III: Severe malnutrition (<85%)

Total no. of children

in bold letters at the ICDS center, so that it could be read from far distance. Growth monitoring chart, midupper arm circumference (MUAC) examination chart and pedal edema examination chart were displayed in the examination room. Height and weight were taken by using tape and weighing machine of 50 children under the age group of 5 years. Month-wise clinical attendance of children and mothers from May to September, 2015 was prepared. Steps were taken for establishment of regular communication between the mothers of severe acute malnutrition (SAM) children. Steps were also taken for the preparation of followup care for SAM children. Clinical care guidelines for treatment (Algorithms) and criteria for referrals were developed. Ambulatory care facilities like treatment of clinical complications i.e., dehydration, infection, hypoglycemia, hypothermia and micronutrient supplementation were set up.

50 45 40 35 30 25 20 15 10 5 0

4 Normal (>95%)

Grade I: Mild malnutrition (90-95%)

Grade II: Moderate malnutrition (85-90%)

Grade III: Severe malnutrition (<85%)

Figure 2. Percentage of reference for height-for-age for girls and boys (under 5).

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COMMUNITY MEDICINE Table 3. Percentage of Reference for Weight-forheight for Girls and Boys (0-5 Years) Total no. of children taken for study works (50) Normal (>90%)

Grade I: Mild malnutrition (80-90%)

Grade II: Moderate malnutrition (70-80%)

Grade III: Severe malnutrition (<70%)

30 20 10 0

No G rm m rad al e al nu I: tri M (>9 0% tio ild n ) (8 090 G % ) m rad al e nu II tri : M G tio o m rad n ( der al e 7 nu II 0-8 ate tri I: S 0% tio e n ve ) (< re 70 % )

Total no of children

Percentage of reference for weight-for-height for girls and boys (0-5 years): Total no. of children taken for study works (50)

Figure 3. Percentage of reference for weight-for-height for girls and boys (0-5).

for children (both boys and girls), 38 (76%) were categorized as normal children in respect of nutritional status, whereas 9 children (18%) belonged to mild malnutrition group, 3 children (6%) grouped as moderate malnutrition and no child was marked as severe malnutrition group (Table 3 and Fig. 3). DISCUSSION Through this study, it has become possible for providing knowledge and motivation to ICDS health workers has boosted their confidence in tackling SAM children. Sensitization of staff of ICDS center has encouraged them to think of SAM children in their regular routine working procedures. Advocacy programs have enriched the knowledge and awareness among the Healthcare Providers of the said center. Moderate-to-severe malnourished children are referred to better healthcare facility center of the district where they are given proper nutritional and clinical management under the supervision of the doctors and dieticians and mothers are given proper health education regarding the practice of appropriate

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nutrition of their malnourished children. Number of malnutrition children (12) and their family members were given proper nutritional and clinical management advice and counseling. Prompt diagnosis and effective management of infections, diarrhea and others of the malnutrition children (12) have enabled them to have improved quality-of-life. CONCLUSION In India, the prevalence of SAM in children depicts a high figure of approximately 8.1 million as per survey report of NFHS-3, despite overall economic growth in India. Children with SAM are more prone to higher risk of dying than well-nourished children. So for, the prevention of death due to malnutrition in children, proper nutritional and clinical management is required. For this purpose, under National Rural Health Mission, Nutrition Rehabilitation Centres have been formed at different health facility centers of the districts to provide facility-based management to SAM children. The facilities are proper monitoring of the child care for 24 hours, early treatment of medical complications, therapeutic feeding, proper counseling of the mothers on right methods of feeding, care and hygiene, education program for the mothers and practical demonstration and practices on the preparation of energy enriched child foods which are locally available, acceptable to the children and affordable food items to the mothers. SAM children with complications like severe infections or diarrhea require hospital admissions for inpatient care and its incidence reaches less than 15% of children under 5 years. Eighty-five percent of such children can be managed in a home-based care. In this regard, a consensus statement by Indian Academy of Pediatrics (IAP) in the year 2013 regarding the integrated management of SAM states that management of SAM should not be a standalone program, but it should integrate with community management therapeutic programs and linkages with child treatment centers, district hospitals and tertiary level centers offering inpatient management of SAM and include judicious use of ready to use therapeutic foods. SUGGESTED READING 1. International Institute for Population Sciences (IIPS) and Macro International. 2007. National Family Health Survey (NFHS-3), 2005-06: India: Volume I. Mumbai: IIPS. 2. The WHO Child Growth Standards. WHO 2006. Available at http://www.who.int/childgrowth/en/. 3. WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards: Length/height-for-age, weightfor-age, weight-for-length, weight-for-height and body

COMMUNITY MEDICINE mass index-for-age: methods and development. Geneva: World Health Organization, 2006. 4. Child and Maternal Nutrition in India, USAID. Available at http://www.usaid.gov/in/Pdfs/mch_star.pdf. 5. Wahiqvist ML, Kouris Bazos A, Ross KA, Setter TL, Tienboon P. Growth and aging. In: Gibney MJ, Margetts BM, Kearney JM, Lenore A (Eds.). Public Health Nutrition. Blackwell Publishing; 2008. pp. 112-44. 6. Black RE, Allen LH, Bhutta ZA, Caulfield LE, de Onis M, Ezzati M, et al; Maternal and Child Undernutrition Study Group. Maternal and child undernutrition: global and regional exposures and health consequences. Lancet. 2008;371(9608):243-60.

8. Coutsoudis A, Bentley J. Infant feeding. In: Gibney MJ, MacDonald IA, Roche HM (Eds.). Nutrition and Metabolism. Blackwell Publishing; 2008. pp. 264-82. 9. Caulfield LE, de Onis M, Blössner M, Black RE. Undernutrition as an underlying cause of child deaths associated with diarrhea, pneumonia, malaria, and measles. Am J Clin Nutr. 2004;80(1):193-8. 10. Pelletier DL, Frongillo EA Jr, Habicht JP. Epidemiologic evidence for a potentiating effect of malnutrition on child mortality. Am J Public Health. 1993;83(8):1130-3.

11. Fishman SM, Caulfield LE, de Onis M, Blossner M, Hyder AA, Mullany L, et al. Childhood and maternal underweight. In: Ezzati M, Lopez AD, Rodgers A, Murray CJL (Eds.). 7. Ramakrishnan U, Nguyen P, Martorell R. Effects of Comparative Quantification of Health Risks: Global and micronutrients on growth of children under 5 y of Regional Burden of Disease Attributable to Selected Major age: meta-analyses of single and multiple nutrient interventions. Am J Clin Nutr. 2009;89(1):191-203. Risk Factors. Geneva: WHO; 2004. pp. 39-161. ■■■■

WHO Releases 1st Situation Report on Public Health Emergency The World Health Organization (WHO) has released its first situation report for the public health emergency that it announced on 1 February, after a spike in cases of microcephaly and Guillain-Barré syndrome in the Americas. These cases are strongly suspected to be linked to Zika virus, a mosquito-transmitted disease that has spread to more than 25 countries and territories in the region.

Summary ÂÂ An Emergency Committee was convened by the Director-General under the International Health Regulations (2005) on 1 February 2016. Following the advice of the Committee, the Director-General announced the recent cluster of microcephaly and other neurologic disorders reported in Brazil to be a Public Health Emergency of International Concern. ÂÂ The Emergency Committee agreed that a causal relationship between Zika infection during pregnancy and microcephaly is strongly suspected, though not yet scientifically proven. All experts agreed on the urgent need to coordinate international efforts to investigate and understand this relationship better. ÂÂ Between January 2014 and 5 February 2016, a total of 33 countries have reported autochthonous circulation of Zika virus. There is also indirect evidence of local transmission in 6 additional countries. ÂÂ The geographical distribution of Zika virus has been steadily increasing since it was first detected in the Americas in 2015. Further spread to countries within the geographical range of competent disease vectors — Aedes mosquitoes — is considered likely. ÂÂ Seven countries have reported an increase in the incidence of cases of microcephaly and/or Guillain-Barré syndrome concomitantly with a Zika virus outbreak. ÂÂ The global prevention and control strategy launched by WHO is based on surveillance, response activities, and research.

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DERMATOLOGY

Clinical Survey with Dermatologists on Benefits and Safety of Minoxidil 10% SUJEET N CHARUGULLA*, AMISHA AHUJA†

ABSTRACT Androgenetic alopecia (AGA) is one of the commonest disorders noted both in men and women, characterized by progressive loss of hair. According to an Indian population-based study (n = 1,005); the prevalence of AGA in Indian males aged 30-50 years was about 58%. Minoxidil is one of the most common treatments offered for hair growth among individuals diagnosed with AGA. While the efficacy of 5% Minoxidil solution has been demonstrated in various studies, there is not sufficient data on clinical use of the 10% formulation. Validating minOxIdil 10% by dermatologists ConsEnsus (VOICE) was a survey conducted across various regions in India to evaluate the dermatologists’ and patients’ perspectives related to the use of Minoxidil 10% formulation for hair growth in alopecia.

Keywords: Androgenetic alopecia, Minoxidil 10%, US Food and Drug Administration, dermatologists

ndrogenetic alopecia (AGA) is one of the commonest disorders noted both in men and women,1 characterized by progressive loss 2 of hair. Although the incidence of AGA is higher in men (affecting about 50% men), it increases greatly in women following menopause, affecting up to 75% women older than 65 years of age.1 The condition, both in terms of incidence and severity, is most prominent in Caucasians, followed by Asians and African Americans, and least common in Native Americans and Eskimos.1 According to an Indian population-based study (n = 1,005); the prevalence of AGA in Indian males aged 30-50 years was about 58%.3 In terms of the Norwood classification, certain studies have shown type 2 and type 3 to be the commonest presentation of AGA in Indian population.2 The condition has been known to significantly affect social well-being of the affected persons and cause significant negative impact on their quality-of-life.2 Accordingly, it is one of the commonest reasons for dermatological consultation.2

*Medical Affairs Dr Reddy’s Laboratories, Hyderabad †Consultant BioQuest Solutions Pvt. Ltd., Bangalore Address for correspondence

Dr Sujeet N Charugulla Medical Affairs TA Lead: Dermatology Dr Reddy’s Laboratories Ltd. 7-1-27, Ameerpet, Hyderabad - 500 016, Telangana E-mail: sujeetnc@drreddys.com

Minoxidil is one of the most common treatments offered for hair growth among individuals diagnosed with AGA.4 Although the exact mechanism remains unclear, it is believed to stimulate hair growth by prolonging the anagen phase of the hair cycle. Minoxidil 2% and 5% solutions have been approved by US Food and Drug Administration in the management of alopecia. Minoxidil has also been demonstrated to be effective in female pattern hair loss.5 While the efficacy of 5% Minoxidil solution has been demonstrated in various studies,5 there is not sufficient data on clinical use of the 10% formulation. Validating minOxIdil 10% by dermatologists ConsEnsus (VOICE) was a survey conducted across various regions in India to evaluate the dermatologists’ and patients’ perspectives related to the use of Minoxidil 10% formulation for hair growth in alopecia. SURVEY DESIGN About 200 dermatologists across various regions in India were invited to be a part of this survey. Their clinical experience related to the benefits and safety of Minoxidil 10% was documented with the help of a simple questionnaire. Each dermatologist was requested to share their clinical experience in at least 10 patients. RESULTS Overall, 200 dermatologists responded to this survey and shared their experiences related to 1,900 patients.

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DERMATOLOGY Among these, data related to 117 patients were incomplete. Data from the rest 1,783 patients were used for further analysis.

Patient Demographics Majority of the patients who visited the dermatologists were males (92.5%; n = 1,651). Only 7.4% females (n = 132) visited for hair loss. The mean age of the male population who visited the dermatologists was 31.9 years (±6.9; age range: 17-67 years) and females was 33.7 years (±10.4; age range: 16-70 years). Most of the patients (70%) who visited for complaints related to hair loss were in the range of 21-35 years. Majority of the patients had stage 3 (according to Norwood-Hamilton grading) hair loss (38.9%), followed by stage 2 (24.1%) and stage 4 (20.5%). The age-wise distribution of stages of hair loss is depicted in Figure 1.

appearance was noted in about 20% of the patients. In terms of hair density, dermatologists noted 20-40% improvement in hair density in more than 45% of patients, after 6 months of therapy with Minoxidil 10% treatment, while 40-60% improvement in hair density was noted in about 30% of patients (Fig. 3). Hair Growth Pattern after 6 Months Based on photographic analysis, after 6 months of therapy with Minoxidil 10%, dermatologists noted ‘moderate increase’ in hair growth pattern in about 47% of the patients, while ‘slight increase’ was noted in about 40% of the patients. Dermatologists noted a ‘significant (great) increase’ in hair growth in about 9% of the patients (Fig. 4). Hair Fall Reduction Dermatologists responded that about 40% patients had a 20-40% reduction in hair fall with Minoxidil 10%

Physicians’ Perspectives Regarding Use of Minoxidil 10%

Time Required for Result

Dermatologists reported that positive results were evident in majority of the patients (89.5%) within 2-6 months of Minoxidil 10% therapy (Fig. 2). Improvement in Scalp Appearance and Change in Hair Density According to the dermatologists’ response, more than half (55.2%) of the patients had 25-50% improvement in scalp appearance after 6 months of therapy with Minoxidil 10%, while 50-75% improvement in scalp Stage 1

Stage 2

Stage 3

Stage 4

Stage 5

Percentage of patients

44.8

30 20 10 0

8.2 2.2 2-3 months

8.7

0 51-65

>65

Age groups

Figure 1. Age-wise distribution of hair loss stages.

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46.7

40 29.5

30 20 10

3.6 36-50

Percentage of patients

33.3

21.7

23 14.5

12.5 1.6 2.9 21-35

33.3 33.3

30.4 30.4

38.1 20.1 7.7

3.7 3.7 4.9

≤20

55.2

21.0

20.2

17.2

3.6

0 0

7.4

>12 months

Stage 6

27.6

10-12 months

Figure 2. Duration of Minoxidil 10% treatment after which results are seen.

43.5

44.4 25.9

Percentage of patients

5-6 months

Duration of treatment

60 50

44.7

Indian Journal of Clinical Practice, Vol. 26, No. 9, February 2016

<25 25-50 50-75 >75 Improvement in scalp appearance (%)

6.5

<20 20-40 40-60 >60 Change in hair density (%)

Figure 3. Improvement in scalp appearance and change in hair density after 6 months treatment with Minoxidil 10%.

DERMATOLOGY treatment. Further, a hair fall reduction of 40-60% was noted in about one-third (31.7%) of the patients, with this treatment (Fig. 5).

(33.8%) had ‘slight improvement’ in their condition. Only about 3% of the patients felt that their condition remained unchanged (Fig. 6).

Patients’ Experience with Minoxidil 10%

Overall Satisfaction

Reduction in Bald Spot

About 60% patients were ‘much satisfied’ with Minoxidil 10% treatment, while one-quarter of patients (24.2%) were ‘very much satisfied’ with this treatment (Table 2).

Of the 1,783 patients; about 43.6% patients reported reduction in bald spot within 4-8 weeks of therapy, while about one-third patients (33.5%) reported improvements 8-16 weeks after initiating the Minoxidil 10% therapy (Table 1). Overall Improvement after 6 Months of Treatment Half of the patients (50%) believed that their condition had ‘moderately improved’ after 6 months of Minoxidil 10% therapy, while 13.2% reported ‘great improvement’ in their condition. About one-third of the patients

Greatly increased (9.4%)

Unchanged (3.5%)

Slightly increased (40.2%)

Safety Safety data related to 1,434 patients was available and was used to analyze the safety of Minoxidil 10%. Table 1. Time after Initiating Minoxidil 10% Therapy when Patient Noted Reduction in Bald Spot Size Duration

Frequency (%)

<4 weeks

147 (8.2)

4-8 weeks

776 (43.5)

8-16 weeks

597 (33.5)

>16 weeks

263 (14.8)

Total

1,783 (100)

Moderately increased (46.9%) Greatly improved (13.2%)

Unchanged (2.9%)

Slightly improved (33.8%)

Figure 4. Dermatologists’ response to treatment on the Norwood-Hamilton scale using photographic analysis, after 6 months of initiation of the treatment.

Moderately improved (50%)

50 44.4

45 Percentage of patients

40 35

31.7

Figure 6. Patient perception about Minoxidil 10% after 6 months of treatment.

30 25 20 15

14.3

13.6

Rating categories

10 5 0

<20%

Table 2. Patient Rating for Minoxidil 10% Treatment

<20-40%

40-60%

>60%

Percentage of hair fall reduction

Figure 5. Percentage of hair fall reduction with minoxidil 10% treatment.

Frequency (%)

Not at all satisfied (1 on the scale)

1 (0.1)

Slightly satisfied (2-4 on the scale)

265 (14.9)

Much satisfied (5-7 on the scale)

1,085 (60.9)

Very much satisfied (8-10 on the sale)

432 (24.2)

Total

1,783 (100)

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DERMATOLOGY Side Effects

Table 3. Stage-wise Therapy Discontinuation Rates

According to the dermatologists, side effects with Minoxidil 10% were reported by about one-fourth of the patients (25.52%), while the rest of the patients (74.48%) did not experience any side effects.

Stage of hair loss

Discontinuation Yes (%) (n = 198)

No (%) (n = 1,236)

Stage 1

2.53

3.72

Headache and lightheadedness were the most common side effects, accounting for more than half (59.6%) of the total side effect. Allergic reactions were reported in about 15% of the patients (Fig. 7).

Stage 2

22.73

24.27

Stage 3

32.83

41.34

Stage 4

29.80

19.01

Stage 5

10.10

9.14

Treatment Discontinuation

Stage 6

2.02

2.51

Of the 1,434 patients; only about 13.81% patients discontinued treatment, while the rest of the patients (86.19%) continued treatment. Resolution of the problem or condition was the main reason (~33%) for discontinuation, while the rest had discontinued

Table 4. Durations of Minoxidil 10% Treatment before Discontinuation Duration of treatment

Frequency (%)

≤ 30 days

5 (2.53)

31-60 days

11 (5.56)

Headaches and lightheadeness

Allergic reactions

61-90 days

24 (12.12)

Unwanted facial hair growth

Weight changes

91-180 days

66 (33.33)

≥181 days

41 (20.71)

Unknown

51 (25.76)

Total

198 (100)

Others

20.2% 9.6% 1.6%

59.6%

14.8%

either due to side effects (29.29%) or preference for alternative therapies (~30%) (Fig. 8). It was also noted that relatively more number of patients with stage 3 hair loss discontinued therapy (Table 3). Among 198 patients who discontinued Minoxidil 10% treatment, about one-third (33.33%) had discontinued it after 91-180 days of use, while more than 20% patients had continued the therapy for ≥181 days before discontinuing it (Table 4).

Figure 7. Common side effects of Minoxidil 10%.

35 29.29

Percentage of patients

29.80

32.83

CONCLUSION

25 20 15 10 5

4.04

0 Worsening of Side effects Preference Resolution of Not the condition for the problem available alternative or condition therapies Reason for treatment discontinuation

Figure 8. Reasons for treatment discontinuation.

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Indian Journal of Clinical Practice, Vol. 26, No. 9, February 2016

Based on the outcomes noted in the survey, it can be concluded that Minoxidil 10% therapy for hair loss was considered to be quite effective by both dermatologists as well as patients. Treatment results were evident as early as 2-6 months, with about 25-50% improvement in scalp appearance after 6 months of therapy and 20-40% reduction in hair fall. Side effects were noted in about 25% of the patients, with headaches and lightheadedness being the most common side effect. Nevertheless, about 60% of the patients felt that they were ‘much satisfied’ with the Minoxidil 10% therapy for hair loss.

DERMATOLOGY HIGHLIGHTS ÂÂ

ÂÂ

More percentage of men consulted dermatologists for hair loss than women (92.4% vs. 7.5%) with stage 2 (24.16%) and stage 3 (38.9%) being the most common stages of hair loss.

ÂÂ

Results were evident within 2-6 months of Minoxidil 10% therapy in about 90% of the patients.

ÂÂ

25-75% improvement in scalp appearance was noted after 6 months of Minoxidil therapy.

ÂÂ

Dermatologists noted a 20-40% reduction in hair fall with 6 months of Minoxidil 10% therapy in more than 40% of the patients.

ÂÂ

Majority of the patients (77.01%) reported reduction in bald spot size with Minoxidil 10% therapy within 4-16 weeks.

ÂÂ

Side effects were noted in about one-fourth of the patients with headaches and lightheadedness being the most commonly reported side effects.

About 85% patients much or very much satisfied with Minoxidil 10% therapy.

REFERENCES 1. Thomas J. Androgenetic alopecia - current status. Indian J Dermatol. 2005;50(4):179-90. 2. Kaliyadan F, Nambiar A, Vijayaraghavan S. Androgenetic alopecia: an update. Indian J Dermatol Venereol Leprol. 2013;79(5):613-25. 3. Krupa Shankar D, Chakravarthi M, Shilpakar R. Male androgenetic alopecia: population-based study in 1,005 subjects. Int J Trichology. 2009;1(2):131-3. 4. França K, Rodrigues TS, Ledon J, Savas J, Chacon A. Comprehensive review and treatment update of hair loss. J Cosmet Dermatol Sci Appl. 2013;3:1-8.

5. Gupta AK, Foley KA. 5% Minoxidil: treatment for female pattern hair loss. Skin Therapy Lett. 2014;19(6):5-7. ■■■■

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DIABETOLOGY

Diabetic Ketoacidosis: Clinical Characteristics and Precipitating Factors in a Tertiary Care Hospital, Bareilly, Uttar Pradesh AMIT VARSHNEY*, ROHIT SINGH†, TANVI SOOD‡, P NIGAM#

ABSTRACT Introduction: Diabetic ketoacidosis (DKA) is a potentially acute life-threatening complication of diabetes mellitus (DM) characterized by a biochemical triad of hyperglycemia, ketonuria and acidemia. Material and methods: This study was conducted at Shri Ram Murti Smarak Institute of Medical Sciences (SRMS-IMS), Bareilly between January 2013 and December 2014. The diagnosis of DKA was based on the presence of hyperglycemia (blood glucose ≥250 mg/dL) acidosis (arterial pH ≤7.3 or serum bicarbonate ≤15 mmol/L) and ketonuria (urine ketones ≥14). Results: Of the 80 patients were included in this study, 25.86% had type 1 DM (T1DM) and 74.14% had type 2 DM (T2DM). Twenty-two patients were excluded from the study. Among 58 DKA patients, 51.72% were female and 48.2% were male. Mean age of patients was 42.3 ± 8.2 years. Dehydration was the most common symptom and pneumonia was the most common precipitating factor. Conclusion: A significant proportion of DKA occurs in patients of T2DM and this can be prevented in many of these patients with proper investigation, education and effective communication with the healthcare provider during illness. Early diagnosis and treatment can avoid morbidity and mortality.

Keywords: Diabetes mellitus, diabetic ketoacidosis, hyperglycemia, clinical profile

iabetic ketoacidosis (DKA) is a potentially life-threatening acute complication of type 1 diabetes mellitus (T1DM) characterized by a biochemical triad of hyperglycemia, ketonemia (ketonuria) and acidemia.1 In accounts for 8-28%2 of all hospital admissions for diabetes mellitus (DM) with mortality rates of 0.15-0.3%.3,4

National Center for Health Statistics showed that most patients with DKA were between the age of 18-44 years (56%) and 45-65 years (24%), with only 18% of patients less than 20 years.5 DKA is also reported in type 2 DM (T2DM); however, it rarely occurs without

*Senior Resident †Post Graduate (2nd Year Resident) ‡Post Graduate (3rd Year Resident) #Professor Dept. of Medicine Shri Ram Murti Smarak Institute of Medical Sciences, Bareilly, Uttar Pradesh Address for correspondence

Dr Amit Varshney F-Block, Room No. 315 Shri Ram Murti Smarak Institute of Medical Sciences Bareilly - 243 001, Uttar Pradesh E-mail: varshneyamit25@gmail.com

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a precipitating event.6-8 Two-third of DKA patients were considered to have T1DM and 34% to have T2DM, 50% were female and 45% were non-white.5 Pathophysiology of DKA involves reduction of the effective insulin concentration in the body which is not able to match the glycemic overload either due to high intake or increased concentration of counter regulatory hormones (catecholamines, cortisol, glucagon and growth hormone). This imbalance leads to hypergylemia.9 Knowledge of factors which are associated with DKA are required to decrease the frequent episodes of DKA and improve the outcome of the disease. The purpose of the present study was to know the clinical profile and precipitating factors of DKA patients. MATERIAL AND METHODS The study was conducted in Dept. of Medicine, Shri Ram Murti Smarak Institute of Medical Sciences (SRMS-IMS), Bareilly between January 2013 and December 2014. A total of 80 patients of T1DM and T2DM admitted from the OPD and Emergency, were involved in this study. Patients were classified as T1DM and T2DM or

DIABETOLOGY noninsulin-dependent diabetes mellitus (NIDDM) on the basis of history and their medical record. History included age, sex, presenting feature, along with thorough general examination and systemic examination was done. Patients were diagnosed as DKA on the basis of criteria that were published by the International Society for Pediatric and Adolescence Diabetes (ISPAD).10 These are as follows: ÂÂ

Blood sugar of concentration >11 mmol/L

ÂÂ

Blood pH level <7.2

ÂÂ

Serum bicarbonate level <11 mmol/L

ÂÂ

Ketonuria.

patients presented with nausea and vomiting, 18 (31.0%) patients presented with polyuria and polydipsia, 22 (37.9%) were having blood pressure below 90/60 mmHg (Table 4). Mean blood glucose at the time of admission was 450 ± 87.5 mg/dL, mean arterial pH 7.12 ± 0.11, mean arterial bicarbonate 9.4 ± 4.9 mmol/L, serum potassium 4.2 ± 1.0 mmol/L and creatinine level 1.7 ± 0.8 were calculated (Table 5). On the basis of pH, patients were divided in mild, moderate and severe DKA. Among 58 patients, Table 2. Age Group Distribution of Diabetic Patients

The severity of DKA is classified11 based on the degree of acidosis into: ÂÂ

Mild: pH 7.2-7.3 (bicarb = 15-18 mmol/L)

ÂÂ

Moderate: pH 7.1-7.2 (bicarb = 10-14 mmol/L)

ÂÂ

Severe: pH <7.1 (bicarb <10 mmol/L).

Clinical profile, precipitating factor were analyzed.

Age (years)

No. of patients

Percentage (%)

18-30

31-40

17.5

41-50

51-60

18.7

≥60

8.80

Total

100

RESULT In this study, a total of 80 patients were included; among 80 patients, 22 (27.5%) did not achieve the diagnostic criteria of DKA and were excluded; among 58 patients of DKA, 28 (48.2%) patients were male and 30 (51.8%) were female; male-to-female ratio was 1:1.07 (Table 1).

Table 3. Precipitating Factor of DKA (n = 58)

The age of the patients ranged between 18-70 years with the mean age of 42.3 ± 8.2 years. The maximum number of diabetic patients were in the range of 40-50 years, i.e., 26 (32.5%). Only 7 patients (8.8%) of T2DM were greater than 60 years of age, whereas 18 (22.5%) were less than 30 years (Table 2). The most common precipitating factor was found to be pneumonia 15 (25.8%), followed by pulmonary tuberculosis 8 (13.7%), urinary tract infection (UTI) 7 (12.07%), stressful condition 7 (12.07%) and diabetic foot 3 (5.17%). Among 58 patients, 8 (13.79%) presented first time and in 5 (8.62%) patients precipitating cause was unknown (Table 3). Clinical presentation was analyzed and it was found that 40 (68.9%) patients were dehydrated, 31 (53.4%) Table 1. Sex Distribution of Total and DKA Patients Gender

DKA

Non-DKA

Total

Male

28 (48.2%)

10 (26.41%)

38 (47.5%)

Female

30 (51.8%)

12 (28.5%)

42 (52.5%)

Total

58 (72.5%)

22 (27.5%)

Precipitating factors

No. of patients

Percentage (%)

Pneumonia

17.24

Pulmonary TB

13.74

UTI

12.07

Diabetic foot

5.17

Stressful condition

12.06

Noncompliance

17.24

First presentation

13.79

Unknown

8.62

Table 4. Clinical Presentation in Patients with Diabetic Ketoacidosis (n = 58) No. of patients

Percentage (%)

Dehydration

68.9

Nausea/vomiting

53.4

Polyuria/polydipsia

31.0

Pain abdomen

20.7

Hypotension

37.9

Kussmaul breathing

17.2

Altered sensorium

13.8

Weakness

27.6

Constitutional symptoms

48.3

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DIABETOLOGY Table 5. Biochemical Profile of DKA Patients at the Time of Admission (n = 58) Variable

Values

Blood glucose (mg/dL)

450 ± 87.5

Arterial pH

7.12 ± 0.11

Arterial bicarbonate

9.4 ± 4.9

Serum Na+ (mmol/L)

132.1 ± 6.7

Serum

K+

(mmol/l)

4.2 ± 1.0

Blood urea

52 ± 12

Creatinine

1.7 ± 0.8

Table 6. Severity of DKA Patients (n = 58) No. of patients (%) Mild

12 (20.69)

Moderate

28 (48.28)

Severe

18 (31.03)

12 (20.69%) presented with mild DKA, 28 (48.28%) were having moderate DKA and 18 (31.03%) presented with severe DKA (Table 6). DISCUSSION Diabetic ketoacidosis is a life-threatening condition caused by a decrease in effective circulatory insulin along with an increase in counter-regulatory hormones (glucagon, catecholamines, cortisol and growth hormone) leading to hyperglycemia, hyperosmolarity, increased lipolysis, ketonemia and metabolic acidosis.12 In our study, a total of 80 patients presented in causality and OPD with the diagnosis of DKA. Among 80 patients, 22 were excluded from the study as didn’t meet the inclusion criteria. Out of 58 patients of DKA, 15 (25.86%) were of T1DM and rest 43 (74.14%) of T2DM. Higher number of T2DM may be attributed to its higher prevalence in population. In the study conducted by Seth et al,13 80% patients of DKA were of T2DM. In a study conducted at a large academic center it was observed that 21.7% had T2DM.14 Moreover, in a developing country like India, due to poor socioeconomic statistics, many patients with T2DM tend to have poor compliance and poor control of blood sugar level, so that DKA can be precipitate in any patient. National Center for Health Statistics and study by Adhikari et al also showed the same.5,15 Mean age of presentation in our study was 42.3 ± 8.2 years. It also points in favor of T2DM to be causing DKA more than

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T1DM. A number of studies were done which support this finding. In the studies by Seth et al,13 Adhikari et al,15 Kreisberg et al16 and Beigelman et al,17 the mean age reported 51.46, 44.78, 40-50 and 47 years, respectively. In our study, female (51.72%) are more as compared to males (48.2%), similar female preponderance was seen in the study of Onyiriuka et al.18 He observed 59.5% female as compared to 40.5% male. This finding can be explained by hormonal changes as level of estrogen is higher in females. In addition, cytokines such as interleukin (IL)-1, 6 and tumor necrosis factor-α (TNF-α) produced during stress antagonize the effects of insulin promoting the occurrence of DKA.19 As noted earlier, this basic pathogenesis of DKA is decrease in the effective circulatory insulin associated with an elevation in the serum counter-regulatory hormones.1,11 In our study, weakness (68.9%) was the most common symptom followed by nausea and vomiting (53.4%) and hypotension (37.9%). Thirty-one percent were complaining of polyurea and polydipsia. Only 17.2% of patient had Kussmaul breathing. Our results were supported by previous studies by Munro et al,20 Umpierrez et al21 and Adhikari et al.15 In our study, pneumonia is the most common infection precipitating DKA in 25.8% patients followed by sputum-positive pulmonary tuberculosis in 13.79% and 5.17% patients had diabetic foot. Several factors including hyperglycemia, leukocytosis dysfunction, macrovascular diseases and acidosis predispose the diabetic with ketoacidosis to common and rare infections. Adhikari et al showed diabetic foot as the infection precipitating DKA in 23-30% patients. The laboratory data for our patients presented in Table 5 are consistent with results that would be predicted with DKA. Potassium levels will tend to be high because of the physiologic hyperosmolarity and insulin deficiency present, although it is known that total body stores of potassium are depleted in DKA.22,23 CONCLUSION Diabetic ketoacidosis remains a frequently observed hyperglycemic emergency with a high incidence and fatality rate. A significant proportion of DKA occurs in patients with T2DM and this can be prevented in many of those patients with proper patient education and effective communication. Therefore, education of diabetic patients about warning symptoms of ketoacidosis such as weakness, abdominal pain, nausea, vomiting and drowsiness are mandatory for early diagnosis and treatment.

DIABETOLOGY REFERENCES

statement on diabetic ketoacidosis in children and adolescents. Arch Dis Child. 2004;89(2):188-94.

1. Norris AW, Wolfsdorf JI. Diabetes mellitus. In: Brook CGD, Clayton PE, Brown RS (Eds.). Brook’s Clinical Pediatric Edocrinology. 5th Edition, Oxford: Blackwell Publishing Ltd; 2005. pp. 436-73.

13. Seth P, Kaur H, Kaur M. Clinical profile of diabetic ketoacidosis: a prospective study in a tertiary care hospital. J Clin Diagn Res. 2015;9(6):OC01-4.

2. Umpierrez GE, Khajavi M, Kitabchi AE. Review: diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome. Am J Med Sci. 1996;311(5):225-33.

14. Newton CA, Raskin P. Diabetic ketoacidosis in type 1 and type 2 diabetes mellitus: clinical and biochemical differences. Arch Intern Med. 2004;164(17):1925-31.

3. Curtis JR, To T, Muirhead S, Cummings E, Daneman D. Recent trends in hospitalization for diabetic ketoacidosis in Ontario children. Diabetes Care. 2002;25(9):1591-6.

15. Adhikari PM, Mohammed N, Pereira P. Changing profile of diabetic ketosis. J Indian Med Assoc. 1997;95(10):540-2.

4. Edge JA, Ford-Adams ME, Dunger DB. Causes of death in children with insulin dependent diabetes 1990-96. Arch Dis Child. 1999;81(4):318-23. 5. Centers for Disease Control and Prevention. National Center for Health Statistics. Available at: http://www.cdc. gov/nchs/about/major/hdasds.html. 6. Welch BJ, Zib I. Case study: Diabetes ketoacidosis in type 2 diabetes: “Look under the sheets”. Clinical Diabetes. 2004;22(4):198-200. 7. Misra S, Oliver N, Dornhorst A. Diabetic ketoacidosis: not always due to type 1 diabetes. BMJ. 2013;346:f3501.

16. Kreisberg R. Diabetic ketoacidosis. In: Rifkin H, Porte D (Eds.). Diabetes Mellitus: Theory and Practice. 4th Edition, New York: Elsevier Science; 1990. pp. 591-603. 17. Beigelman PM. Severe diabetic ketoacidosis (diabetic “coma”). 482 episodes in 257 patients; experience of three years. Diabetes. 1971;20(7):490-500. 18. Onyiriuka AN, Ifebi E. Ketoacidosis at diagnosis of type 1 diabetes in children and adolescents: frequency and clinical characteristics. J Diabetes Metab Disord. 2013;12(1):47.

8. Balasubramanyam A, Zern JW, Hyman DJ, Pavlik V. New profiles of diabetic ketoacidosis: type 1 vs type 2 diabetes and the effect of ethnicity. Arch Intern Med. 1999;159(19):2317-22.

19. Mooney RA, Senn J, Cameron S, Inamdar N, Boivin LM, Shang Y, et al. Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor. A potential mechanism for cytokine-mediated insulin resistance. J Biol Chem. 2001;276(28):25889-93.

9. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335-43.

20. Munro JF, Campbell IW, McCuish AC, Duncan LJ. Euglycaemic diabetic ketoacidosis. Br Med J. 1973;2(5866):578-80.

10. Wolfsdorf J, Craig M, Daneman D, Dunger D, Edge J, Lee W, et al. International Society for Paediatric and Adolescent Diabetes clinical practice consensus guidelines 2009: diabetic ketoacidosis. Pediatr Diabetes. 2009;12(Suppl 12):118-33. 11. Wolfsdorf J, Glaser N, Sperling MA; American Diabetes Association. Diabetic ketoacidosis in infants, children, and adolescents: A consensus statement from the American Diabetes Association. Diabetes Care. 2006;29(5):1150-9.

21. Umpierrez G, Freire AX. Abdominal pain in patients with hyperglycemic crises. J Crit Care. 2002;17(1):63-7. 22. Ennis ED, Kreisberg RA. Diabetic ketoacidosis and the hyperglycemic hyperosmolar syndrome. In: LeRoith D, Taylor SI, Olefsky JM (Eds.). Diabetes Mellitus. Philadelphia, Pa: Lippincott Raven Publishers; 1996. pp. 276-86.

23. Adrogué HJ, Lederer ED, Suki WN, Eknoyan G. Determinants of plasma potassium levels in diabetic 12. Dunger DB, Sperling MA, Acerini CL, Bohn DJ, Daneman D, Danne TP, et al; LWPES. ESPE/LWPES consensus ketoacidosis. Medicine (Baltimore). 1986;65(3):163-72. ■■■■

Dietary Patterns Influence Cardiovascular Risk in Patients with Type 2 Diabetes Mellitus Findings of a cross-sectional study from Japan published February 4 in the Nutrition Journal suggest that dietary patterns correlated with risk factors for cardiovascular disease in patients with type 2 diabetes who had no history of cardiovascular disease. The “Seaweeds, Vegetables, Soy products and Mushrooms” pattern was associated with healthier lifestyles and less use of antidiabetic drugs. Patients with “Noodle and Soup” pattern had higher BMI, liver enzymes and triglycerides, while “Fruit, Dairy products and Sweets” pattern had lower blood pressure, γ -glutamyltranspeptidase levels, albuminuria and brachial-ankle pulse wave velocity. The study led by Yusuke Osonoi, Dept. of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Hongo, Bunkyoku, Tokyo concludes that dietary patterns could be a potentially important therapeutic target in order to achieve appropriate metabolic control and also prevent the onset of future cardiovascular disease in these patients.

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ENDOCRINOLOGY

Thyroid, Obesity and Thyromimetic Compounds PRAGATI KAPOOR*, PANKAJ KUMAR†, AK KAPOOR‡

ABSTRACT Obesity is one of the most important health risks of our times especially owing to modern lifestyle. An association between hypothyroidism and weight gain is well-documented and that thyroid hormones (THs) play a key role in regulating energy homeostasis. An inverse relationship between obesity and energy expenditure (EE) is also well-known. An increase in EE has long been considered for treating obesity. Hence, increasing EE with thyromimetic drugs constitutes an important line of management of obesity. Moreover, TH receptor activation has beneficial effects including lowering of low-density lipoprotein cholesterol and a reduction in whole body adiposity and weight. Selective thyromimetic compounds, though not clinically approved as yet, may be a big leap forward in this direction, because of a close association between THs and EE. The review encompasses the influence of TH in obesity, body mass index, dyslipidemia and thermogenesis. Besides, therapeutic potential of thyromimetic compounds in the treatment of obesity and dyslipidemia as well as their harmful effects have been outlined.

Keywords: Obesity, thyroid hormones, thyromimetic compounds

besity is defined as an excessive accumulation of body fat. Recent years have visualized an unprecedented increase in the prevalence of obesity world over, especially in industrialized nations.1 The enhanced prevalence is basically due to dietary changes associated with modern lifestyles. Obesity is one of the most important health risks of our time2 because of its association with an increased risk of diabetes, dyslipidemia, kidney disease, cardiovascular disease, all-cause mortality and cancer.3 Obesity, especially central obesity is linked to many endocrine abnormalities4 including thyroid dysfunction.5 Thyroid hormones (THs) are the prime regulators of metabolism and play a pivotal role in regulating energy homeostasis6 and a definite relationship exists between TH and obesity.5 Moreover, tri-iodothyronine (T3) regulates energy metabolism and thermogenesis, and plays a critical role in glucose and lipid metabolism,

*Assistant Professor Dept. of Cardiothoracic Surgery Nizam Institute of Medical Sciences, Hyderabad, Andhra Pradesh †Assistant Professor ‡Professor Dept. of Pharmacology Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh Address for correspondence

Dr AK Kapoor Professor Dept. of Pharmacology Rohilkhand Medical College and Hospital, Bareilly - 243 006, Uttar Pradesh E-mail: drakkapoor@rediffmail.com

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food intake and oxidation of fatty acids.5 Further, an association between TH and energy expenditure (EE) as well as an inverse relationship between obesity and EE are well-known. Thus, by increasing EE, obesity can be controlled. Hypothyroidism represented by a higher prevalence of overt and subclinical hypothyroidism (~20%) in morbid obese subjects,7 is generally associated with increased weight, decreased thermogenesis and metabolic rate. Studies support the clinical evidence that mild thyroid dysfunction is linked to significant changes in body weight and likely represents a risk factor for overweight and obesity.2 Moreover, subclinical and overt hypothyroidism correlated with higher body mass index (BMI) and higher prevalence of obesity in both smokers and nonsmokers.8 Conversely, thyroid hyper function leads to weight loss, which could be reversed by proper treatment.9 This partially justifies involvement of thyroid in obesity. Hence, the role of thyromimetic drugs have been explored because of the influence of TH in obesity and that these agents may provide an opportunity for the treatment of obesity or for weight loss. THYROID FUNCTION AND RELATIONSHIP BETWEEN TSH AND BODY WEIGHT IN EUTHYROID INDIVIDUALS Thyroid function is primarily determined by serum thyrotropin (TSH) concentration despite wide fluctuations in TSH levels among healthy individuals,

ENDOCRINOLOGY although variability exists regarding definition of normal thyroid function.10,11 Factors like ethnicity, age, sex, health status and probably, BMI may influence TSH normal range.12 First, the methods for measurement of TSH are highly different in terms of specificity, sensitivity, accuracy and confounding influences such as heterophilic antibodies, second, reference populations used as the basis for a normal range are highly different in terms of e.g., iodine intake, age, gender and presence of thyroid autoantibodies, and should not be confused with cut-off limits.13 Overt hypothyroidism is diagnosed when serum concentration of TSH is at or above 10 mU/liter with a low serum thyroxine (T4) level, while patients with TSH levels between 4 and 10 mU/liter, and serum T3 and T4 within the normal populationbased reference range are defined as having mild (or subclinical) hypothyroidism. However, a consensus on the exact limits for cut-off between normal and subclinical hypothyroid individuals is not around an immediate corner.10 Interestingly, thyroid dysfunction is more common in older persons. A low metabolic rate, which is associated with high TSH level, denotes longevity. Thus, mild hypothyroidism may be harmless or perhaps beneficial for elderly individuals. Studies suggest that even slight variations in thyroid function, lead to the development of regional obesity and tendency to gain weight.14,15 Besides, BMI has been negatively associated with serum free T4 (FT4), and fat accumulation has been associated with lower FT4,14,16 and higher TSH levels among slightly overweight euthyroid individuals, thereby resulting in a positive correlation between TSH and the progressive increase in weight with time.5,14-16 The correlation between TSH and BMI could be mediated by leptin produced by adipose tissue.17,18 TSH stimulates leptin secretion by human adipose tissue. Leptin physiologically regulates energy homeostasis and also affects thyroid deiodinase activities with activation of T4 to T3 conversion.5,19 These observations support the concept of an inverse relationship between TH and leptin. There are still surprising gaps and uncertainties regarding cardiac morbidity and mortality, since evidences are based on surrogate markers such as adverse lipid profile, endothelial dysfunction, increased arterial stiffness and cardiac performance.20 THYROID FUNCTION IN OBESE INDIVIDUALS Workers in the field have observed that in euthyroid obese individuals, the baseline serum TSH levels are generally in the upper limit (or slightly over it) of the normal range.7,21,22 Further, increased TSH levels are

positively correlated with elevated waist circumference and BMI and related to the degree of obesity.15,21 Further, a positive correlation has also been observed between serum leptin and serum TSH levels in obese individuals,21 which could reflect the positive association between TSH and BMI.14-16 Moreover, a moderate increase in total T3 or FT3 levels has been observed in obese individuals.23,24 Progressive fat accumulations have been associated with a parallel increase in TSH and FT3 levels irrespective of insulin sensitivity and metabolic parameters.23 A positive association has been reported between FT3 and FT4 ratio and both waist circumference and BMI in obese patients.23 This suggests a high conversion of T4 to T3 in patients with central fat obesity due to increased deiodinase activity.23 Interestingly, inspite of high plasma TSH levels, TSH receptors are less expressed on adipocytes of obese versus lean individuals, thus further elevating plasma TSH and FT3 levels.24 This sequence of events would be reversed by weight loss, which restores the size and function of mature adipocytes.24 Weight loss leads to significant decrease in both TSH and FT3,2325 thereby increasing reverse T3 (rT3) due to reduced 5â&#x20AC;&#x2122;-deiodination. The observations that increased TSH, FT3 and leptin levels in obese patients are decreased with weight loss supports the hypothesis that the alteration in thyroid function observed in obese subjects may be reversed by losing weight.26 It may be emphasized that evaluation of thyroid structure by ultrasound does not help to diagnose hypothyroidism in obese patients. It may be noted that hypothyroidism should be suspected in obese individuals with slightly increased TSH levels only after measuring plasma levels of THs and thyroid autoantibodies. A link between obesity and risk of autoimmune thyroid dysfunction (AITD); which is the main cause of hypothyroidism in adults, and TSH increase, leptin increase and thyroid morphology alteration have been noted as high levels of leptin increases susceptibility to AITD by regulating immune process, which in turn may facilitate development of subclinical or overt hypothyroidism.27 Though some authors have found that autoimmunity is not a major cause sustaining the high rate of subclinical hypothyroidism in morbid obese subjects. Morbid obese subjects with higher TSH concentrations have shown regularly higher levels of T3 and in some studies a high T4 levels as well.25 Further, an Italian study has reported that an increase in FT3 and TSH levels were also associated with BMI, waist circumference and fat accumulation.23

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ENDOCRINOLOGY One of the major functions of T3 is to control thermogenesis. T3 raises basal metabolic rate and promotes thermogenesis by inducing an increase in the mitochondrial respiratory chain activity.22 Conditions associated with a lack of physical activity exhibit an increase in serum rT3 levels that denotes an elevated thyroxine 3,5-deiodinase enzyme (D3) activity, which converts T3 to the inactive metabolite rT3.28 Resting EE (REE) depends on obligatory and adaptive thermogenesis. THs are important for adaptative thermogenesis characterized by an uncoupling of oxidative phosphorylation in cold exposed brown adipose tissue.29 Around 30% of obligatory thermogenesis depends on TH and this fraction is essential for temperature homeostasis.22 PATHOPHYSIOLOGY The possible mechanism that can unfurl the relation between obesity and thyroid gland activity are being actively explored, since there are conflictive data in the literature regarding relationship between obesity and TH. The positive association between TSH and BMI may be due to changes in TH activity or due to alterations in the regulation of hypothalamic-pituitary thyroid (HPT) axis.22 A direct effect of TSH may be responsible as TSH receptor is expressed in adipose tissue. Besides, there are a number of factors that contribute to FT3 levels in obese subjects. Moreover, a number of authors reported a direct relationship between FT3 and BMI.22 TSH seems to be positively related to degree of obesity.21 Further, a raised TSH levels in obese individuals may be the result of neuroendocrine dysfunction leading to an abnormal secretion rate of TSH. D2 is the main pituitary deiodinase isoenzyme and its activity is a prime factor to release TSH under T3 control, but it does not work properly or is damaged in obese subjects. Some investigators have suggested that there may be certain TH resistance, as well as decreased T3 receptors in obese individuals. Whereas, other authors have suggested presence of partially bioinactive TSH in obese subjects. Additionally, direct and indirect effects of decreased serum leptin contribute to a decreased activity of TRH neurons in paraventricular nucleus.22 SALIENT FEATURES RELATED TO THYROID HORMONE AND OBESITY

Insulin Resistance The link between thyroid disease and glucose metabolism is well-documented. Insulin sensitivity can be affected by thyroid function. Insulin resistance

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with hyperinsulinemia are main features of metabolic syndrome and usually accompany obesity.30 Insulin resistance noted in hypothyroidism is due to decreased tissue sensitivity to insulin, hence reduced glucose disposal. Though, insulin resistance in hypothyroidism is counterbalanced by a reduction in gluconeogenesis.

Thyroid and Adipokines Fat cells produce leptin are thus considered an active endocrine organ.5 Leptin physiologically regulates energy homeostasis. Relationship and modulatory role of leptin on the pituitary-thyroid axis has been investigated.22,31 A leptin regulatory effect on TSH secretion and BMI has been visualized though reasons for this relationship are not clear. Hypothyroidism has been associated with serum leptin levels below,32 above33 or in the normal34 range. Authors observed a significant positive correlation between circulating leptin and TSH levels in obese men and women, whereas correlation between leptin and age was negative.17,22 Leptin directly stimulates thyroid-releasing hormone (TRH) secretion29 and subsequently TSH and TH. Besides, leptin has been shown to have a direct inhibitory effect on several components involved in TH production from thyrocytes,31 and, leptin may directly affect the sensitivity of thyrotroph or the thyrocytes. Leptin modulates the neuroendocrine and behavior responses to overfeeding thereby regulating food intake and energy expenditure. Leptin also effects thyroid deiodinase activities with activation of T4 to T3 conversion.5,19 This supports the concept of an inverse relationship between TH and leptin. Additionally, serum ghrelin levels are reversibly increased by 32% in hypothyroid patients and that a relationship between ghrelin levels and thyroid function exist.35 THYROMIMETIC COMPOUNDS AND OBESITY A reduction in body weight can be achieved by a negative caloric balance though caloric deprivation usually results in reduction of both fat tissue (desirable) and fat-free mass. However, a reduction in fat-free mass is not desirable as loss of fat-free mass due to reduction in muscle tissue is partly responsible for a reduction in REE, which contributes to frequent phenomenon of weight regain. Intense caloric deprivation is usually associated with a decrease in plasma leptin, T3 and sometimes T4 concentrations, and a rise in rT3 as an adaptation process to reduce metabolic needs.36 A number of trials have been carried out to promote weight loss and avoid weight regain with TH supplementation. Selective modulation of TH actions

ENDOCRINOLOGY is an important therapeutic tool for the treatment of obesity and some of its complications. The purpose of thyroid hormone supplementation is to increase fat loss by increasing oxygen consumption and fatty acid oxidation without having either TSH suppression or side effects on muscle, central nervous system (CNS), bone or cardiac function.22 Several animal experimental studies as well as recent human clinical trials strongly point out that thyromimetics are an important group of pharmacological agents that can modify serum lipids without affecting heart rate and causing other major adverse events. Attempts have been made for rational drug designing of synthetic structural analogs of TH that may avoid the adverse cardiac effects of TH, while maintaining its calorogenic, thermogenic activity. It is well-known that TH receptor agonist has beneficial effects including lowering of low-density lipoprotein (LDL) cholesterol and a reduction in whole body adiposity and weight for this reason, TH agonists are among the first antiobesity agents. In a nutshell, they will be useful for the treatment of both obesity and hypercholesterolemia. THYROID HORMONES Thyroid hormones are the prime hormones for normal development and are major modulator of metabolic efficiency, EE and thermogenesis. Thyroid dysfunction is associated with changes in body weight and composition, body temperature, and total and REE independent of physical activity. Both subclinical and overt hypothyroidism are frequently associated with weight gain, decreased thermogenesis and metabolic rate.2 However, the mode of action of TH in promoting mitochondrial uncoupling, which reflects to THinduced calorigenesis and thermogenesis still remained elusive. Obesity and thyroid dysfunction are quite common yet TH have been inappropriately and frequently used to induce weight loss in obese euthyroid subjects; there is no indication for their administration to control body weight except in obese hypothyroid subjects. In fact, long-term treatment with TH does not significantly improve weight loss in obese subjects without thyroid dysfunction and may cause adverse effects.37 Moreover, TH have a plethora of physiological effects/targets hence their therapeutic usefulness in dyslipidemia and obesity is fairly limited. Lomenick et al38 investigated short-term and long-term changes in weight with T4 treatment of hypothyroidism in children. The authors did not support the view that hypothyroidism as a cause

of obesity, and observed that one should not expect significant changes in weight following treatment in most children with hypothyroidism. In a recent review exhibiting results observed in 14 studies with TH treatment (T3 administration) in obese patients submitted to caloric deprivation failed to draw any firm conclusions owing to heterogeneity in the quality and designs of these trials. No studies evaluated body composition vis-a-vis changes in fat tissues or fat-free mass components. Besides, only a few studies measure REE, nitrogen balance, protein breakdown and 3-methylhistidine urinary excretion, with no consistent results. No clear variations in heart rate were seen. Moreover, these studies did not demonstrate any sustained benefit on weight loss despite T3-induced subclinical hyperthyroidism.37 Thyroid extract were quite popular for treating obesity throughout the 20th century but were later abandoned due to severe side effects consisting of cardiac dysrhythmias, osteoporosis, electrolyte and loss of lean body mass.

Thyroid Hormone Receptors and Molecular Basis of Thyroid Hormone Action TH genomic action is mediated by binding of the hormone to nuclear THRs. Binding affinity is higher for T3 hormone than its T4 precursor. THRs are members of the family of nuclear receptors that regulate the expression of genes. THRs are encoded by the α and β C-erbA genes located on chromosomes 17 and 3, respectively, and are expressed as several spliced isoforms. The C-erbA α gene encodes the TH-binding receptor THR α1 and two spliced variants that do not bind hormone (THR α2 and THR α3), whereas the C-erbA β gene encodes the THRβ1, THRβ2 and THRβ3 isoforms. The three β isoforms differ in their aminoterminal domains. Both THRα1 and THRβ1 are expressed ubiquitously. However, THRα1 has its highest expression in skeletal muscles and cardiac muscle, bone and brown fat, whereas THRβ1 is highly expressed in liver, brain and kidney.39 Additionally, TH genomic action may be complemented by TH nongenomic action which require high dose.

Dextrothyroxine and TRIAC Thyroid hormone analogs have been used in past for reduction of fat mass or control of hyperlipidemia and weight loss while avoiding side effects on bone, brain and heart. A large number of TH analogs were synthesized and tested on experimental animal models for their lipid-lowering activity. Dextrothyroxine was

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ENDOCRINOLOGY the first such compound. Analogs may cause weight loss by increasing EE as well as improving lipid profiles in obese patients with low T3 during continued caloric deprivation, though use of dextrothyroxine for hyperlipidemia therapy has been unsuccessful.40 Tri-iodothyroacetic acid, a natural TH metabolite has shown thermogenic capacity in brown adipocytes in culture,41 yet no clinical studies demonstrated its efficacy in obesity treatment. The pace of development of thyroid analogs was slowed down firstly, because of associated mortality with use of analogs, and secondly, because of introduction of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitors, usually referred to as ‘statins’ into clinical practice to lower plasma cholesterol.

Selective Thyroid Hormone Receptor Activations Presence of selectivity has led to the resurgence of this novel class of drugs. The existence of distinct isoforms of THRs and the knowledge of their tissue distribution, regulation and crystal structure has given impetus for the development of selective thyromimetics. More recently agents with specific liver selectivity (affinity to THRβ isoforms) have been developed based on the so called HepDirect liver targeting approach. Thus, selective THRβ analogs have been designed to target liver by adding substituents that promote hepatic firstpass, rather than systemic distribution. Selective modulation of TH actions represents a promising therapeutic tool for the treatment of obesity and some of its complications. Mechanisms of TH action at the cellular level have shown that selective applications of different THR forms are responsible for tissue-specific responses to TH. There are two THR isoforms (α and β) that are encoded by two genes. Thus, THRα mostly present in brain and heart regulates cardiac function; while THRβ present in liver controls effects of TH on lipid metabolism.42 Further, THRβ1 is the systemic form, while THRβ2 is the pituitary form which controls TSH secretion. Investigators have opined that selective THR activation may be beneficial for therapeutic application in some diseases namely dyslipidemia and obesity. Thus, selective thyroid receptor activation for obesity treatment may bring about a rise in REE, a reduction in fat mass, an improvement in insulin sensitivity and lipid profile though, TH overexposure may cause adverse events such as muscle wasting, bone loss, nervousness, hypertension and cardiac dysfunction (arrhythmias, heart failure).22 Hence, development of

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THRβ-selective modulators which preferentially have an effect on liver metabolism will be a step in the right direction. Thus, selective compounds are synthetic structural analogs of TH having tissue-specific TH actions i.e., they bring about lowering of LDL cholesterol and fat loss by an effect on THRβ1 isoforms in the liver. They do not alter the heart rate mediated through THRα1 isoforms in the heart.43 Presently liver selective, cardiac-sparing TH analogs (THRβ-selective compounds) as lipid modifying agents have been developed and have been tested on different animals. A few such compounds are in various phases of human clinical trials. THRβ Agonists The first liver-selective, cardiac-sparing thyromimetics were produced by substitution of iodine moieties by arylmethyl groups at the 3’ position. Other structural TH analogs such as 3,5-diiodothyropropionic acid (DITPA) followed soon thereafter. Sobetirome A selective thyromimetic compound, GC-1 (3,5-dimethyl-4-(4-hydroxy-3-isopropylbenzyl) phenoxy acetic acid - sobetirome) has 10 times more selective action on THRβ1 than over THRα1. Since, affinity of GC-1 for THRα1 is 10 times lower than T3 hence less stimulation of heart rate in relation to increase in energy expenditure. The compound caused an increase in EE of 5-10% and mild tachycardia in mice.44 In a phase 1 clinical trial on 24 patients over 2 weeks. LDL cholesterol was reduced up to 41% at 100 μg/day.45 Further GC-1 administration to primates causes increase in oxygen consumption and reduction of body weight and minimal effect on skeletal muscle mass.46 Animal studies have shown that GC-1 may have a promising role as an antiobesity agent, since it reduces fat mass without increasing food intake and controls dyslipidemia, without causing a deleterious effects on heart or bone mass.45 It increases fatty acid oxidation, decreases inflammatory markers and reduction of liver steatosis and reduction in TSH. Sobetirome is generally well-tolerated and exhibits a promising role as an antiobesity agent. It causes no changes in heart mass, and skeletal mass is minimally affected and induces 20% reduction in fat mass without increasing food intake. KB-141 KB-141 is another THRβ agonist, is 10 times more selective for stimulating metabolic rate and 30 times more selective for cholesterol-lowering than for increase

ENDOCRINOLOGY in heart rate. Besides, KB-141 has been shown to cause weight reduction as well as reduction of cholesterol and lipoprotein(a).22 Increase in EE, reduction of fat mass, increase LDL receptor expression has been observed. GC-24 GC-24 again a THRβ agonist having 40-100 times preference for THRβ over THRα.47 It also reduces body fat accumulation and increases EE.48 These effects are noted without any change in food intake or a significant effect on myocardium. Besides, this compound reduces glucose response to glucose load, improves insulin sensitivity and normalizes the previous hypertriglyceridemia. Total cholesterol is marginally affected and there is no effect on free fatty acids or interleukin (IL-6) levels. Additionally, the compound has significant thermogenic effects as well as effects on EE.22 It prevents increase in fat mass, there reduction in cholesterol and triglycerides, reduction in TSH, T3 and T4 and it has no effect on heart. Eprotirome Chemically eprotirome (KB-2115) is 3-((3,5-dibromo4-(4-hydroxy-3-(1-methylethyl)-phenoxy) phenyl) amino)-3-oxopropanoic acid. It is also THRβ selective compound that has been administered to human beings. It has seven times greater affinity for the β isoforms of TH receptor than does T3.49 The tissue uptake of eprotirome is highly liver selective; uptake in nonhepatic tissues is minimal.50 KB2115 compound leads to 40% reduction in total and LDL cholesterol after 14 days treatment probably owing to an increase in bile acid synthesis. Also, there is a dose-dependent reduction in total and FT4 levels without any affect on TSH concentrations.51 In human data from a clinical trial of 98 hyperlipidemic patients, eprotirome caused 25% reduction in LDL apolipoprotein B, along with 37% decrease in lipoprotein A at 100 μg/day after 16 weeks. There was 40% decline in hyperlipidemia. No cardiac, bone or muscle effects were observed, though mild transient elevation in liver enzymes was noted.50 In phase II trial, eprotirome in combination with atorvastatin or simvastatin caused additional lipid reduction. However, phase III trials to evaluate eprotirome safety and efficacy profile was terminated because of cartilage damage.49 No changes in metabolic rate, body weight, EE or heart have been observed. 3,5-Diiodothyropropionic Acid DITPA chemically is 3,5-diiodothyropropionic acid. It is an early but less selective thyromimetic agent.

The compound has low THR selectivity. In animal experimentations, DITPA did increase the cardiac output by reducing the end-diastolic pressure but was without any positive chronotropic effects on the heart.49 A pilot study on DITPA in 19 patients led to increased cardiac index and decreased vascular resistance index.49 After 24 weeks, it reduced serum LDL cholesterol by 30% and increased cardiac index by 18%, but there was no evidence of symptomatic benefit in congestive heart failure (CHF).52 DITPA was poorly tolerated in a phase II clinical trial of 86 patients with CHF. DITPA was also associated with a significant reduction in body weight of 5.7 kg and an increased bone turn over.53 The compound caused suppression of the hypothalamic pituitary thyroid axis and increased bone turnover. Cardiac symptoms are unaffected.53,54 Reduction in TSH, T3 and T4 and increase in heart rate have been observed. MB07811 This prodrug undergoes first pass hepatic extraction and cleavage of prodrug generates the negatively charged active THR agonist (3,5-dimethyl-4-(4’hydroxy3-isopropyl benzyl) phenoxy) methylphosphonic acid (MB07344) in liver microsomes, which gets poorly distributed in most tissues and is rapidly eliminated into the bile.55 This is essential in limiting the extra hepatic side effects associated with this class of agents. In rats and mice, MB07811 reduces not only cholesterol and triglycerides levels but also hepatic steatosis. Further, in combination with atorvastatin it has additive effects on LDL cholesterol-lowering in animal models. The human phase 1b clinical trial also noted a reduction in LDL cholesterol and triglyceride levels. The main mechanism underlying MB07811 effects seems to be an increased metabolic rate in liver and specifically an increased rate of mitochondrial β-oxidation. Further, in therapeutic doses it is devoid of measurable extra hepatic effects.

Bile Acids Administration of bile acids can modulate EE as well as TH activation via changes in D2 expression, an enzyme involved in BAT thermogenic pathways that regulate EE.56,57 Kaempferol may increase skeletal myocyte oxygen consumption by increasing cAMP generation and inducing protein kinase A activation. Besides, the agent may influence expression of genes involved in thermogenesis, such as UCP-3, and to upregulate D2 gene expression; prolonging its half-life.58 These pathways may be targeted for the treatment of obesity and other metabolic disorders.

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ENDOCRINOLOGY USE OF THYROMIMETICS IN DYSLIPIDEMIA THRβ-selective thyromimetics serve as an important pharmacological tool to modify serum lipids and to treat dyslipidemia. The mechanism of lowering of LDL cholesterol by thyromimetics is different from that of statins, which are first-line drugs for the treatment of hypercholesterolemia. Interestingly, thyromimetics have synergistic action when combined with statins.53 Following are several mechanisms through which thyromimetics act in dyslipidemia.49 ÂÂ

The anti-atherogenic effects of selective thyromimetic is primarily due to upregulation of the LDL receptor in the liver, which leads to a strong reduction in plasma LDL particles, associated with a significant reduction in plasma total cholesterol and triglycerides.

ÂÂ

Inhibition of hepatic transcription factor, sterol regulatory element-binding protein 1 (SREBP-1), leading to reduced very LDL assembly.

ÂÂ

Facilitation of the reverse cholesterol transport, which describes the transport of cholesterol from extra hepatic tissues, for example plaque macrophages, back to liver for fecal excretion.

ÂÂ

Increase hepatic expression of the HDL receptor, scavenger receptor B-1 (SRBI), which increases the clearance of HDL cholesterol without affecting the HDL particle number, thus promoting the delivery of HDL cholesterol derived from atherosclerotic macrophages.

ÂÂ

In human beings, HDL cholesterol can be transferred to LDL particles through the cholesterylester transfer protein (CETP) and then cleared through hepatic LDL receptor. Hepatic cholesterol is than excreted into bile either directly by the transporters ABCG5 and ABCG8 or gets converted into bile acids by cholesterol 7 α-hydroxylase (CYP7A1). Both these mechanisms are facilitated by selective thyromimetics.

ÂÂ

Thyromimetics probably reduce intestinal absorption of dietary sterols due to competition with sterols of biliary origin.

Moreover, selective thyromimetics may have additive LDL cholesterol-lowering when used in combination with statins in animal models.59

Sobetirome reduces body fat in animal studies by increasing fatty acid β-oxidation and increasing oxygen consumption and body temperature. Besides, development and progression of hepatic steatosis is prevented owing to increased mitochondrial and peroxisomal fatty acid β-oxidation and reduced levels of inflammatory marker.54,61 Sobetirome is also less effective than THs in promoting weight loss.49 Similarly, MB07811 reduced hepatic steatosis through increased fatty acid oxidation in animal models. A reduction of hepatic and body fat may be beneficial for glucose homeostasis and type 2 diabetes.62 It may be emphasized, that long-term human clinical trials are required to prove whether thyromimetics will be of use in the treatment of obesity and hepatic steatosis.

Potential Harmful Effects Since, the selectivity of thyromimetics for THRβ and/or the liver is not absolute, but a relative one, hence high doses still activate THRα resulting in adverse events related to positive chronotropic and inotropic cardiac effects as well as enhance bone resorption and muscle catabolism.63 However, muscle and bone catabolism are fairly less common in therapeutic dose.49,50 Less selective DITPA has shown increased bone turnover in human trials.53 Landenson et al,53 in phase II study with DITPA, also noted poor tolerability profile in patients with pre-existing CHF. Development of positive chronotropic effect is deleterious in cases of CHF. Selective THRβ agents may influence regulation of HPT axis as this receptor is also expressed in the pituitary gland and regulates the feedback loop over TSH.49 In human being, eprotirome reduced serum T4, although TSH and serum T3 levels are not significantly affected.50,53 Besides, patients receiving eprotirome may also be watched for mild reversible increases in the levels of serum alanine aminotransferase and potential hepatic toxicity.53

Potential Limitations

USE IN OBESITY AND HEPATIC STEATOSIS

THRβ-selective thyromimetics may result in novel nongenomic effects, hence the safety of THRβ-selective thyromimetic have to be screened particularly in subjects suffering from CHF or coronary heart disease (CHD).52

THs reduce body fat by increasing basal metabolic rate without muscle wasting and effect on heart rate.45,60 Loss of weight was observed in the phase II clinical trial with DITPA.53

Some potential limitations of a liver-specific antisteatotic agent such as MB07811 are, firstly burning hepatic fat may not be sufficient for patients with nonalcoholic steatohepatitis (NASH) (those who really need

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ENDOCRINOLOGY therapy) because the metabolic imbalance, in particular peripheral insulin resistance, will continue and the beneficial effect of thyromimetics could be counteracted by increased lipogenesis in the liver or lipolysis in adipocytes, secondly burning hepatic fat may not be appropriate in a liver, which already has some degree of damage, thirdly systemic fibrogenic stimuli, such as hyperinsulinemia pathways may remain unaffected by thyromimetic agents. CONCLUSION TH-induced calorigenesis and thermogenesis have been shown to reflect uncoupling of mitochondrial oxidative phosphorylation though the mechanism remained elusive. Future therapy of obesity, fatty liver, type 2 diabetes, dyslipidemia, etc. needs designing of new compounds, which selectively modify different metabolic pathways. Till date, therapeutic usefulness of selective thyromimetics in the treatment of dyslipidemia, obesity and atherosclerosis is still hanging in balance at least till the final outcome of long-term phase III clinical trials. However, animal studies have shown that they are quite effective as lipid-lowering agents with minimal effects on heart rate and bone catabolism. Further, more knowledge and clinical trials are required to decipher mechanisms of action, safety and tolerability profile of newer agents. Moreover, newer thyromimetic agents should be safe to heart, bone, HPT axis and CNS. At the moment, the major indication of this novel class of drugs seems to be the treatment of dyslipidemia which is a major cardiovascular risk factor, and they have limited prospects in treating human obesity. REFERENCES 1. Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA. 2010;303(3):235-41. 2. Biondi B. Thyroid and obesity: an intriguing relationship. J Clin Endocrinol Metab. 2010;95(8):3614-7. 3. Golden SH, Robinson KA, Saldanha I, Anton B, Ladenson PW. Clinical review: Prevalence and incidence of endocrine and metabolic disorders in the United States: a comprehensive review. J Clin Endocrinol Metab. 2009;94(6):1853-78. 4. Kokkoris P, Pi-Sunyer FX. Obesity and endocrine disease. Endocrinol Metab Clin North Am. 2003;32(4):895-914. 5. Reinehr T. Obesity and thyroid function. Mol Cell Endocrinol. 2010;316(2):165-71. 6. Yen PM. Physiological and molecular basis of thyroid hormone action. Physiol Rev. 2001;81(3):1097-142.

7. Michalaki MA, Vagenakis AG, Leonardou AS, Argentou MN, Habeos IG, Makri MG, et al. Thyroid function in humans with morbid obesity. Thyroid. 2006;16(1):73-8. 8. Asvold BO, Bjøro T, Vatten LJ. Association of serum TSH with high body mass differs between smokers and neversmokers. J Clin Endocrinol Metab. 2009;94(12):5023-7. 9. Silva JE. Fat and energy economy in hypo- and hyperthyroidism are not the mirror image of one another. Endocrinology. 2010;151(1):4-6. 10. Brabant G, Beck-Peccoz P, Jarzab B, Laurberg P, Orgiazzi J, Szabolcs I, et al. Is there a need to redefine the upper normal limit of TSH? Eur J Endocrinol. 2006;154(5):633-7. 11. Surks MI, Goswami G, Daniels GH. The thyrotropin reference range should remain unchanged. J Clin Endocrinol Metab. 2005;90(9):5489-96. 12. Fatourechi V. Upper limit of normal serum thyroidstimulating hormone: a moving and now an aging target? J Clin Endocrinol Metab. 2007;92(12):4560-2. 13. Waise A, Price HC. The upper limit of the reference range for thyroid-stimulating hormone should not be confused with a cut-off to define subclinical hypothyroidism. Ann Clin Biochem. 2009;46(Pt 2):93-8. 14. Knudsen N, Laurberg P, Rasmussen LB, Bülow I, Perrild H, Ovesen L, et al. Small differences in thyroid function may be important for body mass index and the occurrence of obesity in the population. J Clin Endocrinol Metab. 2005;90(7):4019-24. 15. Fox CS, Pencina MJ, D’Agostino RB, Murabito JM, Seely EW, Pearce EN, et al. Relations of thyroid function to body weight: cross-sectional and longitudinal observations in a community-based sample. Arch Intern Med. 2008;168(6):587-92. 16. Alevizaki M, Saltiki K, Voidonikola P, Mantzou E, Papamichael C, Stamatelopoulos K. Free thyroxine is an independent predictor of subcutaneous fat in euthyroid individuals. Eur J Endocrinol. 2009;161(3):459-65. 17. Santini F, Galli G, Maffei M, Fierabracci P, Pelosini C, Marsili A, et al. Acute exogenous TSH administration stimulates leptin secretion in vivo. Eur J Endocrinol. 2010;163(1):63-7. 18. Oge A, Bayraktar F, Saygili F, Guney E, Demir S. TSH influences serum leptin levels independent of thyroid hormones in hypothyroid and hyperthyroid patients. Endocr J. 2005;52(2):213-7. 19. Zimmermann-Belsing T, Brabant G, Holst JJ, FeldtRasmussen U. Circulating leptin and thyroid dysfunction. Eur J Endocrinol. 2003;149(4):257-71. 20. Fazio S, Palmieri EA, Lombardi G, Biondi B. Effects of thyroid hormone on the cardiovascular system. Recent Prog Horm Res. 2004;59:31-50. 21. Iacobellis G, Ribaudo MC, Zappaterreno A, Iannucci CV, Leonetti F. Relationship of thyroid function with body mass index, leptin, insulin sensitivity and adiponectin in euthyroid obese women. Clin Endocrinol (Oxf). 2005;62(4):487-91.

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ENDOCRINOLOGY 22. Galofre JC, Fruhbeck G, Salvador J. Obesity and thyroid function: Pathophysiological and therapeutic implications. Hot Thyroidol. 2010;6:1-22. 23. De Pergola G, Ciampolillo A, Paolotti S, Trerotoli P, Giorgino R. Free triiodothyronine and thyroid stimulating hormone are directly associated with waist circumference, independently of insulin resistance, metabolic parameters and blood pressure in overweight and obese women. Clin Endocrinol (Oxf). 2007;67(2):265-9. 24. Nannipieri M, Cecchetti F, Anselmino M, Camastra S, Niccolini P, Lamacchia M, et al. Expression of thyrotropin and thyroid hormone receptors in adipose tissue of patients with morbid obesity and/or type 2 diabetes: effects of weight loss. Int J Obes (Lond). 2009;33(9):1001-6. 25. Kok P, Roelfsema F, Langendonk JG, Frölich M, Burggraaf J, Meinders AE, et al. High circulating thyrotropin levels in obese women are reduced after body weight loss induced by caloric restriction. J Clin Endocrinol Metab. 2005;90(8):4659-63. 26. Bray GA, Fisher DA, Chopra IJ. Relation of thyroid hormones to body-weight. Lancet. 1976;1(7971):1206-8. 27. Marzullo P, Minocci A, Tagliaferri MA, Guzzaloni G, Di Blasio A, De Medici C, et al. Investigations of thyroid hormones and antibodies in obesity: leptin levels are associated with thyroid autoimmunity independent of bioanthropometric, hormonal, and weight-related determinants. J Clin Endocrinol Metab. 2010;95(8): 3965-72. 28. van den Beld AW, Visser TJ, Feelders RA, Grobbee DE, Lamberts SW. Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J Clin Endocrinol Metab. 2005;90(12):6403-9. 29. Silva JE. The thermogenic effect of thyroid hormone and its clinical implications. Ann Intern Med. 2003;139(3): 205-13. 30. National Task Force on the Prevention and Treatment of Obesity. Overweight, obesity, and health risk. Arch Intern Med. 2000;160(7):898-904. 31. Feldt-Rasmussen U. Thyroid and leptin. Thyroid. 2007;17(5):413-9. 32. Iglesias P, Díez JJ. Influence of thyroid dysfunction on serum concentrations of adipocytokines. Cytokine. 2007;40(2):61-70. 33. Syed MA, Thompson MP, Pachucki J, Burmeister LA. The effect of thyroid hormone on size of fat depots accounts for most of the changes in leptin mRNA and serum levels in the rat. Thyroid. 1999;9(5):503-12. 34. Sesmilo G, Casamitjana R, Halperin I, Gomis R, Vilardell E. Role of thyroid hormones on serum leptin levels. Eur J Endocrinol. 1998;139(4):428-30. 35. Gjedde S, Vestergaard ET, Gormsen LC, Riis AL, Rungby J, Møller N, et al. Serum ghrelin levels are increased in hypothyroid patients and become normalized by L-thyroxine treatment. J Clin Endocrinol Metab. 2008;93(6):2277-80.

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36. Adler SM, Wartofsky L. The nonthyroidal illness syndrome. Endocrinol Metab Clin North Am. 2007;36(3):657-72, vi. 37. Kaptein EM, Beale E, Chan LS. Thyroid hormone therapy for obesity and nonthyroidal illnesses: a systematic review. J Clin Endocrinol Metab. 2009;94(10):3663-75. 38. Lomenick JP, El-Sayyid M, Smith WJ. Effect of levothyroxine treatment on weight and body mass index in children with acquired hypothyroidism. J Pediatr. 2008;152(1):96-100. 39. Pascual A, Aranda A. Thyroid hormone receptors, cell growth and differentiation. Biochim Biophys Acta. 2013;1830(7):3908-16. 40. Denke MA. Diet, lifestyle, and nonstatin trials: review of time to benefit. Am J Cardiol. 2005;96(5A):3F-10F. 41. Moreno M, de Lange P, Lombardi A, Silvestri E, Lanni A, Goglia F. Metabolic effects of thyroid hormone derivatives. Thyroid. 2008;18(2):239-53. 42. Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM, Mangelsdorf DJ. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell. 2006;126(4):789-99. 43. Webb P. Thyroid hormone receptor and lipid regulation. Curr Opin Investig Drugs. 2010;11(10):1135-42. 44. Trost SU, Swanson E, Gloss B, Wang-Iverson DB, Zhang H, Volodarsky T, et al. The thyroid hormone receptor-betaselective agonist GC-1 differentially affects plasma lipids and cardiac activity. Endocrinology. 2000;141(9):3057-64. 45. Villicev CM, Freitas FR, Aoki MS, Taffarel C, Scanlan TS, Moriscot AS, et al. Thyroid hormone receptor betaspecific agonist GC-1 increases energy expenditure and prevents fat-mass accumulation in rats. J Endocrinol. 2007;193(1):21-9. 46. Grover GJ, Egan DM, Sleph PG, Beehler BC, Chiellini G, Nguyen NH, et al. Effects of the thyroid hormone receptor agonist GC-1 on metabolic rate and cholesterol in rats and primates: selective actions relative to 3,5,3’-triiodo-Lthyronine. Endocrinology. 2004;145(4):1656-61. 47. Borngraeber S, Budny MJ, Chiellini G, Cunha-Lima ST, Togashi M, Webb P, et al. Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor. Proc Natl Acad Sci U S A. 2003;100(26):15358-63. 48. Amorim BS, Ueta CB, Freitas BC, Nassif RJ, Gouveia CH, Christoffolete MA, et al. A TRbeta-selective agonist confers resistance to diet-induced obesity. J Endocrinol. 2009;203(2):291-9. 49. Salam RF. Thyroxine mimetics. Egyptian J Int Med. 2013;25:171-6. 50. Koch L. Lipids: Eprotirome shows promise as a novel way to target dyslipidemia. Nat Rev Endocrinol. 2010;6(7):354. 51. Berkenstam A, Kristensen J, Mellström K, Carlsson B, Malm J, Rehnmark S, et al. The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans. Proc Natl Acad Sci U S A. 2008;105(2):663-7.

ENDOCRINOLOGY 52. Ladenson PW, Kristensen JD, Ridgway EC, Olsson AG, Carlsson B, Klein I, et al. Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med. 2010;362(10):906-16.

57. de Jesus LA, Carvalho SD, Ribeiro MO, Schneider M, Kim SW, Harney JW, et al. The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. J Clin Invest. 2001;108(9):1379-85.

53. Ladenson PW, McCarren M, Morkin E, Edson RG, Shih MC, Warren SR, et al. Effects of the thyromimetic agent diiodothyropropionic acid on body weight, body mass index, and serum lipoproteins: a pilot prospective, randomized, controlled study. J Clin Endocrinol Metab. 2010;95(3):1349-54

58. da-Silva WS, Harney JW, Kim BW, Li J, Bianco SD, Crescenzi A, et al. The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation. Diabetes. 2007;56(3):767-76.

54. Goldman S, McCarren M, Morkin E, Ladenson PW, Edson R, Warren S, et al. DITPA (3,5-Diiodothyropropionic acid), a thyroid hormone analog to treat heart failure: phase II trial veterans affairs cooperative study. Circulation. 2009;119(24):3093-100. 55. Erion MD, Cable EE, Ito BR, Jiang H, Fujitaki JM, Finn PD, et al. Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index. Proc Natl Acad Sci U S A. 2007;104(39):15490-5.

59. Tancevski I, Wehinger A, Demetz E, Hoefer J, Eller P, Huber E, et al. The thyromimetic T-0681 protects from atherosclerosis. J Lipid Res. 2009;50(5):938-44. 60. Cable EE, Finn PD, Stebbins JW, Hou J, Ito BR, van Poelje PD, et al. Reduction of hepatic steatosis in rats and mice after treatment with a liver-targeted thyroid hormone receptor agonist. Hepatology. 2009;49(2):407-17. 61. Perra A, Simbula G, Simbula M, Pibiri M, Kowalik MA, Sulas P, et al. Thyroid hormone (T3) and TRbeta agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats. FASEB J. 2008;22(8):2981-9. 62. Baxter JD, Webb P. Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes. Nat Rev Drug Discov. 2009;8(4):308-20.

56. Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, et al. Bile acids induce energy 63. Yehuda-Shnaidman E, Kalderon B, Bar-Tana J. Thyroid expenditure by promoting intracellular thyroid hormone hormone, thyromimetics, and metabolic efficiency. Endocr Rev. 2014;35(1):35-58. activation. Nature. 2006;439(7075):484-9. ■■■■

Regeneration in the Pituitary after Cell-ablation Injury The regenerative capacity of the pituitary is limited both in age-related terms and final efficacy, and appears to rely on stem cell-associated pathway activation, according to a study published in the journal Endocrinology. Dissection of the molecular profiles may eventually identify targets to induce or boost regeneration in situations of (injury-related) pituitary deficiency. This study meant to characterize this regenerative capacity in relation to age and recovery period and started to search for underlying molecular mechanisms. Extending the recovery period (up to 19 mo) does not result in higher regeneration levels. Previously it has been shown that Young-adult GHCre/iDTR mice, expressing diphtheria toxin (DT) receptor in GH-producing cells, regenerate the GH+ cells, as ablated by 3-day DT treatment (3DT), up to 60% after 5 months.

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INTERNAL MEDICINE

Detection of Pulmonary Nocardiosis Mimicking Tuberculosis: Role of Sputum Microscopy SHASHI CHOPRA*, SHAVETA DHIMAN†, GOMTY MAHAJAN‡, SILKY MAHAJAN#

ABSTRACT Background: Nocardiosis is an opportunistic infection and most commonly presents as pulmonary disease. Unless investigations like Gram’s stain and modified acid-fast stain are specially done, pulmonary infection may be mistaken for tuberculosis. They are useful for early diagnosis of Nocardia infection. Hence, the present study was conducted for the early detection of pulmonary nocardiosis mimicking tuberculosis by sputum microscopy with Gram staining, modified Ziehl-Neelsen (ZN) staining. Material and methods: The current study was conducted on 2,466 sputum samples over a period of 4 years from July 2011 to June 2015 for ZN staining for evaluation of pulmonary tuberculosis. Those sputum samples which were negative with 20% H2SO4 and showed weakly stained acid-fast bacilli (AFB) were confirmed for Nocardia by modified ZN staining with 1% H2SO4, Gram’s staining and culture. Result: Out of 2,466 sputum samples, 433 (17.55%) were found positive for AFB by microscopic examination. Ten (2.30%) out of 433 cases were positive for Nocardia. Amongst the Nocardia positive samples 7 (70%) were of male and 3 (30%) were of female. Conclusion: Gram’s staining and modified acid-fast stain are useful for early diagnosis and appropriate treatment of pulmonary nocardiosis.

Keywords: Pulmonary nocardiosis, sputum microscopy, modified Ziehl-Neelsen staining

ocardiosis is a rare disorder caused by Grampositive, weakly acid-fast, filamentous aerobic actinomycetes, which tends to affect the lung, brain and skin. The genus Nocardia belongs specifically to the family Mycobacteriaceae and contains tuberculostearic acid but differ from the mycobacteria by possession of shorter-chained (40- to 60-carbon) mycolic acids.1

Pulmonary nocardiosis is the most common clinical presentation and have several features similar to tuberculosis. It is a major cause of morbidity and mortality in immunocompromised patients.2 Lack of suspicion, nonspecific clinicoradiological presentation, diagnostic intricacies and lack of systematic reporting are the probable reasons that have hindered the true

estimation of its incidence, worldwide.3 In tuberculosis endemic countries like India, nocardiosis should always be excluded among patients not responding to antitubercular treatment. Early recognition and appropriate individualized treatment is the key to a successful outcome.2 New methodologies were developed for the identification of Nocardia, but evaluation of appropriate specimens by smear and culture remains the principal method of diagnosis.4,5 Unless investigations like Gram’s stain and modified acid-fast stain are specially done, pulmonary infection may be mistaken for tuberculosis and are useful for early diagnosis of Nocardia infection.6 Hence, the present study was conducted for the early detection of pulmonary nocardiosis mimicking tuberculosis by sputum microscopy with Gram staining, modified Ziehl-Neelsen (ZN) staining. AIM

*Professor †Tutor ‡Associate Professor Dept. of Microbiology #Tutor Dept. of Pathology Punjab Institute of Medical Sciences, Jalandhar, Punjab Address for correspondence Dr Shashi Chopra EJ 227-228, Chahar Bagh, Jalandhar City - 144 001, Punjab E-mail: dr.shashichopra@yahoo.com

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Early detection of pulmonary nocardiosis mimicking Mycobacterium tuberculosis by sputum microscopy. MATERIAL AND METHODS The current study was conducted on 2,466 sputum samples which were received in the Microbiology Department of a tertiary care hospital in North India,

INTERNAL MEDICINE over a period of 4 years from July 2011 to June 2015 for acid-fast bacilli (AFB) by ZN staining for evaluation of pulmonary tuberculosis. All the samples were processed in laboratory without delay in order to avoid contaminants to grow. Homogenization of sputum samples were done by Petroff’s method.7 Next, concentrated specimens were used for smear preparation and culture. Few slides on ZN staining showed weakly stained AFB with some filamentary structure. Nocardia spp. are acid-fast and can survive the decontamination of clinical specimens with sodium hydroxide method.8 These patient’s sputum samples were repeated with another two fresh sputum samples to exclude Nocardia by doing Gram’s staining and modified ZN staining9 using 1% H2SO4. On microscopic examination, Gram-stained smear showed thin, delicate, weakly to strongly Grampositive, irregularly stained or beaded branching filament and Modified ZN staining revealed filamentous acid-fast organism suggestive of Nocardia. Further 250 μL of each concentrated sputum specimen suspected to be Nocardia was inoculated onto Sabouraud’s dextrose agar (SDA) media and blood agar. All cultures were incubated at 37°C with 5% CO2 and humidity. Cultures were examined daily for the growth of Nocardia species for up to 3 weeks. On SDA, colonies were white to brown in appearance and on blood agar, filamentous colonies having chalky-white or cotton-ball appearance were seen.4 Colonies were examined with Gram staining and modified ZN staining methods to confirm the growth of Nocardia (Fig. 1).

Figure 1. Microscopic picture of Nocardia (Gram’s staining).

Male patients

Female patients

Figure 2. The percentage of Nocardia positivity in patients.

RESULTS Two thousand four hundred sixty-six samples from patients of all ages and both sexes were studied during a period of 4 years (July 2011 to June 2015). Out of the total, 73.52% were males and 26.48% were females. Of the total cases, 433 (17.55%) were found positive for AFB by microscopic examination. Ten (2.30%) out of 433 cases were positive for Nocardia, which were confirmed by Gram’s staining, modified ZN staining and culture. Out of these 10 cases 70% were males and 30% were female cases (Fig. 2). DISCUSSION Pulmonary nocardiosis is the most common clinical presentation of nocardial infection because inhalation is the primary route of bacterial exposure.10 It can be fatal if untreated. Untreated pulmonary nocardiosis is similar to tuberculosis and Nocardia asteroides is the most frequent cause of pulmonary infection in humans (85%).11 In the present study, we included 2,466 sputum samples, out of which 73.52% were from males and 26.48% were from female patients, whereas in a similar study done by other workers included 44.8% sputum samples of male and 55.2% sputum samples of females.12 Lungs are the most common site of involvement for tuberculosis and nocardia.13 In our study, 17.55% sputum samples were found positive for AFB, whereas other workers reported 7.6% positivity by microscopy examination.14 Pulmonary nocardiosis is the most common clinical presentation of infection and can occurs in persons of all ages, even neonates.10 In our study, out of 433 AFB positive sputum 10 (2.30%) were positive for Nocardia, whereas other workers reported it to be 3.57%,15 which was confirmed by

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INTERNAL MEDICINE Gram’s staining, modified ZN staining (1% H2SO4) and by culture. Nocardia incidence in pulmonary disease have been reported to be 1.4%, 2.7% and 4% by different workers in different area.16-18 McNeil and Brown highlighted the importance of direct microscopic examination because, despite the new methodologies developed, there is no test replacing it.4 Amongst the Nocardia positive samples, 70% samples were of male patients and 30% were of female patients almost similar results were reported by other workers also (75% and 25%, respectively).19 The exact reason for gender difference is not known though hormonal effect may be attributed to virulence or growth of Nocardia species.15 In India, the prevalence of Nocardia as reported in 1973 was 4.6% among patients who were suspected to have tuberculosis.20 The clinical diagnosis of nocardiosis is difficult. Signs, symptoms and radiologic studies may suggest the diagnosis but are not pathognomonic. Serologic diagnosis is unreliable, and serologic tests are not available commercially,5 so isolation and identification of the organism from the clinical specimens form the backbone for diagnosis of pulmonary nocardiosis. CONCLUSION This study highlights the importance of nocardiosis in differential diagnosis of pulmonary disease patients. The initial diagnosis of pulmonary nocardiosis requires fast and accurate methodology for early recognition and appropriate individualized treatment due to the clinical aspects and bacteriologic similarity to the genus Mycobacterium. The direct microscopic examination of sputum specially, with Gram’s stain and modified acid-fast stain with 1% sulfuric acid highlighted the importance in early diagnosis despite of the development of new methodologies. Hence, a microbiologist should process the respiratory tract specimens not only for Mycobacteria but should also be alert to the fact that organisms such as Nocardia may cause pulmonary infection. REFERENCES 1. Saubolle MA. Aerobic actinomycetes. In: McClatchey KD (Ed.). Clinical Laboratory Medicine. 2nd Edition. Philadelphia, Pa: Lippincott Williams & Wilkins; 2002. pp. 1201-20.

4. McNeil MM, Brown JM. The medically important aerobic actinomycetes: epidemiology and microbiology. Clin Microbiol Rev. 1994;7(3):357-417. 5. Saubolle MA, Sussland D. Nocardiosis: review of clinical and laboratory experience. J Clin Microbiol. 2003;41(10):4497-501. 6. Kulkarni SD, Baradkar VP, Kumar S. Pulmonary nocardiosis in an HIV infected patient. Indian J Sex Transm Dis. 2008;29(2):92-5. 7. Arora DR, Arora B. Textbook of Microbiology. 4th Edition, New Delhi: CBS Publishers & Distributors; 2012. p. 298. 8. World Health Organization. Laboratory Services in TB Control: Microscopy. Part II. Geneva, Switzerland; 1998. 9. Duguid JP. Staining methods. In: Colle JG, Duguid JP, Fraser AG, Marmion BP (Eds.). Mackie and McCartney Practical Medical Microbiology. 13th Edition, Edinburgh: Churchill Livingstone; 1989. pp. 46-9. 10. Lerner PI. Nocardia species. In: Mandell GL, Bennett JE, Dolin R (Eds.). Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. 4th Edition, Vol. 2. New York: Churchill Livingstone; 1995:227380. 11. Martínez R, Reyes S, Menéndez R. Pulmonary nocardiosis: risk factors, clinical features, diagnosis and prognosis. Curr Opin Pulm Med. 2008;14(3):219-27. 12. Abu-Saeed MB, Akanbi AA, Abu-Saeed K. Prevalence of nocardiosis in sputum of HIV positive/AIDS patients in a tertiary health institution in North Central Nigeria. Br Microbiol Res J. 2014;4(9):959-67. 13. Vohra P, Sharma M, Yadav A, Chaudhary U. Nocardiosis: A review of clinicomicrobiological features. Int J Life Sc Bt Pharm Res. 2013;2:20-9. 14. Ekrami A, Khosravi AD, Samarbaf Zadeh AR, Hashemzadeh M. Nocardia co-infection in patients with pulmonary tuberculosis. Jundishapur J Microbiol. 2014;7(12):e12495. 15. Swami T, Pannu S, Sharma BP. Pulmonary nocardiosis in immunocompromised patients of Bikaner. Int J Basic Appl Med Sci. 2013;3(2):362-6. 16. Maria CCM and Mendoza MT. Pulmonary nocardiosis in renal transplant recipients. J Microbiol Infect Dis. 2001: pp.144-52. 17. Alnaum HM, Elhassan MM, Mustafa FY, Hamid ME. Prevalence of Nocardia species among HIV-positive patients with suspected tuberculosis. Trop Doct. 2011;41(4):224-6. 18. Singh M, Sandhu RS, Randhawa HS, Kallan BM. Prevalence of pulmonary nocardiosis in a tuberculosis hospital in Amritsar, Punjab. Indian J Chest Dis Allied Sci. 2000;42(4):325-39.

2. Aggarwal D, Garg K, Chander J, Saini V, Janmeja AK. Pulmonary nocardiosis revisited: A case series. Lung India. 2015;32(2):165-8.

19. Shivaprakash MR, Rao P, Mandal J, Biswal M, Gupta S, Ray P, et al. Nocardiosis in a tertiary care hospital in North India and review of patients reported from India. Mycopathologia. 2007;163(5):267-74.

3. Beaman BL, Burnside J, Edwards B, Causey W. Nocardial infections in the United States, 1972-1974. J Infect Dis. 1976;134(3):286-9.

20. Reddy SS, Reddy KM, Saraswathi K. A rare case of pulmonary nocardiasis in an AIDS patient. Indian J Med Sci. 2010;64(4):192-5.

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FOR PRODUCTIVE COUGH

FOR DRY, IRRITATING AND ALLERGIC COUGH

FOR NOCTURNAL COUGH

2015 2016

in Cough Management

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

Sameer Malik Heart Care Foundation Fund An Initiative of Heart Care Foundation of India

E-219, Greater Kailash, Part I, New Delhi - 110048 E-mail: heartcarefoundationfund@gmail.com Helpline Number: +91 - 9958771177

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

Who is Eligible?

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

Objectives Assist heart patients belonging to economically weaker sections of the society in getting affordable and quality treatment. Raise awareness about the fundamental right of individuals to medical treatment irrespective of their religion or economical background. Sensitize the central and state government about the need for a National Cardiovascular Disease Control Program. Encourage and involve key stakeholders such as other NGOs, private institutions and individual to help reduce the number of deaths due to heart disease in the country. To promote heart care research in India.

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

Important Notes The patient must be a citizen of India with valid Voter ID Card/ Aadhaar Card/Driving License. The patient must be needy and underprivileged, to be assessed by Fund Committee. The HCFI Fund reserves the right to accept/reject any application for financial assistance without assigning any reasons thereof. The review of applications may take 4-6 weeks. All applications are judged on merit by a Medical Advisory Board who meet every Tuesday and decide on the acceptance/rejection of applications. The HCFI Fund is not responsible for failure of treatment/death of patient during or after the treatment has been rendered to the patient at designated hospitals.

To promote and train hands-only CPR.

Activities of the Fund Financial Assistance

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

Financial assistance is given to eligible non emergent heart patients. Apart from its own resources, the fund raises money through donations, aid from individuals, organizations, professional bodies, associations and other philanthropic organizations, etc.

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

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

Drug Subsidy

The HCFI Fund has the right to print/publish/webcast/web post details of the patient including photos, and other details. (Under taking needs to be given to the HCFI Fund to publish the medical details so that more people can be benefitted). The HCFI Fund does not provide assistance for any emergent heart interventions.

Check List of Documents to be Submitted with Application Form Passport size photo of the patient and the family A copy of medical records Identity proof with proof of residence Income proof (preferably given by SDM)

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

BPL Card (If Card holder)

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

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

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

Free Diagnostic Facility

Free Education and Employment Facility

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

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

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

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

About Heart Care Foundation of India

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

Heart Care Foundation of India was founded in 1986 as a National Charitable Trust with the basic objective of creating awareness about all aspects of health for people from all walks of life incorporating all pathies using low-cost infotainment modules under one roof. HCFI is the only NGO in the country on whose community-based health awareness events, the Government of India has released two commemorative national stamps (Rs 1 in 1991 on Run For The Heart and Rs 6.50 in 1993 on Heart Care Festival- First Perfect Health Mela). In February 2012, Government of Rajasthan also released one Cancellation stamp for organizing the first mega health camp at Ajmer.

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

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

Committee Members

Chief Patron

President

Raghu Kataria

Dr KK Aggarwal

Entrepreneur

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

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

Advisors Mukul Rohtagi Ashok Chakradhar

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

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

Rishab Soni

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

http://heartcarefoundationfund.heartcarefoundation.org

One Stop for All Diagnostics

MRI

Latest MRI by Siemens

CT Scan

16- Multislice Spiral CT

Health Packages

Executive Health Check Up

Ultra Short Magnet = No Claustrophobia

Safest Scanner

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Least Radiation Dose

Age Based Health Packages

Fully Automated Digital Pathology Laboratory - NABL Accredited

Immunology

Biochemistry

S-63 Greater Kailash Part 1 Opposite M Block Market, New Delhi 110048 Tel.: 011- 41234567

Haematology

Special Tests

INTERNAL MEDICINE

Self-injected “Harpic” Poisoning: A Case Report MANTU JAIN*, RITESH RUNU*, MANISH KUMAR*, SANTOSH KUMAR*

ABSTRACT Intentional poisoning that are nonfatal particularly with household products is a major public health problem in many developing countries including ours. Most of such poisoning is seen in young adults and related to family problems, marriage issues and professional or life settlement. The cheap and easy availability of toilet cleaners in household and shops and simplicity to carry or conceal make them one of favored product for consumption. Our patient was unique, where the mode of contact was self-injected. Such unconventional and novel route of consumption can pose difficulty in prompt diagnosis, management and can lead to permanent disability, which are unreported for the product.

Keywords: Harpic toilet cleaner, poisoning, injected, ulcer, necrosis, permanent disability

ommercially available harpic (10% hydrochloric acid [HCl] with butyl oleylamine) is used for home toilet cleansing. The contents being acidic can be toxic when used in any form by humans. We present a case, where a lady had injected harpic though a syringe in her left anterior elbow. Though the outcome was not catastrophic yet the purpose of this case report is to highlight the underlying changes in subcutaneous and muscles in this unusual intentional poisoning.

CASE REPORT A 35-year-old female paramedic presented to us with ulcerating wound over left anterolateral elbow since 4 days. Her past history revealed that she had bouts of depression and recently 4 days back after quarrel with her husband following which she loaded a 10 mL syringe with home toilet cleaner commercially available as “Harpic” (Fig. 1) and tried to inject intravenously in her left cubital area. On examination, the ulcer was 4 × 5 cm geographical in shape with inverted margin and necrotic base (Fig. 2). She had burning discomfort and there was painful full range of movement. Her distal pulsations and nerve examinations were normal. Fresh plain X-ray of left elbow anteroposterior and lateral did not reveal any bony involvement. Blood investigations were within normal limits.

*Dept. of Orthopedics Indira Gandhi Institute of Medical Sciences, Patna, Bihar Address for correspondence

Dr Mantu Jain E-mail: montu_jn@yahoo.com

Figure 1. Harpic the commercially available household toilet cleaner.

Figure 2. Clinical presentation of patient with ulceration over anterolateral elbow.

Indian Journal of Clinical Practice, Vol. 26, No. 9, February 2016

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INTERNAL MEDICINE Under short GA, the wound was extended both proximal and distally (Fig. 3). The muscles of superficial extensor compartment were found to be partially burned and were removed (Fig. 4). Deep compartment was not involved. Thorough wash was given and wound left open with wet dressing. An above elbow slab was applied. Postoperatively, the patient had a wrist drop, hence a cock up splint was added to the slab. After three sitting of dressings, the wound was closed secondarily on 7th day. Prognosis about radial nerve palsy was explained. When she came for followup after 5 weeks, she had regained her radial nerve power and was doing well.

DISCUSSION Poisoning due to household products is particularly common in our country. A study of poisoning cases reported to National Poisons Information Centre at All India Institute of Medical Sciences, New Delhi suggests: household products (44.1%) as the leading cause of such hospitalization.1 People consume these products which are easily available in a way of relieving their financial, personal and professional stress. The list of household items, which can be misused includes toilet cleansers, mosquito coil, spot remover, paint, flea/cockroach powder, correction fluid, hair color, shoe polish, liquid soap, detergent perfumes and fresheners.2 Khokhan et al found savlon (49.2%), harpic (34.3%), dettol (4.6%), shampoo (2.5%), Finix powder (1.6%) as common brands used for poisoning.3 The average house has an estimated 3-10 gallon of hazardous products.2 While it is accidental ingestion in children, it is intentional ingestion in adults (more common in teenagers) and inhalational in abusers/addictors.2-4 Our patient was unique in its unconventional mode of consumption of the poison that is injection, which has not been reported till now. Harpic contains HCl in a concentrations of around 10% along with butyl oleylamine. HCl is a chemical having a wide use in industry and domestic products. The substance is deleterious having strong corrosive property in concentrations greater than 10%. Substances with concentration up to 10% are classified as skin irritant to skin and those up to 4% are slightly irritating.5 Most of the domestic cleansers have composition in this range.

Figure 3. Intraop exploration of wound showing necrosis of muscles of superficial extensor compartment.

Figure 4. Post debridement picture of the wound.

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The toxicity of this product has not been determined. After ingestion of the product â&#x20AC;&#x153;Harpicâ&#x20AC;?, patient complaints of upper gastrointestinal irritation with symptoms of nausea, vomiting, burning, salivation and sore throat. In our patient, since, it was injected we believe it must have caused coagulation necrosis. The hydrogen ions desiccate epithelial cells producing an eschar leading to edema, erythema, mucosal sloughing and ulceration. The subcutaneous fat is destroyed by ester hydrolysis and even the muscle protein can undergo amide hydrolysis.6 Patients consuming household products are usually hospitalized for 1-2 days, seldom requiring more than 5 days treatment.3 No case of mortality was observed in their study by Khokan et al.3 Our patient was hospitalized for 8 days, however was lucky to escape without any permanent damage to the nearby neurovascular structure.

INTERNAL MEDICINE CONCLUSION Poisoning due to household products is common though underestimated in a developing country like ours. Prompt recognition and early treatment is important. This is an unusual case, where the mode of contact with poison was injection and self-induced. Though the quantity of this injectable was small yet the patient was lucky to escape without any catastrophic effect to the vital neurovascular structures in proximity, which could have led to permanent disabling. REFERENCES

2. Chaudhuri S, Das BC. Poisonous household items and their social impact. Indian J Res Pharm Biotechnol. 1(1):150-2. 3. Khokon K, Islam S, Basher A, Alam R, Faiz A. Patterns of self-poisoning by household substances. Int J Med Toxicol Foren Med. 2012;1(2):59-64. 4. Jesslin J, Adepu R, Churi S. Assessment of prevalence and mortality incidences due to poisoning in a South Indian tertiary care teaching hospital. Indian J Pharm Sci. 2010;72(5):587-91. 5. International Programme on Chemical Safety (IPCS). Hydrogen chloride. Screening Information Data Sets (SIDS). Organization for Economic Co-operation and Development (OCED). Geneva: WHO; 2002. pp. 1-9.

1. Srivastava A, Peshin SS, Kaleekal T, Gupta SK. An epidemiological study of poisoning cases reported to the National Poisons Information Centre, All India Institute 6. Naik RR, Vadivelan M. Corrosive poisoning. IJCP. of Medical Sciences, New Delhi. Hum Exp Toxicol. 2005;24(6):279-85. 2012;23(3):131-4. ■■■■

New Vaccines Added to the 2016 Adult Immunization Schedule The 2016 adult immunization schedule has added the recently licensed meningococcal serogroup B and human papillomavirus vaccines in its latest recommendations. Also, the interval recommendation for pneumococcal immunization has been changed between receipt of the 13-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal polysaccharide vaccine from “6 to 12 months” to “at least 1 year” for immunocompetent adults aged 65 years and older. The recommendations are published online February 2 in the Annals of Internal Medicine and on the Centers for Disease Control and Prevention website.

Bradycardia During Targeted Temperature Management Predicts Favorable Outcome in Out-of-hospital Cardiac Arrest Patients A post hoc analysis of a prospective randomized study conducted in 36 ICUs in 10 countries has confirmed an independent association of bradycardia and lower mortality and favorable neurologic outcome in a large group of comatose out-of-hospital cardiac arrest patients treated by targeted temperature management at 33°C. Bradycardia less than 50 beats/min was independently associated with lower 180-day mortality (hazard ratio adjusted = 0.50 and lower odds of unfavorable neurologic outcome (odds ratio adjusted = 0.38) in models adjusting for potential confounders including age, initial rhythm, time to return of spontaneous circulation and lactate at admission. The study with Jakob Hartvig Thomsen, Dept. of Cardiology, The Heart Centre, Copenhagen University Hospital Rigshospitalet, Denmark as the first author is published in the journal Critical Care Medicine.

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INTERNAL MEDICINE

Can Snake Bite Present as Jaundice - It Can! MANISH N MEHTA*, HEMANTH K ACHARYA†, AC TANNA‡, JEMIMA BHASKAR#, PRATIK M VORA$

ABSTRACT Snake bite with envenomation is very common in our country especially in the villages. Poisonous snakes belonging to Viperidae family produce hemotoxic effects and Elapidae (Kraits and Cobras) produce neurotoxic effects. Our patient had both hemotoxic and neurotoxic effects. In addition, he had jaundice which is very rare as one of the presentation of snake bite.

Keywords: Snake bite, envenomation, jaundice, hemolytic anemia, DIC, hemotoxic and neurotoxic effects

nake bite due to envenomation by Elapidae produces neurological problems including respiratory failure. One of the two patients had respiratory failure, but strangely he also had hemolytic anemia and jaundice. Envenomation being the cause of jaundice, he had both hemotoxic and neurotoxic features. Although, there was no evidence of disseminated intravascular coagulation (DIC) as the usual etiology of microangiopathic hemolytic anemia and jaundice in this patient, hemolysis and defibrination occurred due to direct effect of the toxin.

CASE REPORTS

Patient 1 History of snake bite in the right hand. Clinically, there were no signs of severe envenomation. He was given anti-snake venom. The next day patient had icterus. Investigations revealed as: ÂÂ

Hemoglobin (Hb) - 11.9 g/dL

ÂÂ

Total count (TC) - 15,800; differential count (DC) P60L33E4M3

ÂÂ

Platelets - 3,41,000 cells/mm3

ÂÂ

Reticulocyte count 1%

ÂÂ

Prothrombin time (PT) - 18.2 sec; international normalized ratio (INR) - 1.48; activated partial thromboplastin time (aPTT) - 34.8 sec

ÂÂ

Blood sugar/urea/creatinine - normal

ÂÂ

Peripheral smear: Microcytic, hypochromic picture with mild poikilocytosis, few pencil cells and target cells.

ÂÂ

Serum bilirubin - 5.0 mg/dL (direct - 1.8 mg/dL and indirect - 3.2 mg/dL)

ÂÂ

Serum glutamic pyruvic transaminase (SGPT) 37 IU/L

ÂÂ

Hepatitis B surface antigen (HBsAg)/hepatitis C virus (HCV)/hepatitis E virus (HEV) - negative.

Patient 2 History of snake bite in left foot. Patient had neurotoxic signs of envenomation with ptosis and went into respiratory failure and was intubated and given mechanical ventilation. He improved and was extubated after 3 days. He was given anti-snake venom and injection neostigmine. This patient also developed jaundice. Investigations revealed as:

*Professor and HOD †Professor and HOU ‡Assistant Professor #Senior Resident $First Year Resident Dept. of Medicine Govt. MP Shah Medical College and GG Hospital, Jamnagar, Gujarat Address for correspondence

Dr Jemima Bhaskar 404, Kings Palace, Opp. BSNL Telephone Exchange Mehul Nagar, Jamnagar - 361 006, Gujarat E-mail: jemimabhaskar@yahoo.com

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Indian Journal of Clinical Practice, Vol. 26, No. 9, February 2016

ÂÂ

Hb - 13.4 g/dL

ÂÂ

TC - 6,100 cells/mm3

ÂÂ

DC - P63L31E5M1

ÂÂ

Platelets - 1,28,000 cells/mm3

ÂÂ

DCT - negative , ICT - negative

ÂÂ

Blood sugar/urea/creatinine - normal

ÂÂ

Reticulocyte count 1%

ÂÂ

PT - 21.3 sec; INR - 1.37

INTERNAL MEDICINE ÂÂ

Serum bilirubin 3.1 mg/dL (direct - 1.1 mg/dL, indirect - 2.0 mg/dL)

ÂÂ

Peripheral smear - normocytic normochromic picture

ÂÂ

LDH >900 IU/L

ÂÂ

USG abdo-borderline hepatosplenomegaly.

DISCUSSION Snake venoms are complex mixtures of enzymes, low molecular weight polypeptides, glycoproteins and metal ions. Hemorrhagins promote vascular leakage and systemic bleeding. Proteolytic enzymes cause local tissue necrosis, affect the coagulation pathway and impair organ function. Neurotoxins act pre- and post-synaptically to inhibit peripheral impulses. Poisonous snakes belong to the families Viperidae, Elapidae (Kraits and Cobras) and Hydrophiidae. Envenomation by viperids causes local swelling, ecchymosis and hemorrhagic bullae. Systemic findings include tachycardia or bradycardia, hypotension, pulmonary edema, hemorrhage from any site and renal dysfunction. Envenomation by elapids causes neurological dysfunction with cranial nerve weakness manifested by ptosis, altered mental status, paralysis including the muscles of respiration and death due to respiratory failure. Rarely, hemotoxic effects are seen even in elapid bites. One of the hemotoxic effects in envenomation is DIC. DIC causes uncontrolled thrombin generation leading to fibrin deposits in microcirculation and consumption of platelets and clotting factors. These fibrin deposits lead to red blood cell damage and hemolysis. There is microangiopathic anemia and red cell fragmentation. In this disorder, the pathognomic feature is a microvascular lesion that results in luminal narrowing due to deposition of fibrin and platelets. These vascular changes produce shear stresses that mechanically injure passing red cells and cause hemolysis. In addition, snake venom per se can cause hemolysis.

form fibrin monomer in circulation which is cleared by fibrinolysis resulting in defibrination. These fibrin deposits lead to red cell damage and hemolysis. The intermediate stages of coagulation are not influenced and thrombocytopenia does not occur. In both patients, there was no laboratory evidence of DIC, namely thrombocytopenia, raised PT and/or aPTT. Hence, defibrination probably occurred by the second mechanism. In our patients, defibrination caused by the snake venom led to microangiopathic hemolytic anemia and direct hemolysis by the venom itself. This is most probably the cause of jaundice, a hemolytic jaundice caused by snake venom due to hemolytic anemia caused by defibrination syndrome and directly by the venom. There was no evidence of liver dysfunction and viral work-up for hepatitis viruses was normal. The work-up for congenital causes of hemolytic anemia was also normal. CONCLUSION This case reports were presented due to the rarity of two features, namely, snake bite causing both hemotoxic and neurotoxic features and envenomation presenting clinically as icterus. However, these rare features are possible as discussed in text above. SUGGESTED READING 1. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J (Eds.). Harrison’s Principles of Internal Medicine. 18th Edition, Volume 1, New York: McGraw Hill; 2012. 2. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J (Eds.). Harrison’s Principles of Internal Medicine. 18th Edition, Volume 2, New York: McGraw Hill; 2012. 3. Kumar V, Abbas AK, Fausto N, Aster JC (Eds.). Robbins & Cotran Pathologic Basis of Disease. 8th Edition, Saunders; 2010. 4. De Gruchy’s Clinical Haematology. 5th Edition, 2011.

5. Munjal YP, Sharma SK, Agarwal AK, Singal RK, Gupta P, Sundar S, et al (Eds.). API Textbook of Medicine. 10th Edition, Volume 2; 2015. ■■■■

The other mechanism of defibrination by a snake venom is a direct thrombin like action on fibrinogen. They

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OBSTETRICS AND GYNECOLOGY

Enlarged Ovaries Following IVF/ICSI as an Etiology of Obstructive Uropathy Resulting in Acute Renal Failure: A Case Report PRATIBHA VISHWAKARMA*, PRIYA MOHAN†, KUNDAVI SHANKAR‡, THANGAM R VARMA#

ABSTRACT In vitro fertilization (IVF) is one of the most comprehensively registered interventions in clinical medicine. IVF is regarded as safe with very few complications. We report a woman who developed acute renal failure due to compression of both ureters from enlarged stimulated ovaries. The condition was diagnosed using magnetic resonance imaging. It was treated with insertion of double-J stents in both ureters and dialysis. Compression of the ureters due to enlarged ovaries should be considered if a patient especially with pre-existing endometriosis develops acute renal failure following IVF.

Keywords: Acute renal failure, in vitro fertilization, ovarian hyperstimulation syndrome, ultrasound

uring the last 35 years, in vitro fertilization, (IVF) has become an important treatment option in patients with infertility. Following hormone stimulation, the oocytes are collected from the ovaries transvaginally using ultrasound guidance. The procedure is regarded as safe. The most common complications are hemorrhages, pelvic abscesses and pain. There are also some reports of ureteric damage after puncture by the collecting needle.1,2 We report a case, where a woman with pre-existing endometriosis developed acute renal failure due to compression of both ureters from enlarged stimulated ovaries. CASE REPORT A 28-year-old woman married for 8 years, with two previous first trimester miscarriages presented to us for treatment of secondary subfertility. She had history of 2 laparoscopies elsewhere suggestive of bilateral tubal block and extensive adhesions between tubes, ovaries

*Post Doctor Fellow †Private Practitioner ‡Senior Consultant #Medical Director Institute of Reproductive Medicine and Women’s Health Madras Medical Mission Hospital, Chennai, Tamil Nadu Address for correspondence Dr Pratibha Vishwakarma H. No. 1/2641, Street No-3, Loni Road, Ram Nagar, Shahdara, New Delhi -110 032 E-mail: pratibha_vish@yahoo.co.in

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and uterus suggestive of stage IV endometriosis. She had regular cycles with a body mass index (BMI) of 20. She had a past history of surgically corrected atrial septal defect at 5 years of age, asymptomatic; since then with good left ventricular ejection fraction. She had ureteric calculi diagnosed on both sides on ultrasound done outside with no renal changes 3 years back, for which she underwent conservative management. Her follicle-stimulating hormone (FSH) was 12.3 mIU/L and luteinizing hormone (LH) was 14.2 mIU/L, antimullerian hormone (AMH)-1.2 pmol/L with reduced antral follicle count with 2 cm endometriotic cyst on both ovaries. Kidneys were normal. Husband’s semen analysis was normal. Hysteroscopy and trial transfer was done as preIVF evaluation. She was counseled for therapeutic trial and a flexible antagonist protocol was followed. Recombinant FSH was used for stimulation. Five oocytes were retrieved under ultrasound guidance after 35 hours of human chorionic gonadotropin (hCG) trigger. Three embryos were fertilized and three 8 cell Grade A embryos were transferred without any difficulty. Six days following embryo transfer, she reported with loin pain and high-grade fever and reduced urinary output. There was no tenderness on abdominal examination. Investigations revealed normal leukocyte count with more than hundred pus cells on routine urine analysis. Renal function test revealed a picture of

OBSTETRICS AND GYNECOLOGY ectopic pregnancy. She was posted for an emergency laparoscopy as she was hemodynamically stable, which needed conversion to laparotomy in view of frozen pelvis. Approximately, 1 liter of blood and clots were removed along with necrotic and hemorrhagic tissue scattered in the abdominal cavity. Right tube was the seat of rupture and salpingectomy was done. Right ovary was stuck to the back of uterus, and left ovary stuck to lateral pelvic wall. Abdomen was washed with saline and a drain was placed. Two units of packed cells were transfused postoperatively. Histopathology confirmed ruptured ectopic gestation in the right tube. She was discharged in a stable condition. DJ stent was removed 6 weeks later. DISCUSSION Figure 1. Ultrasound showing bilateral stimulated enlarged ovaries compressing both ureters resulting in bilateral hydronephrosis.

pre-renal failure with a serum urea of 100 mg/dL and creatinine of 7.9 mg/dL. Serum electrolytes showed hyperkalemia. Investigations to rule out other causes of pyrexia were normal. Ultrasound showed bilateral enlarged ovaries measuring right 5 × 6 cm and left 6 × 7 cm and bilateral hydronephrosis (Fig. 1). Magnetic resonance imaging (MRI) scan showed bilateral hydronephrosis and enlarged ovaries, which led to compression of ureters. She was catheterized and her urine output was only 300 mL/24 hours. Nephrologist’s and urologist’s opinion were taken. Injection carbapenem following sensitivity to Klebsiella and extended-spectrum beta-lactamase (ESBL) growth on culture was started. Patient was transferred to nephrology department and dialysis was done as her creatinine showed increasing trend and persistent oliguria. Serum creatinine started to decline following dialysis. Double-J (DJ) stent was inserted. The postoperative course was uneventful and her creatinine level showed declining trends. Oral progesterone was continued as luteal support and on Day 16 of embryo transfer, β-hCG was positive. Her β-hCG showed an increasing trend. Renal sonogram was repeated and it was normal. The patient was asymptomatic and urine culture was negative. At 6 weeks from last menstrual period (LMP), ultrasound showed evidence of echogenic ring and presence of yolk sac with no cardiac activity and fluid collection was seen in the right adnexa suggestive of right

Transvaginally, ultrasound-guided oocyte retrieval has become the gold standard for IVF therapy. It is considered as a well-tolerated, cost-effective and safe procedure.3,4 A few cases of ureteral damage due to puncture of the ureter by the collecting needle have been described. In one case, the ureter was compressed by a stimulated ovary in a patient with a transplanted pelvic kidney.5 The diagnosis of ureteral compression was confirmed by MRI scan, a procedure without ionizing radiation and which should not cause any harm to fertilized embryos.6 Severe pelvic adhesions may have worsened the situation by limiting the normal movement of the ovaries. Ovarian hyperstimulation syndrome (OHSS) is a common complication in assisted reproductive technologies. In spite of frequent occurrence of abdominal compartment syndrome and oliguria in OHSS, acute renal failure secondary to obstructive uropathy is uncommon in OHSS.7 Acute renal failure due to a hypovolemic state following production of protein-rich ascites in patients with OHSS has been reported,8 but in this case, no ascites and only slight hemoconcentration was noted. The most pronounced finding was the huge enlargement of the ovaries and bilateral hydronephrosis. To date, there have been just two case reports of obstructive uropathy associated with OHSS.9 The patient was diagnosed earlier as having stage 4 endometriosis and frozen pelvis. Even though the complication risk related to IVF is low, one should be aware of a possible compression or damage to the ureters with subsequent development of acute renal failure. Injury, either by direct puncture or extrinsic compression, compromised ureteral function, but did not completely halt urination—a testimony to the

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OBSTETRICS AND GYNECOLOGY resilient nature of this structure and an intimation of more frequent, unrecognized injury. We, therefore, suggest that obstructive uropathy should also be considered as a possible etiology in patients with enlarged ovaries who develop oliguria or acute renal failure. REFERENCES 1. Coroleu B, Lopez Mourelle F, Hereter L, VeigaA, Calderon G, Martinez F, et al. Ureteral lesion secondary to vaginal ultrasound follicular puncture for oocyte recovery in in-vitro fertilization. Hum Reprod. 1997;12(5):948-50. 2. Miller PB, Price T, Nichols JE Jr, Hill L. Acute ureteral obstruction following transvaginal oocyte retrieval for IVF. Hum Reprod. 2002;17(1):137-8. 3. L enz S, Lauritsen JG, Kjellow M. Collection of human oocytes for in vitro fertilization by ultrasonically guided follicular puncture. Lancet. 1981;1(8230):1163-4.

5. Khalaf Y, Elkington N, Anderson H, Taylor A, Braude P. Ovarian hyperstimulation syndrome and its effect on renal function in a renal transplant patient undergoing IVF treatment: case report. Hum Reprod. 2000;15(6): 1275-7. 6. Vilos AG, Feyles V, Vilos GA, Oraif A, Abdul-Jabbar H, Power N. Ureteric injury during transvaginal ultrasound guided oocyte retrieval. J Obstet Gynaecol Can. 2015;37(1):52-5. 7. Malbrain ML, Cheatham ML, Kirkpatrick A, Sugrue M, Parr M, De Waele J, et al. Results from the International Conference of Experts on Intra-abdominal Hypertension and Abdominal Compartment Syndrome. I. Definitions. Intensive Care Med. 2006;32(11):1722-32. 8. Winkler J, Pinkas H, Tadir Y, Boner G, Ovadia J. Acute decline in renal function as a consequence of ovarian hyperstimulation syndrome. Nephron. 1992;60(1): 104-7.

9. 4. Tanbo T, Henriksen T, Magnus Ø, Abyholm T. Oocyte retrieval in an IVF program. A comparison of laparoscopic and transvaginal ultrasound-guided follicular puncture. Acta Obstet Gynecol Scand. 1988;67(3):243-6. ■■■■

Merrilees DA, Kennedy-Smith A, Robinson RG. Obstructive uropathy as the etiology of renal failure in ovarian hyperstimulation syndrome. Fertil Steril. 2008;89(4):992.e1-2.

Soy may Protect Against Detrimental Effects of Endocrine Disruptors Fertility in Women BPA is present in plastic water bottles and the lining of tin cans. Over 90% of people in the US have BPA in their urine and is linked to reproductive disorders. A Boston study has found that among women who were undergoing infertility treatment with assisted reproductive technologies, urinary BPA levels were related to nearly 50% lower chances of live birth among women who did not consume soy, but BPA levels had no impact on live births among women who did consume soy. Jorge E Chavarro, MD, ScD, associate professor at Harvard TH Chan School of Public Health, Boston, Massachusetts and first author of the study said, “Our study highlights the need to consider the possibility that the health effects of environmental chemicals can be modified by lifestyle factors such as diet.” The study is published January 27 in the Journal of Clinical Endocrinology & Metabolism.

Cervical Pessary use Reduces Spontaneous Preterm Birth Rate PECEP-Twins trial, a multicenter randomized-controlled trial from Spain, reported that insertion of a cervical pessary significantly reduced the spontaneous preterm birth rate. The trial was conducted in asymptomatic women with short cervical length (≤25 mm) carrying twins and reported in the February 2016 issue of the American Journal of Obstetrics and Gynecology by Maria Goya, Maternal Fetal Medicine Units, Dept. of Obstetrics at Hospital Universitari Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona and coauthors. The spontaneous preterm birth <34 weeks of gestation was significantly less frequent in the pessary group vs. the expectant management group, 16.2% vs. 39.4%, respectively. Use of pessary was also associated with a significant reduction in the rate of low birth weight <2,500 g.

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OBSTETRICS AND GYNECOLOGY

Neurocysticercosis - A Cause of Convulsions During Pregnancy: A Case Report JAYA KUNDAN GEDAM*, MINAL BHALERAO†

ABSTRACT Cysticercosis affects 50 million people worldwide. It is mostly seen in Central and South America, sub-Saharan Africa, India and Asia. Convulsions in pregnancy mostly results from eclampsia, epilepsy or central nervous system disorders. Neurocysticercosis is a common cause of adult-onset epilepsy. Neurocysticercosis is a rare cause of convulsions occurring for the first time during pregnancy and difficult to differentiate with other pregnancy related causes. We present a case with convulsions during pregnancy due to neurocysticercosis diagnosed by magnetic resonance imaging.

Keywords: Convulsions, pregnancy, neurocysticercosis

CASE REPORT A 23-year-old female, unbooked, gravida 2, para 1, at 26 weeks’ gestation, with history of one episode of generalized tonic-clonic seizures 2 hours before, reported to casualty. On examination, patient was drowsy. She was responding to verbal commands, no evidence of pallor, icterus, pedal edema and lymphadenopathy. She was afebrile and her vitals were stable. Systemic examination was normal including central nervous system (CNS) examination. On abdominal examination, uterus was 26 weeks size. External ballotment was present. She denied any history of seizures, right upper quadrant pain or visual changes. She was normotensive with no proteinuria. Her liver function and basic metabolic profile test results were normal. Her hemoglobin was 9.6 g/dL, white blood cell (WBC) count 10,000/mm3, platelet count 3,00,000/lac. Fasting blood sugar 82 mg/dL, blood urea nitrogen (BUN) 5 mg/dL, serum creatinine 0.5 mg/dL, serum total protein 5.8 g/dL, total bilirubin 0.8 mg/dL. She was started with tablet phenytoin with provisional diagnosis of grand mal epilepsy.

*Associate Professor †Senior Resident Dept. of Obstetrics and Gynecology ESI-PGIMSR, MGM Hospital, Parel, Mumbai, Maharashtra Address for correspondence Dr Jaya Kundan Gedam L-1, RH-2 Ground Floor, Sector-6, Vashi, Navi Mumbai, Maharashtra E-mail: jayagedam@gmail.com

On further evaluation, magnetic resonance imaging (MRI) study with contrast showed left high parietal vasculonodular stage of neurocysticercosis seen as 8 × 5 × 6 mm granuloma with perifocal edema and mass effect (Fig. 1). Diagnosis of neurocysticercosis

8 × 5 × 6 mm granuloma

Figure 1. MRI of brain using T1-weighted spin echo sequences: Left high parietal vasculonodular stage of neurocysticercosis seen as 8 × 5 × 6 mm granuloma with perifocal edema and mass effect.

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OBSTETRICS AND GYNECOLOGY was made. Anticysticercidal drug was started. Tablet albendazole was given for 1 month. She had second episode of tonic-clonic seizures along with enteric fever after 1 month. She received treatment for the same. She was irregular for her antenatal care (ANC) checkups. She reported with labor pains at term. She was admitted in ward. Fetal heart tracing was reassuring. With the diagnosis of full-term pregnancy with previous lower segment cesarean section (LSCS) with labor pains with neurocysticercosis, decision of emergency cesarean section was taken. She underwent LSCS under general anesthesia, delivered a 3.3 kg male child. Postoperative period was uneventful. Sutures were removed on postoperative Day 8. Wound was healthy. She was discharged in stable condition on tablet carbamazepine and levetiracetam. DISCUSSION Most common cause of convulsion during pregnancy is eclampsia accounting for 1 in 2,000 to 1 in 3,448 pregnancies in developed countries. Neurologic disorders may complicate pregnancy, leading to convulsions or altered mental status. Until the diagnosis is confirmed, all new-onset convulsions occurring during pregnancy should be considered eclampsia. However, new-onset seizures during pregnancy without increased blood pressure or proteinuria merit a full neurologic investigation to rule out cerebral, parenchymal or metabolic diseases. Convulsions are the most common cause of manifestations of brain abnormalities caused by Taenia solium cysticercosis in developing countries. In countries where it is endemic, cysticercosis may affect 2-4% of the population. The condition is caused by the encysted larval stage, Cysticercus cellulosae, of the pork tapeworm T. solium. Man is the only definitive host of T. solium harboring adult tapeworm in the intestine (teniasis), whereas both man and pig can act as intermediate hosts and harbor the larvae in different internal organs (cysticercosis) including brain neurocysticercosis. Human and pig both acquire cysticercosis through ingestion of eggs excreted in feces by human T. solium carrier. Cysticercosis may develop in tapeworm carriers through autoinfection. Cysticercosis is common in communities where pigs are allowed to roam freely, the residents consume undercooked pork and the basic sanitary facilities are lacking. Fecal contamination of the vegetables is the most likely mode of acquiring the disease in vegetarians.

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Both MRI and computed tomography (CT) are diagnostic of neurocysticercosis. In this patient, MRI studies combined with clinical history led to the diagnosis of neurocysticercosis. MRI is superior to a CT scan in such cases. Usually, scolex may be seen within the cyst wall as an eccentric, enhancing hyperdense spot on T1 sequences and is regarded as a pathognomonic feature. There is usually marked edema surrounding the cyst and contrast enhancement during the transitional phase, which diminishes during resolution. In 65% of cases with multiple lesions, small calcifications will also be seen, although each cysticercus may not necessarily calcify before resolution. Del Bruto et al have given diagnostic criteria for neurocysticercosis. They are as follows: ÂÂ

Absolute criteria: Histological proof, fundoscopic evidence and imaging (visualization of cyst).

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Major criteria: Imaging suggestive of neurocysticercosis, immunological test and plain X-ray revealing soft tissue shadow.

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Minor criteria: Subcutaneous nodule, intracranial calcification, clinical manifestation and response to cysticidal drug (lesions go away).

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Epidemiological criteria: Patient belonging to an endemic area, frequent travel to an endemic area and house-hold contact with T. solium.

The two principal serological tests in use are the enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunotransfer blot (EITB). The immunoblot is regarded as more reliable with a specificity of 100% and sensitivity of up to 97% in both blood and cerebrospinal fluid. Anticysticercidal drugs used are: Praziquantel and albendazole. They decrease the burden of parasites and are safe and effective, at least in reducing seizures and generalization. Initial treatment is control of seizures using antiepileptic drugs. Safe use of antihelminthics during pregnancy has been reported, these are often withheld until the postpartum period if symptoms are well-controlled. Antihelminthic drugs produce an inflammatory response around the cysticerci, thus, patients receiving them should receive corticosteroids during treatment. The diagnosis of neurocysticercosis was clear-cut in this patient with MRI features and clinical correlation. She was managed conservatively on antiepileptics and anticysticecidal drugs successfully. Neurocysticercosis should be kept in mind if the patient comes from an endemic area, even if they do not consume pork.

OBSTETRICS AND GYNECOLOGY SUGGESTED READING 1. Andersgaard AB, Herbst A, Johansen M, Ivarsson A, Ingemarsson I, Langhoff-Roos J, et al. Eclampsia in Scandinavia: incidence, substandard care, and potentially preventable cases. Acta Obstet Gynecol Scand. 2006;85(8):929-36. 2. Karnad DR, Guntupalli KK. Neurologic disorders in pregnancy. Crit Care Med. 2005;33(10 Suppl):S362-71. 3. Chestnut DH. Obstetric Anesthesia: Principle and Practice. 3rd Edition, Philadelphia: Elsevier Mosby; 2004. pp. 825-7. 4. Vazquez V, Sotelo J. The course of seizures after treatment for cerebral cysticercosis. N Engl J Med. 1992;327(10):696-701. 5. Prasad KN, Prasad A, Gupta RK, Pandey CM, Singh U. Prevalence and associated risk factors of Taenia solium taeniasis in a rural pig farming community of north India. Trans R Soc Trop Med Hyg. 2007;101(12):1241-7.

7. McCormick GF, Zee CS, Heiden J. Cysticercosis cerebri. Review of 127 cases. Arch Neurol. 1982;39(9):534-9. 8. Wadia NH. Neurocysticercosis. In: Shakir RA, Newman PK, Poser CM (Eds.). Tropical Neurology. London (UK): WB Saunders; 1996. p. 73. 9. Rajashekar V, Oommen A. Serological tests using ELISA and EITB in patients with solitary cysticercus granulomaand seizures. Neurol Infect Epidemiol. 1997; 2:177-80. 10. Garcia HH, Pretell EJ, Gilman RH, Martinez SM, Moulton LH, Del Brutto OH, et al; Cysticercosis Working Group in Peru. A trial of antiparasitic treatment to reduce the rate of seizures due to cerebral cysticercosis. N Engl J Med. 2004;350(3):249-58. 11. Takayanagui OM. Therapy for neurocysticercosis. Expert Rev Neurother. 2004;4(1):129-39.

12. Flisser A, Madrazo I, Plancarte A, Schantz P, Allan J, Craig P, et al. Neurological symptoms in occult 6. García HH, Del Brutto OH. Imaging findings in neurocysticercosis after single taeniacidal dose of praziquantel. Lancet. 1993;342(8873):748. neurocysticercosis. Acta Trop. 2003;87(1):71-8. ■■■■

Women Account for 40% of HIV Infection Cases in India Women continue to account for 40% of cases of HIV infection in the country, as reported in the Times of India Feb 8 by Sushmi Dey. There has been a 66% decrease in the number of new HIV cases in the last 5 years. There were 21.17 lakh HIV infection cases in the country in 2015 as compared to 22.26 lakh in 2007. Children below 15 years of age constituted 6.54% of the total cases. The cases of HIV infection in women are a cause of concern as this could hamper achieving the target of ending AIDS by the year 2030. Nochiketa Mohanty, country program manager, AIDS Healthcare Foundation said, “There is a huge need to ramp up education and awareness about HIV infection among women besides upgrading the social status of women in order to empower her to make choices related to her sexual partner. They fear getting identified socially because of the stigma attached to it.”

Perimenopausal Women with Migraine have More Headaches Results of the American Migraine Prevalence and Prevention Study published online in the journal Headache suggest that perimenopause and menopause are associated with high frequency headache in women with migraine. This cross-sectional observational study compared the frequency of headaches in these premenopausal, perimenopausal and menopausal women and found that the headaches increased with the approach of menopause, thus confirming the largely ‘anecdotal’ evidence. Among women who were premenopausal, 8.0% were in the high frequency headache group vs. 12.2% of perimenopausal vs. 12.0% of postmenopausal women. Richard B. Lipton, MD, director of the Montefiore Headache Center and the Edwin S. Lowe Chair in Neurology, Albert Einstein College of Medicine, Bronx, New York and co-author of the study said, “When headaches worsen during the menopausal transition, clinicians can explain the now-established connection with headache severity. This can be reassuring for patients.”

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ONCOLOGY

Malignant Peripheral Nerve Sheath Tumor Arising in a Neurofibroma: A Case Report MONICA KUMBHAT M*, LEENA DENNIS JOSEPH†, ARCHANA B*, ARULAPPAN‡

ABSTRACT Malignant peripheral nerve sheath tumor (MPNST) is a rare variety of soft tissue sarcoma of ectomesenchymal origin. These tumors present diagnostic difficulties in differentiating from other high-grade spindle sarcomas. This is a case of a 45-year-old lady who presented with pain and swelling in the groin for past 4 months, which on excision and histopathology revealed an MPNST in a neurofibroma.

Keywords: Malignant peripheral nerve sheath tumor, soft tissue sarcoma, ectomesenchymal, neurofibroma

alignant peripheral nerve sheath tumor (MPNST) is a malignant neurogenic tumor that occurs with high frequency (8-13%) in association with neurofibromatosis type 1 (NF-1), arising either de novo or in transition from neurofibroma.1 It either develops from peripheral nerves, pre-existing benign neurofibromas or schwann cells. NF-1 patients are more frequently diagnosed with MPNST in the third or fourth decades of life, whereas the sporadic form of MPNST is most frequently diagnosed in the sixth or seventh decades of life. CASE REPORT

On ultrasound, there was a well-defined heterogeneous mass involving predominantly deep subcutaneous and muscular planes of proximal right thigh measuring 9.7 × 5.7 × 5.8 cm. Fine needle aspiration cytology (FNAC) of the same lesion showed fibrocytes, mature adipocytes, a few spindle-shaped cells with sharp ends suggestive of wavy nerve fibers. She had history of excision of the swelling in the same region 2 years ago, which was histologically proved to be a neurofibroma. In the same region, the patient presented with the present swelling. On excision of the mass, histologically it showed an undifferentiated pleomorphic sarcoma (Fig. 3), which was confirmed on immunohistochemistry

A 45-year-old female developed pricking type of pain in the right groin extending to right knee for a duration of 4 months. There was also a history of fever on and off for 1 month. She gave a history of neurofibromatosis for 35 years. On local examination, a large neurofibroma was seen in the right inguinal region. Neurofibromas were also seen in the knee and arms (Figs. 1 and 2).

*Postgraduate Student †Professor Dept. of Pathology ‡Professor Dept. of General Surgery Sri Ramachandra Medical College, Chennai, Tamil Nadu Address for correspondence

Dr Leena Dennis Joseph Professor Dept. of Pathology Sri Ramachandra University, Porur, Chennai - 600 116, Tamil Nadu E-mail: leenadj@gmail.com

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Figure 1. Single, small neurofibroma seen on lateral aspect of the left knee.

ONCOLOGY to be positive for vimentin and S-100 (Fig. 4) suggesting a neural origin. The tumor cells were markedly pleomorphic with increased mitosis, many of them being atypical. Thus, a diagnosis of MPNST in a neurofibroma was given. Patient was referred to a radiation oncologist for further management. DISCUSSION MPNST is a rare malignant tumor with poor prognosis accounting for 3-10% of all soft tissue sarcomas. It is the second most common variety of soft tissue sarcomas seen. A combination of gross and microscopic findings along with immunohistochemical studies is commonly used to diagnose a case of MPNST.

Figure 2. Both arms showing multiple neurofibromas of varying sizes.

Figure 3. Pleomorphic tumor cells with mitotic figures (H&E x400).

Figure 4. S-100 positivity in the tumor cells (IHC x100).

These tumors occur in equal frequency in males and females and some series have shown a female preponderance. The majority of these tumors are seen involving the extremities; although tumor were also seen in unusual sites, such as the pelvis, retroperitoneum and infratemporal fossa. Imaging is routinely performed to assess the extent of the disease and plan surgical resection. However, it does not reliably determine the malignant transformation from neurofibroma to MPNST. Magnetic resonance imaging (MRI) is the investigation of choice because it can reveal the nerve of origin. Grossly, the tumor size ranges from 4 to 24 cm in greatest dimension.2 Histologically, following criteria are used for the diagnosis of MPNST: a) Gross fusiform tumors in relation to nerves; b) microscopic feature of spindle cell with fascicular pattern and varying degrees of mitosis, necrosis and tumor calcification; c) presence of associated benign neurofibroma or schwannanian cells and d) positive immunohistochemical staining for S-100 protein, neuron-specific enolase and others like actin, cytokeratin, smooth muscle actin and vimentin to differentiate from other spindle cell sarcomas. The tumors are classified as low-grade and high-grade on the basis of their cellular differentiation, mitotic count, tumor necrosis and expression of MIB-1 proliferation marker.3 However, it is not always possible to demonstrate the origin from a nerve, especially when it arises from a small peripheral branch. This point was exemplified in a series by Nambisan et al, in which nerves could not be identified in 61% of cases of MPNST and in the series Bilge et al, in which nerve origin could be identified only in 45-56% cases.4 Still, there are several other distinct features, such as proliferation of tumor in the subendothelial zones of vessels with neoplastic cells

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ONCOLOGY herniating into vessel lumen and proliferation of small vessels in the walls of the large vessels, which are very characteristic features of MPNST. Syndromes that are associated with MPNST are NF-1 and NF-2. Histologically, strict morphologic criteria must be applied to distinguish the spectrums of MPNSTs from cellular schwannoma, atypical and malignant meningioma and from a variety of rarely occurring intracranial sarcomas, such as high-grade pleomorphic sarcoma “malignant fibrous histiocytoma” fibrosarcoma, synovial sarcoma and leiomyosarcoma. On the benign side of the spectrum, cellular schwannoma is another tumor to be distinguished from MPNST. This tumor is particularly prone to be mistaken for malignancy, given the presence of hypercellularity, mitotic activity, and occasional locally aggressive growth. Strong S-100 protein as well as collagen IV/laminin immunoreactivity is the rule in this tumor. With respect to separating MPNST from benign nerve sheath tumors, p53 may be useful, strong immunostaining being seen in the majority of MPNSTs.5 Ten percent of MPNSTs exhibit focal divergent differentiation, either mesenchymal (rhabdomyosarcoma, chondrosarcoma, osteosarcoma, angiosarcoma) or epithelial (mucin-producing, neuroendocrine or squamous type). CONCLUSION MPNSTs are aggressive, high-grade, therapy resistant and associated with poor prognosis. A combination of clinical, pathological and immunohistochemistry helps in diagnosing these tumors. Proliferation marker (MIB1) can be a good adjunct to grade and tailor the

treatment in MPNST. Sex and cellular differentiation are the new adverse prognostic factors for survival of the patients. Postoperative radiotherapy has a definitive role in both disease free and overall survival. Though multimodality therapy, including surgical resection and adjuvant radiotherapy, is available, the prognosis remains dismal. Modern clinical studies and the development of effective targeted chemotherapy are needed to gain control of the disease. REFERENCES 1. Sun D, Tainsky MA, Haddad R. Oncogene Mutation Survey in MPNST cell lines enhances the dominant role of hyperactive Ras in NF1 associated pro-survival and malignancy. Transl Oncogenomics. 2012;5:1-7. 2. Kar M, Deo SV, Shukla NK, Malik A, DattaGupta S, Mohanti BK, et al. Malignant peripheral nerve sheath tumors (MPNST) - clinicopathological study and treatment outcome of twenty-four cases. World J Surg Oncol. 2006;4:55. 3. Trojani M, Contesso G, Coindre JM, Rouesse J, Bui NB, de Mascarel A, et al. Soft-tissue sarcomas of adults; study of pathological prognostic variables and definition of a histopathological grading system. Int J Cancer. 1984;33(1):37-42. 4. Nambisan RN, Rao U, Moore R, Karakousis CP. Malignant soft tissue tumors of nerve sheath origin. J Surg Oncol. 1984;25(4):268-72.

5. Scheithauer BW, Erdogan S, Rodriguez FJ, Burger PC, Woodruff JM, Kros JM, et al. Malignant peripheral nerve sheath tumors of cranial nerves and intracranial contents: a clinicopathologic study of 17 cases. Am J Surg Pathol. 2009;33(3):325-38. ■■■■

Tobacco-induced Cancer Rising in India Of all the cancers prevalent in men in India, says Indian Council of Medical Research, 50% are due to tobacco, both smoking and chewing. Whereas, breast and cervical cancer remain the most common cancers in women, reports Prabeerkumar Sikdar in The Times of India dated Feb 4, 2016. The Operational Guidelines of the National Tobacco Control Program issued by the National Tobacco Control Cell (NTCC), Ministry of Health and Family Welfare (MoHFW) in 2012 have implicated tobacco as the cause for 80% of all oral cancers.

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PEDIATRICS

Chromosome 3p Duplication: A Rare Chromosomal Anomaly BRAJA KISHORE BEHERA*, RISHAV RAJ*, SAILABALA SHAW†, MITALI MAHAPATRA‡

ABSTRACT Partial trisomy 3p results from either unbalanced translocation or de novo duplication. Common clinical features consist of dysmorphic facial features, congenital heart defects, psychomotor and mental retardation, abnormal muscle tone and hypoplastic genitalia. In this paper, we report a case of partial trisomy 3p with rare clinical manifestations. A full-term, female newborn was admitted to our hospital with complaints of repeated seizures and developmental retardation. On evaluation chromosome 3p duplication was detected.

Keywords: Partial trisomy 3p, unbalanced translocation, seizures, developmental retardation, chromosome 3p duplication

hromosome 3p duplication is an anomaly that occurs with an extra copy of genetic material on the short arm (p) of third chromosomes. Another name for chromosome 3 duplication is, trisomy 3p. It is a rare chromosomal disorder, where a portion of the short arm (p) of chromosome 3 is duplicated, so there are three copies of it rather than the normal two.

The severity along with the signs and symptoms depends on location and the size of duplication. Features that often occur in people with chromosome 3p duplication include developmental delay, behavioral problems, intellectual disability and distinctive facial features. Chromosome 3p duplication can be inherited from a parent with balanced translocation or de novo origin.1,2 Treatment is based on the signs and symptoms on individual basis. Sign and symptoms are brachycephaly, square face, frontal bossing, flat back of skull, small jaw, full

cheeks, malformed auricles, widely spaced eyes, bushy eyebrows, downward slanting of eyes, short nose, large mouth, short upper lip, cleft lip and palate, short neck, short hand, stubby feet, excessive whorls, hemivertebrae, reduced muscle tone, seizure, congenital heart defect, esophageal atresia, hypoplastic kidney, ureteric duplication, growth retardation, speech retardation, mental retardation, feeding difficulty. “De novo” duplications occurs randomly during the formation of the egg or sperm. In these cases, a person would have no family history of the condition but could pass the duplication on to children. Other cases of chromosome 3p duplication are the result of a balanced translocation in one of the parents. Carriers of a balanced translocation generally do not have any unusual symptoms or health problems; however, they have an increased risk of having children with chromosomal abnormalities. CASE REPORT

*Post Graduate Dept. of Pediatrics †Post Graduate Dept. of Obstetrics and Gynecology Utkal University, Bhubaneswar, Odisha ‡Consultant Dept. of Obstetrics and Gynecology Christian Hospital, Berhampur, Odisha Address for correspondence Dr Rishav Raj Post Graduate Resident (Final Year) Dept. of Pediatrics Hi-Tech Medical College, Pandra, Rasulgarh, Bhubaneswar - 751 010 Odisha E-mail: drrishavraj@gmail.com

A 2½-year-old female child, a product of nonconsanguineous marriage with proper antenatal check-up and normal antenatal ultrasonography (USG) delivered through normal vaginal delivery (NVD) at hospital. Baby had not cried immediately after birth and was admitted to neonatal intensive care unit (NICU) and discharged after 3 days. At 2½-years baby came to the hospital with c/o delayed developmental milestones, repeated episodes of seizures at 20-25 days interval from the age of 7 months and poor weight gain. Baby recognized mother at 6 months, neck holding at

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PEDIATRICS 7 months, bi-syllable sound at 2 years, walked with support at 2 years. Baby was having head circumference of 40 cm, weight was 9 kg, mid-arm circumference was 12 cm, antimongoloid slant of eyes, brachycephaly, small jaw, broad and short nose, short neck, epicanthic fold, large mouth (Fig. 1), malformed auricle (Fig. 2),

Figure 3. CT scan of brain.

Figure 1. Facial anomaly.

Figure 4. Chromosomal anomaly showing 3p duplication.

reduced muscle tone, seizures, growth retardation, mental retardation and speech retardation. On evaluating the child, completed blood count was normal. Electroencephalograms (EEG) show normal sleep-wake cycle and normal EEG, CT brain showed no apparent anomaly (Fig. 3), on chromosomal analysis there was presence of duplication of segment between 3p22 and 3p25 (Fig. 4). For recurrent seizures, child was treated with levetiracetam and valproate, dietary modification advice and developmental counseling was properly given. DISCUSSION

Figure 2. Ear anomaly.

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Our bodies are made of billions of cells. In each cell is a set of structures called chromosomes that carry all of the instructions (genes) for the cell to function. We generally have 23 pairs of chromosomes and inherit one in each pair from each parent. Sometimes,

PEDIATRICS a section from one chromosome of a particular pair changes places with a section from a chromosome of another pair. When the two breaks do not pass through a gene and there is no gain or loss of material when the chromosomes are looked at under a microscope, it is called a balanced translocation. Some people discover from a blood test when they have had a child with special needs or health problems caused by a chromosome disorder. Some people have repeated miscarriages or other fertility problems. Some people have a blood test as part of family investigations. Others find out by chance when they have a chromosome test for other reasons. Occasionally, a balanced translocation is found in a baby during pregnancy. Translocations can be new or they can be passed down in families from parent to child through the generations. New translocations occur when sperm or egg cells are forming or just after fertilization during the copying of the early cells that will become an embryo, then a fetus and then a baby. One study suggests that most new balanced translocations arise during sperm production and particularly in older fathers. They are not caused by men’s lifestyle, environment or work. Duplication of the short arm of chromosome 3 is associated with severe delay in mental development. More than 50% of children die within the first 2 years of life. Duplications may be due to paternal or maternal balanced translocation.

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Central nervous system: Seizures.

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Muscles: Severe hypotonia.

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Gastrointestinal: Esophageal atresia, atresia of the colon and rectum.

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Miscellaneous: Hemivertebrae, reduced muscle tone, accessory nipples, esophageal atresia, atresia of colon, rectal atresia, hypogonadism, hypospadias small penis, undescended testes, duplication of ureters, kidney hypoplasia, kidney cysts, hypercholesterolemia, growth retardation, motor retardation, speech retardation, mental retardation and feeding difficulty.

There are several different specialized tests that can be used to diagnose a chromosome 3p duplication. These include:1 ÂÂ

Karyotyping: A karyotype is a laboratory test that produces an image of a person’s chromosome. This test can be used to diagnose large duplications.

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FISH: A laboratory technique that is used to detect and locate a specific DNA sequence on a chromosome. A chromosome is exposed to a small DNA sequence called probe that has a fluorescent molecule attached to it. The probe sequence binds to its corresponding sequence on the chromosome. This test can be used in combination with karyotyping for duplications that are too small to be seen on karyotype. However, FISH is only useful if the person ordering the test suspects there is a duplication of a specific region of 3p.

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Array CGH - A technology that detects duplications that are too small to be seen on karyotype.

The list of signs and symptoms mentioned in various sources for chromosome 3, trisomy 3p includes.3-5 ÂÂ

Skull: Brachycephaly, holoprosencephaly, flat back of skull, temporal indentations.

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Face: Square face, frontal bossing, small jaw, facial clefts, full cheeks.

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Eyes: Widely spaced eyes, iris coloboma, small eyes, telecanthus, bushy eyebrows, downward slanting space between eyelids, cyclopia, epicanthal folds.

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Nose: Short nose, broad nose, flat nose, prominent philtrum, choanal atresia.

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Ear: Malformed auricles.

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Mouth: Large mouth, short upper lip, cleft lip, cleft palate.

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Neck: Short neck.

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Extremities: Short hands, stubby hands, short feet, stubby feet, camptodactyly, syndactyly, brachymesophalangy, clubfoot, excessive fingertip whorls, joint contractures.

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Cardiac defects: Congenital heart defects including tetralogy of Fallot, ventricular septal defect, hypoplastic heart and transposition of the great vessels.

REFERENCES 1. Han DH, Chang JY, Lee WI, Bae CW. A case of partial trisomy 3p syndrome with rare clinical manifestations. Korean J Pediatr. 2012;55(3):107-10. 2. Natera-de Benito D, García-Pérez MA, Martínez-Granero MÁ, Izquierdo-López L. A patient with a duplication of chromosome 3p (p24.1p26.2): a comparison with other partial 3p trisomies. Am J Med Genet A. 2014;164A(2): 548-50. 3. Allen DL, Foster RN. Anaesthesia and trisomy 3p syndrome. Anaesth Intensive Care. 1996;24(5):615. 4. Kotzot D, Krüger C, Braun-Quentin C. De novo direct duplication 3 (p25-->pter): a previously undescribed chromosomal aberration. Clin Genet. 1996;50(2):96-8. 5. Walzer S, Favara B, Ming PM, Gerald PS. A new translocation syndrome (3/B). N Engl J Med. 1966;275(6):290-8.

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PEDIATRICS

Vital Nutritional Requirements in the Growing Years SHWETA PATHAK

ABSTRACT Docosahexaenoic acid (DHA) is crucial for the function of the central nervous system (CNS) at the cellular as well as the neurobiological level. It enhances learning and memory by playing a significant part in the development of pre- and postsynaptic proteins facilitating synaptic transmission. Zinc deficiency during growth periods retards growth and may even cause growth failure. Vitamin D insufficiency jeopardizes bone mineral accumulation, while deficiency of vitamin D leads to growth retardation and rickets in children. The innate factors, including complement C3 and phagocytic activity, are enhanced immediately after intake of zinc indicating the potential to stimulate a quick protection. Omega-3 fatty acids or n-3 PUFAs (DHA and eicosapentaenoic acid [EPA]) have immunomodulatory properties that are potentially allergy-protective. The effect of vitamin D on T-cell development during infancy may have long-term clinical implications. Postnatal DHA supplementation improves neurodevelopmental outcomes in preterm infants. Zinc supplementation during infancy supports a profile of normative information processing and active attentional profiles. Low vitamin D status is associated with poor performance in neurocognitive testing. DHA supplementation has positive effects on functions related to attention in very low birth weight (VLBW) infants. Vitamin D treatment of low birth weight (LBW) infants significantly increases standard deviation (z) scores at 6 months for weight, length and arm circumference and decreases the proportion of children with stunted growth. Oral zinc supplementation reduces morbidities and mortality in VLBW preterm neonates.

Keywords: Docosahexaenoic acid, immunomodulatory properties, neurocognitive development, zinc supplementation,

vitamin D

DHA: ROLE IN NEUROCOGNITIVE DEVELOPMENT Docosahexaenoic acid (DHA), an omega-3 (n-3) longchain polyunsaturated fatty acid (LC-PUFA), is critical for brain functions.1 DHA gets accumulated within the brain during gestation and the first year of life during the “brain growth spurt”. Literature suggests that DHA is crucial for the function of the central nervous system (CNS) at the cellular as well as the neurobiological level. The concentration of DHA within the brain can significantly modulate the neuronal membrane fluidity and physical structure of neurons. LC-PUFAs also modulate synaptic transmission and substrate binding to membrane receptors.1 DHA stimulates the process of neurite outgrowth in hippocampal neurons. This eventually promotes learning since the hippocampus is critical for memory formation. Moreover, DHA also

Dept. of Pediatrics and Neonatology Fortis Escorts and Research Centre, Faridabad, Haryana Address for correspondence Dr Shweta Pathak Dept. of Pediatrics and Neonatology Fortis Escorts and Research Centre, Faridabad, Haryana E-mail: dr.shwetapgupta@gmail.com

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has the potential to enhance learning and memory by regulating the development of pre- and postsynaptic proteins facilitating synaptic transmission. DHA is thus well-known to impact neurocognitive development and subsequent performance.1 ROLE OF ZINC IN THE GROWING YEARS Zinc deficiency is known to be a significant malnutrition problem globally and is more prevalent in areas of high cereal and low animal food consumption.2 Deficiency of zinc is a huge problem in under five children in India. A cross-sectional study conducted over 5 Indian states including children below 5 years of age reported the overall prevalence of zinc deficiency to be 43.8%.3 Infants and children have increased requirements for zinc and zinc deficiency during growth periods retards growth and may even cause growth failure.2 Additionally, zinc deficiency is associated with increased risk of infections like diarrhea and pneumonia, during the growing years.2 Complementary foods containing absorbable zinc need to be given to fulfill the kids’ requirements. VITAMIN D - GROWTH IN CHILDHOOD Vitamin D has a significant role in the prevention of rickets and osteomalacia and affects prenatal

PEDIATRICS and postnatal linear growth.4 Vitamin D stimulates osteoblastogenesis in human mesenchymal stem cells and production of insulin-like growth factor-1 (IGF-1) in osteoblasts. Vitamin D insufficiency frequently jeopardizes bone mineral accumulation. Deficiency of vitamin D leads to growth retardation and classic signs and symptoms of rickets in children. Muscle weakness is also associated with vitamin D deficiency.5 Vitamin D is required for normal calcification of the growth plate and bone mineralization.6 Moreover, vitamin D deficiency is prevalent in epidemic proportions in India, ranging from 70% to 100% in the general population.7 A study conducted in 2013 in Mumbai, India reported 14% of the evaluated children to have vitamin D dependent rickets (VDDR). It was also highlighted that majority of patients with VDDR showed skeletal changes of rickets in the first 2 years of life.8 Thus, appropriate vitamin D supplementation seems essential in the growing years to promote bone growth and development. SUPPLEMENTATION WITH ZINC, DHA AND VITAMIN D: IMPACT ON OVERALL GROWTH AND DEVELOPMENT OF A CHILD As evident from the data mentioned above, DHA, zinc and vitamin D are all crucial for the overall growth and development of children during the period of growth spurt, particularly in the first 5 years of life and supplementation with these nutrients seems reasonable to correct the deficiencies or insufficiencies.

Role of Supplementation to Boost Immunity in Children Zinc is a significant micronutrient with potential role in immune function and defense against free radicals. Zinc deficiency heightens the risk and severity of several infections. Zinc is pivotal for adequate functioning of both innate and acquired immunity and impaired immune function.9 Acquired immune deficiency syndrome (AIDS) substantially compromises oneâ&#x20AC;&#x2122;s immune system rendering one prone to opportunistic infections.10 Vitamin D supplementation was found to delay mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) and to reduce oxidative stress and HIV viral load.10 While zinc deficiency is related with decreased immunity and increased risk of infection, preventive zinc supplementation can reduce mortality due to common infections like diarrhea, pneumonia and malaria.11 A study evaluated the immunological effect

of zinc treatment and supplementation in children with diarrhea due to enterotoxigenic Escherichia coli (ETEC). Zinc administration helped enhance innate immunity against ETEC infection in children. The innate factors, including complement C3 and phagocytic activity, are enhanced immediately after intake of zinc indicating the potential to stimulate a quick protection.12 Postnatal fish oil supplementation (DHA and eicosapentaenoic acid [EPA]) has been shown to augment infant n-3 PUFA levels and decrease allergenspecific Th2 responses and enhance polyclonal Th1 responses. It can therefore be deduced that n-3 PUFA have immunomodulatory properties that are potentially allergy-protective.13 Vitamin D plays a significant role in maintaining bone health as well as optimum cardiovascular and immune function. Supplementing school children with vitamin D over winter months has been shown to decrease influenza infections.14 Epidemiologic studies have found that vitamin D supplementation during infancy was associated with a reduced risk of type 1 diabetes, but an increased risk of atopic disease (Th2 mediated) in adulthood, thereby implicating that the effect of vitamin D on T-cell development during infancy may have long-term clinical implications.4

DHA, Vitamin D and Zinc Supplementation for Neurocognitive Development There is a positive correlation between blood DHA levels and enhancement in cognitive or visual function outcomes of breast-fed and formula-fed infants. Literature suggests that infants must be given at least 0.3% DHA in infant feedings.15 Milte et al16 noted that increasing erythrocyte EPA + DHA by means of dietary supplementation in children with attention deficit hyperactivity disorder (ADHD) was associated with improved spelling and attention as well as decrease in oppositional behavior, hyperactivity, cognitive problems, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) hyperactivity and DSM-IV inattention. Postnatal DHA supplementation improves neurodevelopmental outcomes in preterm infants.17 Eilander et al18 revealed that supplementing term infants with daily doses of 100 mg DHA plus 200 mg arachidonic acid (AA) improves visual development. A study randomized 9-month-old infants to fish oil (n-3 fatty acid) for 3 months and suggested that n-3 fatty acid intake even in late infancy could affect brain development.19 Supplementing both infants

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PEDIATRICS and toddlers with 100 mg DHA seems beneficial for maintaining optimum DHA levels, thereby promoting growth and development.20 DHA given during the first year of life is associated with improved cognitive development at 18 months of age. Drover et al21 reported the Mental Development Index (MDI) scores of DHA-supplemented children to be higher (104.1 vs. 98.4; Fig. 1) as compared to control children. Zinc deficiency may be associated with impaired cognitive function, behavioral problems, impaired memory, learning disability and neuronal atrophy. Several physiological and metabolic functions, including physical growth, immunocompetence, reproductive function and neurobehavioral development are all influenced by an individual’s zinc status.22 A recent study noted that zinc supplementation during infancy supported a profile of normative information processing and active attentional profiles during the first 2 years of life.23 The skeletal muscle and brain have a vitamin D receptor and the CNS has the potential to activate vitamin D. Low vitamin D status is associated with poor performance in neurocognitive testing. Thus, correcting vitamin D deficiency and preventing vitamin D deficiency in children should be a high priority for healthcare professionals in order to reduce risk for an array of neurological disorders.24

Combined Supplementation in Low Birth Weight Infants Westerberg et al25 determined the impact of supplementation with DHA and AA in early neonatal life on cognitive functions among human milk fed very low birth weight (VLBW) infants (<1,500 g) at 20 months chronological age. Results suggested positive

98.4

96 Study population

Figure 1. MDI scores in DHA-supplemented and control children.

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Table 1. Effect of Vitamin D Supplementation on Plasma Calcidiol Levels at 6 Months Variables

Vitamin D group (n = 216)

Placebo group (n = 237)

55.0 (22.5)

36.0 (25.5)

Severe (<25 nmol/L)

18 (8)

92 (39)

Mild (10-20 nmol/L)

76 (35)

82 (35)

Adequate (>50 nmol/L)

122 (57)

63 (27)

Mean (SD) calcidiol level (nmol/L) Type of deficiency:

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Zinc group

30 Daily weight gain (g/kg/day)

MDI scores

100

Oral zinc supplementation reduces morbidities and mortality in VLBW preterm neonates. A study

Control

104.1

102

A study conducted among low birth weight (LBW) infants in Delhi, India noted that vitamin D supplementation led to better vitamin D status among the study subjects (Table 1). In adjusted analyses, vitamin D treatment significantly increased standard deviation (z) scores at 6 months for weight, length and arm circumference and decreased the proportion of children with stunted growth (length for age z score ≤2) or with arm circumference z scores of <2.27

DHA-supplemented

106 104

effects from supplementation on functions related to attention. Plasma DHA concentration at discharge was positively correlated with both ‘Sustained attention’ and the Bayley MDI according to chronological age. VLBW infants receiving an IV fat emulsion containing fish oil had lesser retinopathy requiring laser treatment and less cholestasis than those receiving a standard lipid emulsion. These infants also had higher plasma and erythrocyte DHA levels at 7 and 14 days, pointing towards potential long-term neurodevelopmental benefits.26

Control group

25 20

18.2 ± 5.6

17.0 ± 8.7

15 10 5 0

Intervention

Figure 2. Daily weight gain among VLBW neonates in zinc and control groups.

PEDIATRICS conducted among VLBW neonates noted morbidities to be significantly lower in the zinc group as compared to placebo group (26.8% vs. 41.7%). The occurrence of necrotizing enterocolitis was significantly higher in the control group (6.3% compared with 0%). Mortality risk was also higher in the placebo control group (relative risk [RR]: 2.37; 95% confidence interval [CI]: 1.08, 5.18). Daily weight gain was 18.2 ± 5.6 g/kg/d in the zinc group compared with 17.0 ± 8.7 g/kg/d in the control group (Fig. 2).28 Zinc supplementation results in better motor development and more playfulness in LBW infants and increased vigorous and functional activity in infants and toddlers.29 CONCLUSION The first 5 years of life are the most crucial with regard to the overall growth and development of an individual, both physical and neurocognitive. It must be noted that zinc, DHA and vitamin D are three of the pivotal nutrients that a child needs during the growing years to lay the foundation of a healthy future. Deficiencies of these vital nutrients considerably restrict the growth of a child and thus, it seems important to provide children with adequate supplementation of zinc, DHA and vitamin D to improve their overall growth, cognitive function and enhance immune responses. REFERENCES 1. Heaton AE, Meldrum SJ, Foster JK, Prescott SL, Simmer K. Does docosahexaenoic acid supplementation in term infants enhance neurocognitive functioning in infancy? Front Hum Neurosci. 2013;7:774. 2. Roohani N, Hurrell R, Kelishadi R, Schulin R. Zinc and its importance for human health: an integrative review. J Res Med Sci. 2013;18(2):144-57. 3. Kapil U, Jain K. Magnitude of zinc deficiency amongst under five children in India. Indian J Pediatr. 2011;78(9):1069-72. 4. Kim SY. The pleiomorphic actions of vitamin D and its importance for children. Ann Pediatr Endocrinol Metab. 2013;18(2):45-54. 5. Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008;87(4):1080S-6S. 6. Shin YH, Shin HJ, Lee YJ. Vitamin D status and childhood health. Korean J Pediatr. 2013;56(10):417-23.

9. Maggini S, Wenzlaff S, Hornig D. Essential role of vitamin C and zinc in child immunity and health. J Int Med Res. 2010;38(2):386-414. 10. Maggie Z, He G, Wang H. Effects of nutritional supplementation on children with HIV/AIDS in China. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2012;37(3): 305-10. 11. Yakoob MY, Theodoratou E, Jabeen A, Imdad A, Eisele TP, Ferguson J, et al. Preventive zinc supplementation in developing countries: impact on mortality and morbidity due to diarrhea, pneumonia and malaria. BMC Public Health. 2011;11(Suppl 3):S23. 12. Sheikh A, Shamsuzzaman S, Ahmad SM, Nasrin D, Nahar S, Alam MM, et al. Zinc influences innate immune responses in children with enterotoxigenic Escherichia coli-induced diarrhea. J Nutr. 2010;140(5):1049-56. 13. D’Vaz N, Meldrum SJ, Dunstan JA, Lee-Pullen TF, Metcalfe J, Holt BJ, et al. Fish oil supplementation in early infancy modulates developing infant immune responses. Clin Exp Allergy. 2012;42(8):1206-16. 14. Madden K, Feldman HA, Smith EM, Gordon CM, Keisling SM, Sullivan RM, et al. Vitamin D deficiency in critically ill children. Pediatrics. 2012;130(3):421-8. 15. Hoffman DR, Boettcher JA, Diersen-Schade DA. Toward optimizing vision and cognition in term infants by dietary docosahexaenoic and arachidonic acid supplementation: a review of randomized controlled trials. Prostaglandins Leukot Essent Fatty Acids. 2009;81(2-3):151-8. 16. Milte CM, Parletta N, Buckley JD, Coates AM, Young RM, Howe PR. Increased erythrocyte eicosapentaenoic acid and docosahexaenoic acid are associated with improved attention and behavior in children with ADHD in a randomized controlled threeway crossover trial. J Atten Disord. 2015;19(11):954-64. 17. Rogers LK, Valentine CJ, Keim SA. DHA supplementation: current implications in pregnancy and childhood. Pharmacol Res. 2013;70(1):13-9. 18. Eilander A, Hundscheid DC, Osendarp SJ, Transler C, Zock PL. Effects of n-3 long chain polyunsaturated fatty acid supplementation on visual and cognitive development throughout childhood: a review of human studies. Prostaglandins Leukot Essent Fatty Acids. 2007;76(4):189-203. 19. Harbild HL, Harsløf LB, Christensen JH, Kannass KN, Lauritzen L. Fish oil-supplementation from 9 to 12 months of age affects infant attention in a free-play test and is related to change in blood pressure. Prostaglandins Leukot Essent Fatty Acids. 2013;89(5):327-33.

7. Ritu G, Gupta A. Vitamin D deficiency in India: prevalence, causalities and interventions. Nutrients. 2014;6(2):729-75.

20. Hawthorne KM, Abrams SA, Heird WC. Docosahexaenoic acid (DHA) supplementation of orange juice increases plasma phospholipid DHA content of children. J Am Diet Assoc. 2009;109(4):708-12.

8. Joshi RR, Patil S, Rao S. Clinical and etiological profile of refractory rickets from western India. Indian J Pediatr. 2013;80(7):565-9.

21. Drover JR, Hoffman DR, Castañeda YS, Morale SE, Garfield S, Wheaton DH, et al. Cognitive function in 18-month-old term infants of the DIAMOND study:

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PEDIATRICS a randomized, controlled clinical trial with multiple dietary levels of docosahexaenoic acid. Early Hum Dev. 2011;87(3):223-30. 22. Bhutta ZA. The role of zinc in child health in developing countries: taking the science where it matters. Indian Pediatr. 2004;41(5):429-33. 23. Colombo J, Zavaleta N, Kannass KN, Lazarte F, Albornoz C, Kapa LL, et al. Zinc supplementation sustained normative neurodevelopment in a randomized, controlled trial of Peruvian infants aged 6-18 months. J Nutr. 2014;144(8):1298-305. 24. Nimitphong H, Holick MF. Vitamin D, neurocognitive functioning and immunocompetence. Curr Opin Clin Nutr Metab Care. 2011;14(1):7-14.

26. Pawlik D, Lauterbach R, Walczak M, Hurkała J, Sherman MP. Fish-oil fat emulsion supplementation reduces the risk of retinopathy in very low birth weight infants: a prospective, randomized study. JPEN J Parenter Enteral Nutr. 2014;38(6):711-6. 27. Kumar GT, Sachdev HS, Chellani H, Rehman AM, Singh V, Arora H, et al. Effect of weekly vitamin D supplements on mortality, morbidity, and growth of low birthweight term infants in India upto age 6 months: randomised controlled trial. BMJ. 2011;342:d2975. 28. Terrin G, Berni Canani R, Passariello A, Messina F, Conti MG, Caoci S, et al. Zinc supplementation reduces morbidity and mortality in very-low-birth-weight preterm neonates: a hospital-based randomized, placebo-controlled trial in an industrialized country. Am J Clin Nutr. 2013;98(6): 1468-74.

25. Westerberg AC, Schei R, Henriksen C, Smith L, Veierød MB, Drevon CA, et al. Attention among very low birth weight infants following early supplementation with 29. Bhatnagar S, Taneja S. Zinc and cognitive development. docosahexaenoic and arachidonic acid. Acta Paediatr. 2011;100(1):47-52. Br J Nutr. 2001;85(Suppl 2):S139-45. ■■■■

Interim Guidelines on Zika Virus Infection Issued by CDC The US Centers for Disease Control and Prevention (CDC) has issued interim guidelines for the evaluation, testing, and management of infants with possible congenital Zika virus infection. Developed in conjunction with the American Academy of Pediatrics, the guidelines address the care of infants with microcephaly or intracranial calcifications detected prenatally or at birth, as well as infants without these findings whose risk is based on maternal exposure and testing for Zika virus infection. The guidelines are published in the January 26 earlyrelease issue of the Morbidity and Mortality Weekly Report.

Mom in Control Even before Child is Born! Researchers have uncovered previously unappreciated means by which epigenetic information contained in the egg influences the development of the placenta during pregnancy. The research, which was performed in mice, indicates that a mother’s health, even before conception, may influence the health of her fetus, and opens questions on how a mother’s age may influence placental development. The researchers set out to explore the importance of this type of methylation on the development of the placenta, a vital organ in pregnancy and their findings are presented in the latest issue of the journal Developmental Cell.

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EXPERT VIEW

Are β-blockers Contraindicated in Patients with Congestive Heart Failure? OP YADAVA

ince 1970s, usage of b-blockers in treatment of patients with heart failure was recommended by several investigators but the fact that if reduces myocardial contractility, precluded their use. The past decade has shown significant improvement in the understanding of heart failure, shifting from a hemodynamic to a neurohormonal basis.1

Recent primary evidence from randomized clinical trials has demonstrated a significant benefit to patients with heart failure when b-blockers therapy is added to standard therapy.2 While it is known that b-blockers do not cause overt heart failure, a large proportion of clinical heart failure is diastolic dysfunction, nearly 30-40%, which is improved by b-blocker therapy.3 The rationale for their use in heart failure is that the concentration of circulating catecholamines is increased in patients with congestive heart failure (CHF). Thus, constant adrenergic stimulation can adversely affect cardiac myocytes. b-blockers improve left ventricular systolic function, in the long run regress myocardial hypertrophy and normalization of ventricular shape can occur through a ‘reverse remodeling effect’.1 They also reduce oxygen demand and produce bradycardia,4 which restores contractility in left ventricular dysfunction. When patients are treated with b-blockers postmyocardial infarction, mortality is lower amongst those who begin with a low ejection fraction.5 In patients who had previous heart failure, the incidence of sudden cardiac death is significantly lower with b-blockers and overall mortality is considerably reduced.6 A recent meta-analysis showed that b-blockers reduce all-cause mortality in CHF patients by 29%. Studies like the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study have shown metoprolol-induced neurohormonal modifications by decreasing renin and angiotensin II

Chief Executive Officer and Chief Cardiac Surgeon National Heart Institute, New Delhi

concentrations. Their effect on exercise capacity and quality-of-life is not convincing. US Carvedilol Program, Cardiac Insufficiency Bisoprolol Study 2 (CIBIS-2) and Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) testing carvedilol, bisoprolol and metoprolol, respectively, impressively established the fact that b-blockers in heart failure have reduced sudden death and total mortality, and led to decrease in hospitalization rate.1 Carvedilol was the first b-blocker to be approved by US FDA (Food and Drug Administration) in 1997 for treatment of heart failure. Carvedilol Prospective Cumulative Survival (COPERNICUS) trial demonstrated 35% reduction in mortality by carvedilol versus placebo in patients with severe heart failure.7 Carvedilol reduced sudden death in patients with symptomatic heart failure and impaired left ventricular functions. It also has a vasoactive profile, increases vasodilatation in peripheries and high compliance, thus, reducing the occurrence of cold hands and feet among patients treated for heart failure.8 Hence, b-blockers are indicated in patients with chronic stable mild-to-moderate symptomatic heart failure (New York Heart Association [NYHA] functional class II and III) with depressed left ventricular function.1 Bisoprolol can be used effectively at the maximum recommended doses for outpatient treatment of heart failure. It significantly improves functional status, quality-of-life and ejection fraction.9 Carvedilol or Metoprolol European Trial (COMET) was initiated to evaluate effects of carvedilol and metoprolol on mortality in patients with CHF.7 In conclusion, it can be said that b-blockers are a heterogeneous group with regard to efficacy, safety profile, tolerability and ancillary properties. Hence, optimal selection and use of agents with better reverse remodeling effects and peripheral vasodilatation in the cardiovascular continuum will assist in providing improved management.10 Though once contraindicated, b-blockers are now an evidence-based recommendation for the treatment of heart failure.1

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EXPERT VIEW REFERENCES 1. Maggioni AP. Heart Failure: Treatment strategies for heart failure; beta-blockers and antiarrhythmics. Heart. 2001;85(1):97-103. 2. Kennedy HL. Current utilization trends for beta-blockers in cardiovascular disease. Am J Med. 2001;110 Suppl 5A:2S-6S. 3. Cuocolo A, Betocchi S, Perrone-Filardi P, et al. Effects of beta-blocking therapy on left ventricular diastolic function in patients with hypertension. 11th Scientific Meeting of the International Society of Hypertension. Heidelberg 1986. Abstract 0444. 4. Nagatsu M, Spinale FG, Koide M, Tagawa H, DeFreitas G, Cooper G 4th, et al. Bradycardia and the role of beta-blockade in the amelioration of left ventricular dysfunction. Circulation 2000;101(6):653-9.

Multicenter Diltiazem Post-Infarction Research Group. J Am Coll Cardiol. 1990;16(6):1327-32. 6. Chadda K, Goldstein S, Byington R, Curb JD. Effect of propranolol after acute myocardial infarction in patients with congestive heart failure. Circulation. 1986;73(3): 503-10. 7. Maack C, Elter T, Böhm M. Beta-blocker treatment of chronic heart failure: comparison of carvedilol and metoprolol. Congest Heart Fail. 2003;9(5):263-70. 8. Klemsdal TO, Mundal HH, Gjesdal K. Effects of carvedilol and atenolol on arterial pulse curves (plethysmography) and finger temperature after hand cooling. Euro J Clin Pharmacol. 1996;50(6):483-9. 9. González-Juanatey JR, Alegría Ezquerra E, García Saavedra V, Pérez Ojeda G, Ruiz Ros JA, Espinosa Caliani JS, et al; Investigadores del Estudio BISCOR. Use of bisoprolol in heart failure. The BISOCOR observational study. Rev Esp Cardiol. 2003;56(9):873-9.

5. Lichstein E, Hager WD, Gregory JJ, Fleiss JL, Rolnitzky LM, Bigger JT Jr. Relation between beta-adrenergic 10. Abraham WT. Switching between beta blockers in heart blocker use, various correlates of left ventricular function failure patients: rationale and practical considerations. Congest Heart Fail. 2003;9(5):271-8. and the chance of developing congestive heart failure. The ■■■■

Study Identified Risk Factors of Mortality after Surgical Repair of Post-AMI VSDs Surgical repair of ventricular septal defects (VSDs) following acute myocardial infarction carries a high operative mortality. This was the conclusion drawn from a Retrospective analysis and review of the literature that analyzed the associated risk factors and outcomes of surgical repair of post-infarction VSDs. Alexandre Cinq-Mars, Research Center, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, Canada and coauthors identified older age (hazard ratio [HR] = 1.11, p = 0.0001) and shorter time between AMI and surgery (HR = 0.90, p = 0.015) as independent predictors of 30-day and long-term mortality. Concomitant coronary artery bypass graft (CABG) had no impact on early or late survival.

Flu Vaccine can Prevent Atrial Fibrillation Atrial fibrillation is a risk factor for developing complications from influenza and also with an increased risk for developing Afib. In a case-control study from Taiwan, influenza infection was significantly associated with new onset atrial fibrillation. The study participants who had the flu during the previous year having an 18% increased risk for an Afib diagnosis. Getting a flu shot may reduce at-risk patients’ risk for developing the arrhythmia, Dr Su-Jung Chen, of Taipei Veterans General Hospital in Taiwan wrote in the journal Heart Rhythm.

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MEDILAW

Medical Negligence and Internationally Accepted Never Events KK AGGARWAL

What is medical negligence?

What are some examples of medical negligence?

Negligence may be defined as the “breach of a duty caused by the omission to do something which a reasonable man, guided by those considerations which ordinarily regulate the conduct of human affairs would do, or doing something which a prudent and reasonable man would not do”. It is the lack of reasonable degree of care and skill or willful negligence on the part of a medical practitioner while treating a patient resulting in bodily injury, ill-health or death (damage). For these problems a doctor can be sued in civil/criminal courts, respective councils and/or Consumer forum. A patient cannot sue the doctor if no damage has occurred; however, negligent the doctor might be.

Some examples of medical negligence are:

“The essential components of negligence, as recognised, are three: ‘Duty’, ‘breach’ and ‘resulting damage.1 ÂÂ

The existence of a duty to take care, which is owed by the defendant to the complainant;

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The failure to attain that standard of care, prescribed by the law, thereby committing a breach of such duty; and

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Damage, which is both causally connected with such breach and recognised by the law, has been suffered by the complainant (Para 1.23).

If the claimant satisfies the court on the evidence that these three ingredients are made out, the defendant should be held liable in negligence (Para 1.24).” The standard of care has to be judged in the light of knowledge or equipment available at the time of the incident and not at the date of the trial. Reference 1. 334/2005/SCI/144-145 of 2004: Jacob Mathew vs State of Punjab and Anr: 5th day of August 2005 CJI R C Lahoti, G P Mathur, P K Balasubramanyan.

Senior Physician and Cardiologist, Moolchand Medcity, New Delhi Group Editor-in-Chief, IJCP Group, eMedinewS and eMediNexus

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Making a mistake during surgery

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Giving a wrong drug

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Making a wrong diagnosis

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Delaying a diagnosis unnecessarily.

Medical negligence also includes not doing things that should be done, such as: ÂÂ

Not giving treatment as needed

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Not getting consent (agreement) for treatment

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Not warning about the risks of a particular type of treatment.

What are internationally accepted never events? Never events are events or situations that should not occur under any circumstance. These are serious reportable events where deficiency of service and/or negligence is presumed. Never events are avoidable if the required preventable measures are in place. As defined by the National Quality Forum and commonly agreed upon by healthcare providers, the 28 internationally accepted never events are: 1. Artificial insemination with the wrong donor sperm or donor egg 2. Unintended retention of a foreign object in a patient after surgery or other procedure 3. Patient death or serious disability associated with patient elopement (disappearance) 4. Patient death or serious disability associated with a medication error (e.g., errors involving the wrong drug, wrong dose, wrong patient, wrong time, wrong rate, wrong preparation or wrong route of administration 5. Patient death or serious disability associated with a haemolytic reaction due to the administration of ABO/HLA incompatible blood or blood products 6. Patient death or serious disability associated with an electric shock or elective cardioversion, while being cared for in a healthcare facility

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MEDILAW 7. Patient death or serious disability associated with a fall, while being cared for in a healthcare facility 8. Surgery performed on the wrong body part 9. Surgery performed on the wrong patient 10. Wrong surgical procedure performed on a patient 11. Intraoperative or immediately postoperative death in an ASA Class I patient 12. Patient death or serious disability associated with the use of contaminated drugs, devices or biologics provided by the healthcare facility 13. Patient death or serious disability associated with the use or function of a device in patient care, in which the device is used or functions other than as intended 14. Patient death or serious disability associated with intravascular air embolism that occurs, while being cared for in a healthcare facility 15. Infant discharged to the wrong person 16. Patient suicide, or attempted suicide resulting in serious disability, while being cared for in a healthcare facility 17. Maternal death or serious disability associated with labor or delivery in a low-risk pregnancy, while being cared for in a healthcare facility 18. Patient death or serious disability associated with hypoglycemia, the onset of which occurs, while the patient is being cared for in a healthcare facility 19. Death or serious disability (kernicterus) associated with failure to identify and treat hyperbilirubinemia in neonates 20. Stage 3 or 4 pressure ulcers acquired after admission to a healthcare facility 21. Patient death or serious disability due to spinal manipulative therapy 22. Any incident in which a line designated for oxygen or other gas to be delivered to a patient contains the wrong gas or is contaminated by toxic substances 23. Patient death or serious disability associated with a burn incurred from any source, while being cared for in a healthcare facility 24. Patient death or serious disability associated with the use of restraints or bedrails, while being cared for in a healthcare facility. 25. Any instance of care ordered by or provided by someone impersonating a physician, nurse, pharmacist or other licensed healthcare provider

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26. Abduction of a patient of any age 27. Sexual assault on a patient within or on the grounds of the healthcare facility 28. Death or significant injury of a patient or staff member resulting from a physical assault (i.e., battery) that occurs within or on the grounds of the healthcare facility.

What are the examples of never events cited in judgements of courts in India? Following examples of never events have been rectified by various court judgements in India. ÂÂ

Removal of the wrong limb

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Performance of an operation on the wrong patient

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Giving injection of a drug to which the patient is allergic without looking into the outpatient card containing the warning

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Use of wrong drug or gas during anesthesia

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Leaving swabs or other items of operating equipment after surgery inside the patient.

No trial or expert evidence is necessary in such situations. It was stated in Nizam Institute of Medical Sciences Vs. Prasanth S. Dhananka and Ors “…… The issues arising in the complaints in such cases can be speedily disposed of by the procedure that is being followed by the Consumer Disputes Redressal Agencies and there is no reason why complaints regarding deficiency in service in such cases should not be adjudicated by the Agencies under the Act.” In the M/S Spring Meadows Hospital & Anr Vs. Harjol Ahluwalia, the Supreme Court of India held: “Even delegation of responsibility to another may amount to negligence in certain circumstances. A consultant could be negligent where he delegates the responsibility to his junior with the knowledge that the junior was incapable of performing his duties properly.” Suggested Reading 1. IMA vs VP Shantha & Ors 1995 (6) SCC 651 (37). 2. Spring Meadows Hospital & Anr. Vs. Harjol Ahluwalia & Anr. (1996) 4 SCC 39. 3. Nihal Kaur vs. Director, P.G.I.M.S.R. (1996) CPJ 112. 4. Achutrao Haribhau Khodwa vs. State of Maharashtra & Ors, 1996 SCC (2) 634, JT 1996 (2) 624. 5. 334/2005/SCI/144-145 of 2004: Jacob Mathew vs State of Punjab and Anr: 5th day of August 2005 CJI R C Lahoti, G P Mathur, P K Balasubramanyan. 6. Nizam Institute of Medical Sciences Vs. Prasanth S. Dhananka and Ors, SC/4119 of 1999 and 3126 of 2000, 14.05.2009.

MEDILAW What is a medical accident? If something goes wrong when one is undergoing medical treatment, it is called a ‘medical accident’ or ‘adverse event’. If the treatment has not worked or there have been complications, this does not always mean that there has been a mistake, or that someone is to be blamed. In some cases, one has to accept errors or complications as unavoidable risks of the treatment and, the doctor or other healthcare professional should not be blamed. For example, when one has a major heart surgery, he or she can expect that there would be risks because of the surgery. However, there can be complications with minor procedures too.

Similarly, when the charge of negligence arises out of failure to use some particular equipment, the charge would fail if the equipment was not generally available at that particular time (that is, the time of the incident) at which it is suggested it should have been used.”

Reference 1. 334/2005/SCI/144-145 of 2004: Jacob Mathew vs State of Punjab and Anr: 5th day of August 2005 CJI R C Lahoti, G P Mathur, P K Balasubramanyan.

Is difference of opinion negligence? No, a difference of opinion is not negligence as observed by the Supreme Court of India. ÂÂ

In Bolam v. Friern Hospital Management Committee (1957) 2 All ER 118, the law was stated thus: “Where you get a situation which involves the use of some special skill or competence, then the test...is the standard of ordinary skilled man exercising and professing to have that special skill. A man need not possess the highest expert skill; it is well-established law that it is sufficient if he exercises the ordinary skill of an ordinary competent man exercising that particular art... A doctor is not guilty of negligence if he has acted in accordance with a practice accepted as proper by a responsible body of medical men skilled in that particular art.. Putting it the other way round, a doctor is not negligent, if he is acting in accordance with such a practice, merely because there is a body of opinion that takes a contrary view.”1

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“A doctor cannot be held negligent either in regard to diagnosis or treatment or in disclosing the risks involved in a particular surgical procedure or treatment, if the doctor has acted with normal care, in accordance with recognised practices accepted as proper by a responsible body of medical men skilled in that particular field, even though there may be a body of opinion that takes a contrary view. Where there are more than one recognised school of established medical practice, it is not negligence for a doctor to follow any one of those practices, in preferences to the others.”2

Can a medical accident be termed medical negligence? The Supreme Court of India has observed in its judgement in Jacob Mathew v. State of Punjab SC/0457/2005: (2005) 6 SCC 1: “Mere accident is not evidence of negligence.” The order also clarifies that difference of opinion or error of judgement cannot be termed negligence, also adverse reactions cannot be classified under medical negligence.

Is simple lack of care negligence? A simple lack of care does not mean negligence. In one of its judgements, the Supreme Court of India stated: “A simple lack of care, …., is not proof of negligence on the part of a medical professional. So long as a doctor follows a practice acceptable to the medical profession of that day, he cannot be held liable for negligence merely because a better alternative course or method of treatment was also available or simply because a more skilled doctor would not have chosen to follow or resort to that practice or procedure which the accused followed. When it comes to the failure to taking precautions what has to be seen is whether those precautions were taken which the ordinary experience of men has found to be sufficient; a failure to use special or extraordinary precautions which might have prevented the particular happening cannot be the standard for judging the alleged negligence. So also, the standard of care, while assessing the practice as adopted, is judged in the light of knowledge available at the time of the incident, and not at the date of trial.

References 1. 334/2005/SCI/144-145 of 2004: Jacob Mathew vs State of Punjab and Anr: 5th day of August 2005 CJI R C Lahoti, G P Mathur, P K Balasubramanyan.

2. SCI, Civil Appeal No. 1949 of 2004, 16.01.2008, Samira Kohli vs Dr. Prabha Manchanda and Anr Bench: B N Agarwal, P P Naolekar and R V Raveendran. ■■■■

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CONFERENCE UPDATE

53rd Annual Conference of Indian Academy of Pediatrics (PEDICON 2016) prednisolone therapy beyond 2 months (Kidney Int. 2014;87:225-32).

COUNSELING ADOLESCENTS: PRACTICAL TIPS Dr Pukhraj Bafna, Rajnandgaon, Chhattisgarh ÂÂ

Establishing a comfortable and open relationship is the foundation for communication and education. It increases the chance that the client will return.

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On sensitive issues like sexuality, adolescents may be reluctant or embarrassed to disclose information due to fear of being scolded or mocked.

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While communicating, it is important to be respectful, to ensure privacy, to maintain confidentiality, to be honest, to use language they understand and to be open to their ideas and choice, even if they are not the ones you would have wanted them to make.

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Some communication and counseling tips are: Start conversation by building rapport and by discussing nonthreatening issues, ask indirect questions and try to reduce stigma around a sensitive issue by normalizing it.

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Young adolescents require more activity-based approaches like storytelling, games, reading, art, etc.

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Good communication is the key component to effective counseling.

NEPHROTIC SYNDROME: PRECISE DIAGNOSIS AND CURRENT MANAGEMENT PROTOCOL

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Idiopathic nephritic syndrome is the frequently occurring disease in children.

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Estimated incidence of nephritic syndrome in Japan is 6.49/10,000 per year i.e., 1,000 new patient per year.

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Literature shows that the incidence of nephrotic syndrome is much higher in Asian children than in non-Asian children. Nephrotic syndrome is severe proteinuria (≥40 mg/h/m2 in pooled night urine) or early morning urinary total protein to creatinine ratio ≥2.0 g/gCr and serum albumin ≤2.5 g/dL.

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For initial episode of nephrotic syndrome, there is no benefit of increasing the duration of

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Avoid excessive and unnecessary limitation on exercise and diet.

Encourage the child to spend his/her daily life as healthy children.

Rituximab is effective and safe for the treatment of childhood-onset complicated frequent relapsing and steroid-dependent nephrotic syndrome (Lancet. 2014;384:1273-81).

Dr Preeti M Galagali, Bangalore ÂÂ

To some degree, novelty seeking, sensation seeking and thrill seeking ‘at risk’ behavior is normative, desirable and adaptive in adolescence like learning a new skill, visiting new places and trying out various adventurous and sporting activities under supervision.

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It enables adolescents to accomplish normal developmental tasks of independence, to explore different identities, to be creative, to test adult boundaries, to experience consequences of their choices and to ultimately attain a stable identity. But in 15-20% cases such behavior has potential negative health outcomes.

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Adolescent high risk behaviors that result in mortality and morbidity include rash driving, suicide, violence, drug abuse, poor dietary and physical activity patterns, media addiction and unsafe sexual behavior.

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Neurobiologically, adolescent brain is wired to seek ‘quick ’rewards. Also, a poor control center in the form of an immature prefrontal cortex and a highly labile emotional/limbic system may result in the adolescent indulging in impulsive unhealthy high risk behavior at times.

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Pediatricians should screen for high risk behavior in adolescence by eliciting the HEEADSSS psychosocial

most

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HIGH RISK BEHAVIOR IN ADOLESCENCE: IS IT NORMATIVE?

Dr Shuichi Ito, Japan ÂÂ

Japanese Society of Pediatric Nephrology has published new guidelines for pediatric nephrotic syndrome: Medical therapy and general therapy (Clin Exp Nephrol. 2015;19:6-53).

CONFERENCE UPDATE history. They should also provide anticipatory guidance to parents, adolescents and teachers. Management of high risk behavior problems in adolescence is usually multidisciplinary. ÂÂ

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Connectedness with family and school, religiosity, positive peer affiliation, media literacy, involvement in academic, extra academic activities and sports and learning life skills protect against dangerous risk behavior. Impulse control and other psychiatric disorders in adolescents, chaotic family and school environment, delinquent peers and a violent neighborhood are risk factors for dangerous behavior. Research has shown that decreasing access to drugs, junk food and vehicles by appropriate legislation is the most effective factor in preventing high risk behavior in adolescence.

CELIAC DISEASE: CASE-BASED VARIOUS PRESENTATION - DIAGNOSIS AND MANAGEMENT

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Diagnostic algorithm for celiac disease: Detect by serology, diagnose by intestinal biopsy and confirm by response to gluten-free diet.

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Celiac disease should not be diagnosed on the basis of celiac serology alone (tTG), as it can be falsely elevated in nonceliac cases as well. Intestinal biopsy is a must in diagnosing celiac disease.

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Endoscopic duodenal biopsy can be avoided only when tTG is >10 times upper limit of normal in a symptomatic case with positive anti-EMA and HLA (all three; tTG, EMA and HLA are positive).

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Gluten-free diet (wheat, rye, barley) is the only treatment and outcome is excellent. About 70% will have symptomatic improvement in 2 weeks.

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Don’t start gluten-free diet without confirming the diagnosis as it is lifetime commitment, expensive and it limits patient socially.

WHITE MATTER DISEASES

Dr Ujjal Poddar, Lucknow ÂÂ

Celiac disease is no longer synonymous with diarrhea.

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CD is a permanent intolerance to gluten (waterinsoluble protein present in wheat, rye, barley) in genetically predisposed (HLA-DQ2/DQ8) individuals.

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It is common in North India but not so in South India and East/North East India due to low prevalence of HLA DQ2/DQ8 compared to North.

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Classical presentation (with malabsorption) used to be very common (80%) in the 90s, but scenario has changed over the years even in India due to increasing awareness about atypical presentations.

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What we see as symptomatic CD is only the tip of the iceberg. For every one case of diagnosed CD, there are 7 undiagnosed CD. Almost half of all celiac disease cases are atypical or nondiarrheal type and they can present to other specialties like Endocrinology (short stature), Hematology (anemia), Orthopedics (rickets/deformity), Dermatology (dermatitis herpetiformis, recurrent aphthous ulcers), Pediatric Surgeon (abdominal distension with constipation), Neurology (seizures, ataxia, neuropathy, depression, dementia, cerebral calcification) and Gynecology (infertility, amenorrhea, impotency).

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Awareness across specialty is the need of the hour, especially for atypical presentations.

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All suspicious cases should be screened for CD.

Dr Sarbani Raha, Vadodara ÂÂ

Appropriate neuroimaging goes a long way in diagnosis of leukoencephalopathies or leukodystrophies.

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MRI including gradient echo; MRS, contrast, MRI spine, CT, follow-up imaging.

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Static versus progressive; acquired versus inherited are important points of differentiation.

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Infective diseases need to be kept in mind in tropics where demyelinating disorders are not as highly prevalent as in Western countries.

METABOLIC SYNDROME: TREATMENT AND BEYOND Dr Piyali Bhattacharya, Lucknow ÂÂ

The prevalence of cardiovascular disease is rising steeply in India and is more extensive and premature than in the West or European countries (10 times more).

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Improved care and thereby, improved outcomes can be achieved by early detection and control of obesity, HT, diabetes and dyslipidemia.

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Waist circumference is the single most important indicator for obesity in a child and should be kept below 90th percentile for age.

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Ethnic traits are important and should be taken into consideration before diagnosing as metabolic syndrome as Asians appear to have lower cut offs compared to white Caucasians.

Indian Journal of Clinical Practice, Vol. 26, No. 9, February 2016

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CONFERENCE UPDATE ÂÂ

Scientific research has shown evidence that yoga has a preventive and therapeutic role in modifying the cardiovascular outcome in metabolic syndrome.

ANEMIA: CASE-BASED DISCUSSION

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Duration <2 weeks: Infectious; >2 weeks but <1 year: infections, malignancy, drug reaction, autoimmune; 1 year: likely to be pathologic but not malignancy.

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Generalized, firm, discrete, nontender, >2 cm, fixed and occipital, auricular, supraclavicular or posterior cervical LN are more likely to be malignant.

Dr Nitin K Shah, Mumbai ÂÂ

Take a proper history with ODP: Consanguinity.

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Complete and detailed examination from head to toe.

Localized, warm, tender, matted, erythematous are more likely to be associated with infections.

Do basic screening investigations: Peripheral smear, chest X-ray, stool for occult blood for 5 days.

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Investigate and refer if anemia, bleeding, not responding to antibiotics, hepatosplenomegaly, unexplained generalized LN↑.

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Screen carefully the results of the blood tests done: Ferritin, bone marrow aspirate.

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Do confirmatory tests, if required: BAL in pulmonary hemosiderosis.

In low risk patients, do biopsy if does not resolve in 3-4 weeks; in all high risk patients, do excisional biopsy.

If no response to iron therapy, think of secondary causes: Polyps, bleeding, malabsorption, Meckel’s diverticulum.

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Treatment options depend on the cause and presentation.

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Sometimes a disease can evolve e.g., celiac, GI bleeding.

Key Points ÂÂ Lymphadenopathy in children is largely inflammatory and infectious in etiology. ÂÂ Clinical presentation can point to possible causes in most cases. ÂÂ Causes can range from simple to rare. ÂÂ Final diagnosis is always by excisional biopsy.

Vital clues are sometimes available in the work-up done, which often lead to a correct diagnosis. CLINICAL APPROACH IN A CASE OF LYMPHADENOPATHY Dr Sanjay K Ghorpade, Satara ÂÂ

Lymphadenopathy is nodes that are abnormal in size, number or consistency. Lymphadenitis is lymphadenopathy that is due to inflammation. Along with LN swelling there is pain, fever, edema, skin changes; purulent collections ±.

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Cervical LN up to 1 cm are normal in children aged ≤12 years. Consider lymphadenopathy if submandibular LN >1.5 cm, inguinal LN >1.5 cm, epitrochlear nodes >0.5 cm.

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Assess: Location (single or multiple), progression (whether ↓, ↑, stable), associated systemic symptoms.

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Conditions that mimic lymphadenopathy: Cystic hygroma, thyroglossal duct cyst, sternocleidomastoid tumor, epidermoid cyst, branchial cleft cyst.

MONITORING INTRACRANIAL PRESSURE Dr K Rafiq Ahmed, Kurnool ÂÂ

IVD is the most accurate and reliable method of monitoring ICP and enables therapeutic CSF drainage.

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ICP monitoring helps early detection of intracranial hypertension, monitor response to drug therapy and progress of the unconscious patient.

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Invasive monitoring of ICP is generally indicated in patients who meet all 3 of the following criteria: Patient is suspected to be at risk for elevated ICP, comatose patient (Glasgow Coma Scale score ≤8) and ICU treatment is available.

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Head injury is the most frequent indication for ICP monitoring.

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CONFERENCE UPDATE

46th Annual Conference of The Indian Society of Nephrology (ISNCON 2015) DONOR SPECIFIC ANTIBODIES: TECHNOLOGY AND INTERPRETATION Dr MK Phanish, UK ÂÂ

The paradigm of transplant has moved from crossmatch positive or negative to immunological risk stratification of the recipient: zz

Low (standard) risk: No DSAs - current or historic

Intermediate risk: Low level DSA present at the time of transplantation or historic DSA

High risk: High levels of DSAs specific for mismatched donor HLA present at the time of Tx (Current DSA).

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Luminex assay detects HLA specific antibodies including rare specificities.

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It is a sensitive assay and the results should be used in conjunction with clinical picture and flow cytometry crossmatch results.

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False-positive and false-negative results can occur and antibodies detected may not be always clinically relevant.

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MFI values may not correlate with crossmatch positivity.

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Presence of a DSA with negative flow cytometry crossmatch is not a contraindication for transplantation. Desensitization in this scenario is not recommended. It will be high immunological risk transplantation and risk of AMR is high. Kidney sharing scheme/swap should be used when possible particularly when the DSA levels are high.

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Any desensitization protocol should aim at flow cytometry crossmatch negativity.

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I do not recommend Luminex crossmatch using donor cell lysates to coat the beads.

with diabetes worldwide is expected to increase from 366 million in 2011 to 552 million in 2030. First step in prevention is control of modifiable risk factors: HT, hyperglycemia and cessation of smoking. Treatment of HT is perhaps the most important intervention in the management of CKD. There is evidence from many large RCTs that correct BP control in DM delays development and progression of kidney disease. Obesity is an independent risk factor for CKD and progression in type 2 DM. A recent meta-analysis suggests that RAAS blockade prevents onset of moderately increased albuminuria (microalbuminuria). High intensity leisure time physical activity (LTPA) reduces onset of moderately increased albuminuria. DPP-4 inhibitors reduce risk of onset of moderately increased albuminuria. SGLT2 inhibitors reduce risk of onset of moderately increased albuminuria. Newer experimental therapies are coming up. So, can we prevent diabetic nephropathy? May be… Learn from the past, Live in the present, Believe in the future… PROGRESSIVE ASTHENIA IN DIALYSIS Dr Kamal Sud, Australia ÂÂ

Asthenia can be part of frailty in elderly patients on dialysis.

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Look for systemic conditions and dialysis-related conditions that may predispose to asthenia.

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Treatment is challenging and often ineffective.

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Few strategies that have shown short-term benefit include nutritional support, exercise training and androgens.

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It is associated with poor QoL and poor prognosis.

PLASMA CELL-RICH REJECTION

CAN WE PREVENT DIABETIC NEPHROPATHY? Dr Santosh Varughese, Vellore In India, total 66.85 million people have diabetes, 1 out of 12 have diabetes. Every 10 seconds... Two people develop diabetes. Every 10 sec, one person dies from diabetes-related complications. The number of patients

Dr Pranaw Kumar Jha, Gurgaon ÂÂ

Plasma cell-rich rejection is an uncommon and poorly responsive form of rejection.

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Poor compliance with immunosuppressive medications is an important risk factor.

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Late presentation is common.

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CONFERENCE UPDATE ÂÂ

It has poor treatment response and high graft loss rate.

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Treatment of plasma cell-rich rejection entails higher immunosuppression, which is associated with high morbidity and mortality.

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Best plan for treatment is not clear.

ELECTRONIC HEALTH RECORDS: WHAT ARE THE STANDARDS? Dr Ajay Kher, Gurgaon ÂÂ

Electronic health records are increasingly being used. They can include a basic EHR or a comprehensive EHR.

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Their impact on quality and safety depends on the components included and physician focus on those parameters.

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Setting up an EHR can be extremely costly and disruptive to workflow and efficiency, hence physician buy-in and input should be present before embarking on it.

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Future efforts to improve interoperability between EHRs are needed to improve its usefulness.

WHAT DO NEPHROLOGISTS NEED TO KNOW ABOUT AUTOIMMUNE INFLAMMATORY DISEASES? Dr MM Satish Kumar, Bengaluru ÂÂ

There is a need to look out for varied presentations of vasculitis.

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Remission or relapse? Decision about stepping up or decreasing immunosuppression! All based on urine examination.

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ANA: Do only IF; ANCA: Do both IF and ELISA; EURO Pattern Suite Technology is a novel approach. PLEX: A lot more role to play? PEXIVAS will answer.

AZILSARTAN: NEW SARTAN ON THE BLOCK FOR MOVING MORE MILLIMETERS

HT. Recent studies comparing Azilsartan with ARBs and an ACEI have demonstrated that Azilsartan was more effective at lowering ambulatory systolic BP.2-4 In studies comparing the potencies of different ARBs, Azilsartan was approximately twice as potent as the most potent of all clinically approved ARBs for blocking angiotensin II binding to AT1 receptors. The greater potency of Azilsartan for AT1 receptor blockade could help explain why Azilsartan lowers BP more than maximum approved doses of other ARBs.5 CKD and HT are closely associated with an overlapping and intermingled cause and effect relationship. Masked uncontrolled HT is more prevalent among individuals with CKD with rates ranging from 40% to 70%.6 Dosage adjustments are not required in patients with mild-tosevere renal disease.5 Azilsartan can thus be used in CKD patients for attaining BP control.

References 1. Volpe M, et al. Integr Blood Press Control. 2012;5: 19-25. 2. Jones JD, et al. P T. 2011;36(10):634-40. 3. Bönner G, et al. J Hum Hypertens. 2013;27(8):479-86. 4. White WB, et al. Hypertension. 2011;57(3):413-20. 5. Kurtz TW, et al. Vasc Health Risk Manag. 2012;8:133-43. 6. Judd E, et al. Adv Chronic Kidney Dis. 2015;22(2):116-22.

AUDITS IN NEPHROLOGY: THE UK EXPERIENCE Dr Charlie Tomson, UK The National Registry of Rare Kidney Diseases (RaDaR) is a Renal Association initiative designed to pull together information from patients who have certain rare kidney diseases. As of 01/12/2015 there are: 3,531 UK patients in RaDaR from 58 Renal Units. A further 17 units are currently in set-up. Automated electronic collection of national audit data is cheap, helps to drive policy, formulate research questions and drive quality improvement. IRON IN CKD: TO GIVE OR NOT TO GIVE?

Dr Sree Bhushan Raju, Hyderabad

Dr Ashok L Kirpalani, Mumbai

The clinical efficacy of ARBs has been established in hypertensive patients, particularly in terms of reduction in cardiovascular morbidity and mortality, prevention and regression of end-organ damage and the slow progression of nephropathy. Among the compounds that antagonize the RAS, ARBs represent today the best-tolerated class among antihypertensive agents.1 Azilsartan medoxomil is the eighth ARB to be approved by the US FDA for the treatment of

Patients with stage IV and V CKD have many symptoms, which are alleviated by the correction of the concomitant anemia. With the advent of the ESAs there has been a very satisfactory improvement in the QoL of patients in stage III and IV CKD, both before dialysis and while on maintenance hemodialysis (MHD), particularly in the West. The management of anemia in India is confounded in a large proportion of patients manifesting ESA hyporesponsiveness.

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CONFERENCE UPDATE At the very beginning of CKD care by the nephrologist, we find that a larger proportion of the patients in early CKD i.e., in stage III (a) and III (b) also exhibit anemia unlike their western counterparts. Women in child-bearing age and vegetarian patients in particular are prone to iron deficiency. Even those who claim to be nonvegetarian in India are comparable to the nonvegetarians of the West and many should be called “occasional” or “partial” vegetarian. Dietary intake of iron in most Indian patients is much less than their western counterparts. Azotemia also produces a state of inability to absorb orally ingested iron, probably due to excess hepcidin, generated in the liver and in inflammatory cells. Many patients will be EPO resistant, if the iron deficiency is not corrected. The KDOQI guideline for nondialysis CKD (ND-CKD) recommend IV iron only after a 1-3 month trial of oral therapy, if there is no urgent need to correct the hemoglobin to target. Serum iron, iron binding capacity, serum transferrin saturation and serum ferritin are the standard methods of assessing iron status of the patient. Serum iron gives information of iron circulating in the blood attached to transferrin and available to the reticulocytes in the bone marrow for fresh erythropoiesis to raise Hb. TIBC is an indirect measure of the serum transferrin and is often reduced in inflammatory and infectious states, that are common in CKD, particularly in MIA syndrome (malnutrition, inflammation, accelerated atherosclerosis) seen in dialysis patients. Transferrin saturation is the most reliable parameter for assessing the freely available iron for erythropoiesis (normal 20-40%, undesirable >50% and iron overload when >60%). Serum ferritin should be maintained between 300-500 µg/L, it is a unreliable marker of iron status because it can be high in inflammatory states and it reflects intracellular iron but not that available for erythropoiesis. In patients who are hyporesponsive to EPO and IV iron, particularly those on dialysis, it is not uncommon to be confronted with reports showing high ferritin and low TSAT (implying a functional iron deficiency) in whom there is a dilemma whether to give more IV iron or not. In an effort to correct TSAT, IV iron is now being used routinely post dialysis in most Indian dialysis centers, very often 100 mg every week. Bolus/maintenance dosing are not free of risk. Too much IV iron can release labile iron from cell stores into

the plasma and cause high risk of infection, reactive oxygen species-induced cellular damage and vascular damage and deposition in the tissues (hemosiderosis). A much higher potential for the release of labile plasma iron is noted with sodium ferric gluconate, iron sucrose and iron dextran preparations vs. a much lower release with ferumoxytol, ferric carboxymaltose and iron isomaltoside. The newer iron preparations are considered less risky as they are prepared as polymeric iron particles (nanoparticles comprising polyiron oxide/ hydroxide core coated with a carbohydrate). These preparations do not generate free labile iron, which is the cause of adverse reactions. Labile iron is more toxic in diabetics, inflammatory states producing elevated hepcidin and with low ferroportin activity leading to splenic/hepatic retention of labile iron and elevation of serum ferritin. In the DOPPS study, patients who achieved target Hb between 10-12 g by receiving >300 mg/month of IV iron, had higher hospitalization rate, all-cause mortality, CV events and infections. Ferric citrate is a recent addition to the available oral iron preparations, which not only provides some absorbable oral iron but has been primarily investigated as a useful phosphate binder and may be used as an adjunct to reduce the frequency and dose of IV iron in dialysis patients. But, it is not yet available in India. The treating nephrologists should ideally be doing frequent iron studies particularly TSAT and serum ferritin to avoid iatrogenic toxicity of IV iron. The cost of testing being prohibitive, it is observed that the number of patients with iron overload and unresponsive anemia is definitely increasing in our dialysis units. Judicious use of IV iron, frequent estimations of TSAT and serum ferritin and search for reversible causes of infection and inflammation in a patient on MHD followed by correction of reversible factors is necessary. IV iron is a two-edged sword that can be both useful and cytopathic. The question to ask before writing a prescription is “To use or not to use?”

Suggested Reading 1. Slotki I, et al. The labile side of iron supplementation in CKD. J Am Soc Nephrol. 2015;26(11):2612-9.

2. Bailie GR, et al. Variation in intravenous iron use internationally and over time. The DOPPS study. Nephrol Dial Transplant. 2013;28(10):2570-9. ■■■■

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56th Annual Conference of Indian Society of Gastroenterology (ISGCON 2015) ROBOTICS IN GI ENDOSCOPY Dr D Nageshwar Reddy, Hyderabad

Advantages of Robotics ÂÂ Operating in the deep and narrow space. ÂÂ Movements simulate wrist movements. ÂÂ 3D view. ÂÂ Suturing and knot tying. ÂÂ Elimination of physical tremors by computers. Limitations of Robotics ÂÂ Cost factor. ÂÂ Availability. ÂÂ Learning curve. ÂÂ Increase size. ÂÂ Transmitted strength. ÂÂ Haptics. Robot-assisted endoscopic submucosal dissection is effective in treating patients with early-stage gastric neoplasia.

Phee SJ, et al. Int J Med Robot. 2008;4(1):15-22.

Phee SJ, et al. Clin Gastroenterol Hepatol. 2012;10(10):1117-21.

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GI BLEEDING AFTER CORONARY EVENT: DILEMMA AND SOLUTIONS Dr Ajay C Anand, New Delhi ÂÂ

Dual antiplatelet therapy is the standard of care.

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Risk significantly more with dual combination vs. aspirin alone. Risk of overt bleeding with DAPT may be as high as 1.3% within the first 30 days of therapy and ~5% in 1 year.

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Death due to cardiac event more common in GI bleeding (ACUITY) (JACC. 2009).

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PPIs reduce the risk of bleeding to less than half (Gastroenterology. 2011).

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Famotidine is inferior to pantoprazole; not protective against clopidogrel.

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PPIs reduce conversion of clopidogrel to active metabolites → ↑CV events and death.

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Keep interval between PPI and antiplatelet ~12 hours.

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Restrictive transfusion practice recommended.

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RBC transfusion if Hb <7 g/dL in patients with stable angina, Hb 8-10 g/dL, if unstable angina (ACS).

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Use the Rockall scoring system to calculate risk of re-bleeding and death after hospitalization with acute GI bleeding.

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If score ≤3: Continue both antiplatelets; investigate and treat for other causes such as H. pylori.

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If score ≥ 4: Withhold aspirin alone with an aim to restart within 5 days and investigate and treat for other causes.

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If GI bleeding continues: Withhold both aspirin and clopidogrel with an aim to restart within 3 days and investigate and treat for other causes; reassess daily.

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Patients with upper GI bleed who require secondary CV prophylaxis should start aspirin as soon the CV risk outweighs the GI risk (Ann Intern Med. 2010).

The dilemma is in deciding if and when to stop antiplatelet agents.

CONFERENCE UPDATE IMMUNE TOLERANT HBV INFECTION IN CHILDREN: DO THEY NEED TREATMENT? Dr Ujjal Poddar, Lucknow There is a controversy about the root of transmission of hepatitis B in India. Largely, people believe that it is horizontal based on some old studies in pregnant women. However, recent data and clinical experience suggest that a significant proportion of chronic hepatitis B is perinatally transmitted and to substantiate that we from SGPGI, Lucknow have done genotyping of a mother-baby pair and have shown that they are identical in genotype and in their sequence homogeny suggesting that the predominant mode of transmission, especially in children, is vertical. These groups of patients (immune tolerant) have been usually following a benign course in the past 2 decades and two-third of them become inactive in their career by 30 years of age and one-third develop chronic liver disease. The age of seroconversion determines the outcomes of chronic hepatitis B. Studies have shown early seroconversion in childhood days prevents development of chronic liver disease in adulthood. Hence, the target of therapy in children with immunotolerant hepatitis B should be to achieve seroconversion. The trial of sequential combotherapy of lamivudine followed by lamivudine + interferon showed a promising response in the treatment of immunotolerant hepatitis B in children. In our study of 28 children, HBsAg seroconversion was seen in 21% of cases. A similar study from King’s College also shows HBsAg seroconversion in 18% of cases. Hence, there is some hope of cure with sequential combotherapy in immunotolerant hepatitis B. ARE WE READY TO TAKE UP THE CHALLENGE OF CHANGING THE SCENARIO? Prof VI Mathan, Chennai Is the gastroenterologist just a man at the end of a tube? Dr Mathan began by asking this question at the inauguration of the CME session on Day 1 of ISGCON. Not so, Dr Mathan continued to say. On the contrary, a GE should primarily be a physician with the 3 key qualities of Care, Compassion and Excellent Care. These are the 3 legs on which we are perched when treating a patient. When you train to be a GE, remember you are treating not the investigations but a human being Dr Mathan cautioned.

Healthcare has unfortunately become an industry rather than a vocation of the earlier days. These days most people seem to be perched on a bar stool with a single leg of-cash! As we go forward are we going to change? Are we going to contribute to the solution of a problem or be a part of the commercialization? Are we ready to take up the challenge of changing the scenario back once again of healthcare being a vocation? This concluded Dr Mathan is food for thought for the upcoming Gastroenterologist. I wish you all the best in this endeavor! ADVANCED IMAGING OF COLON AND THE NEW AGE COLONOSCOPES Dr Shaesta Mehta, Mumbai ÂÂ

Colonoscopy with biopsy: Gold standard for CRN detection.

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Conventional contrast enhanced SD-WLE/HD-WLE remains superior to VCE in Average Risk Groups and IBD, with limited data in Polyposis syndromes.

ÂÂ

FUSE scopes/Panoramic view the way ahead.

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Traditional methods for enhanced mucosal inspection remain the cornerstone for better diagnosis and therapy.

Principles of New Age Techniques ÂÂ

Efficiency: Wider field of mucosal inspection.

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Enhanced characterization: HD, CE.

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Higher acceptance: Reduction of loops and pain.

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Better range of operation: Diagnosis, therapy.

OPTIMIZING BIOLOGICAL THERAPY IN IBD Dr Vijay Yajnik, USA ÂÂ

Crohn’s disease has an inflammatory signature regulated by cytokine TNF.

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Sixty percent patients respond but by the end of 1 year only 40% do well.

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Recognize the dynamics between the biologic and the patient’s immune system.

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Role of concurrent immune modulators is still debatable.

ÂÂ

To treat a flare you can adjust dose or switch biologics.

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Early treatment is more effective than late.

ÂÂ

Biologics are indicated when there is inflammation or fistula.

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Risk of infection is higher with biologics in elderly IBD patients.

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Long-term safety data is good, but recognize drugrelated events.

Goals of Medical Therapy in IBD ÂÂ

Induction therapy: Reduce s/s of disease within 4-6 weeks.

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Maintenance therapy: Suppress disease activity and restore bowel function by sustained mucosal healing.

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Follow-up: Focus is to prevent long-term complications such as stricture, fistula, malnutrition and cancer.

RENAL INSUFFICIENCY IN CIRRHOSIS: MAGNITUDE, OUTCOMES AND IMPACT ON LIVER TRANSPLANTATION

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OLTx is the only definitive therapy with survival benefit in patients with HRS.

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If MELD is used for allocation, presence of HRS ↑ probability of receiving an organ.

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Independent of MELD, type 1 HRS should be considered as a high priority.

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In patients with AKI pre-OLTx: 12-70% may require RRT post-OLTx (variable duration).

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Pre-transplant renal function predicts post-OLTx survival (Nair et al. Hepatology. 2002) and postOLTx ESRD (Gonwa et al. Transplantation. 1995).

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Pre-transplant reversal of HRS improves the OLTx outcome to ‘no HRS’ group (Restuccia et al. J Hepatol. 2004).

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Simultaneous Liver-Kidney Transplant (SLKT) should only be done with irreversible kidney injury: ESRD + cirrhosis + symptomatic portal hypertension or a HVPG >10 mmHg; AKI (or HRS) with dialysis >8 weeks; liver failure + ESRD (GFR <30 mL/min) or >30% glomerulosclerosis/ fibrosis in a renal bx.

Dr Ashish Goel, Vellore ÂÂ

A mild ↑ in serum creatinine represents a much greater ↓ in kidney function in cirrhotics.

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Serum creatinine is not ideal to assess renal function, but is the best available.

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Other potential markers: GFR estimation by inulin (or other agents) clearance, serum cystatin C (>1.25 mg/dL), vascular resistive index on renal Doppler, serum and urinary neutrophil gelatinase associated lipocalin (NGAL).

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Renal insufficiency: Deranged kidney function but can support life (c/w renal failure).

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Normal serum creatinine does not r/o renal insufficiency (Wong et al. J Hepatol. 2015).

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AKI is seen in 19% cirrhotic patients at admission (Garcia-Tsao et al. Hepatology. 2008).

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Even mild AKI not amounting to ↑ in serum creatinine impacts short-term survival (Bucsics et al. J Gastroenterol Hepatol. 2015).

Key Points ÂÂ

Acute renal insufficiency, even if mild is a landmark in natural history of cirrhosis.

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Not all AKI is hepatorenal syndrome (look and correct precipitants).

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Renal insufficiency affects post-OLTx outcome.

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OLTx reverses kidney function in majority.

EUS-GUIDED TX OF PANCREATIC TUMOR Dr Vinay Dhir, Mumbai ÂÂ

Still investigational in many areas.

ÂÂ

Needs more data and refinement of devices.

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With rapid progress in interventional EUS, great potential for future treatment of pancreas tumor.

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AROUND THE GLOBE

News and Views Botox Gets FDA Nod for Lower Limb Spasticity

New Depression Screening Guidelines Released

The US Food and Drug Administration (FDA) has approved onabotulinumtoxinA (Botox, Allergan Inc) to decrease the severity of stiffness in ankle and toe muscles among adults with lower limb spasticity.

In an update to its recommendations on screening of depression in the general adult population aged 18 years and older, the US Preventive Services Task Force (USPSTF) has added screening of pregnant and postpartum women, regardless of risk factors to its previous recommendations of screening of all individuals by primary care practitioners using effective screening tests. These guidelines are published online January 26 in JAMA.

Govt Expands Coverage of Jan Aushadhi Scheme In a roadmap drawn under the supervision of the PMO, the Dept. of Pharmaceuticals plans to open 300 Jan Aushadhi stores across the country by March and yet another 3,000 by 2017. Only 45 medicines are available in 121 such stores at present. But now, the Govt. will offer 439 life-saving medicines, including cancer and cardiovascular drugs, as well as 250 medical devices like stents and implants at 40-50% discounted prices at these stores… (ET Healthworld – Sushmi Dey)

Heart Attack Statement on Women Despite some improvements in cardiovascular care, women today remain understudied, underdiagnosed and undertreated leading to the publication of the first scientific statement from the American Heart Association (AHA) on heart attacks in women. The statement published in the journal Circulation concluded that the undertreatment with guideline-based recommendations is “leading to worse outcomes and increased rates of readmissions, reinfarctions and deaths in the first year after myocardial infarction.”

CDC Releases Guidelines on Zika Virus Infection in Infants The Centers for Disease Control and Prevention (CDC) guidelines for possible Zika virus infection in infants recommend testing the mother as the first step to detect any potentially infected infant and then the infant for the virus if they were born with microcephaly or intracranial calcifications and their mothers resided in or traveled to an area with Zika virus transmission. Even if the infant test is negative, the guidelines recommend an ophthalmologic evaluation within the first month of life and a repeat hearing test at 6 months, as reports of abnormal eye findings and delayed hearing loss have been present in infants potentially infected with the virus. The guidelines are published in the January 26 early-release issue of the Morbidity and Mortality Weekly Report.

A New Campaign to Raise Prediabetes Awareness in the US The American Diabetes Association (ADA), American Medical Association (AMA) and CDC have jointly sponsored a new public service campaign to raise awareness about prediabetes. The campaign will run TV and radio ads and include an interactive text messaging initiative. https://doihaveprediabetes.org/ is the campaign website. Andrew W Gurman, MD, AMA president-elect said, “We’re hoping that people will visit the website and take a very simple test to see if they are at risk. If they are, the site will encourage them to go to their physician so they can have a discussion about screening and treatment.”

Oral Propranolol Effectively Reduces Infantile Hemangioma A meta-analysis of 18 studies reported online January 15 in the journal Pediatrics concluded that propranolol, a β-blocker was effective in reducing the size and volume of infantile hemangiomas versus placebo and other treatments. The largest mean estimate of expected clearance was for oral propranolol, at 95%, followed by timolol at 62% and intralesional triamcinolone at 58%. Oral steroids had a moderate clearance rate of 43%, while for placebo it was 6%.

Fecal Immunochemical Test Screening Effective at 4 Years The fecal immunochemical test (FIT) is highly effective for annual colorectal cancer screening programs for averagerisk patients, according to results of a retrospective cohort study published online January 26 in the Annals of Internal Medicine. The study which evaluated the performance of FIT over 4 rounds of annual screening

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AROUND THE GLOBE concluded that annual FIT screening had high sensitivity for CRC, with high adherence to annual follow-up screening among initial participants. Also, unlike fecal occult blood test, it does not require dietary and medication restrictions.

Could Stem Cell Transplantation Yield a Cure for MS? Multiple sclerosis has no cure at present; however, researchers at UK’s Royal Hallamshire Hospital believe they are close to uncovering one from stem cell treatment. Some wheel-chair bound MS patients who received the treatment as part of a clinical trial have been able to walk again. The groundbreaking treatment being trialed is called autologous hematopoietic stem cell transplantation (AHSCT), which is currently used to treat multiple myeloma and leukemia. The trial results are published in the January issue of the BMJ.

Fresh Farm Milk Helps Asthma and Allergies Children fed fresh unprocessed farm milk are less likely to develop asthma as they grow than kids who are brought up on industrially processed milk. This is on account of high omega-3 content in fresh farm milk, reveals a study from Ludwig-Maximilians-Universitaet (LMU) and published in the Journal of Allergy and Clinical Immunology. However, the authors of the study refrain from recommending the consumption of untreated milk, since it may contain pathogenic micro-organisms.

Clues to Schizophrenia’s Origins Uncovered Steven McCarroll, director of genetics for the Broad Institute’s Stanley Center for Psychiatric Research and an associate professor of genetics at Harvard Medical School in Boston claims to have discovered clues to Schizophrenia’s origin. A gene that contributes to synaptic pruning, which takes place as children move into adulthood, may increase a person’s risk of schizophrenia if certain mutations cause things to go wrong.

Prenatal Vitamin D has a Weak Effect on Wheezing Two new studies have suggested that pregnant women cannot dramatically reduce the risk of wheezing in their babies by taking vitamin D supplements. However, the studies did show enough benefit for researchers to be optimistic. The studies conducted at the University of Copenhagen and published in January 26 issue of JAMA. “[A]

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clinically important protective effect cannot be excluded, and a protective effect is suggested by the observed effect on airway immunology and symptomatic episodes,” investigator Bo L Chawes remarked.

New Imaging Technique could Reduce Need for Amputation A new MRI technique could reduce the need for amputation in patients with critical limb ischemia, according to a new study led by Surgeon, Mr Bijan Modarai BHF Intermediate Fellow and Reader/ Consultant in Vascular Surgery at King’s College London/St Thomas’ Hospital. The technique uses a new way of mapping blood delivered to the leg muscle immediately after operations on people with severely reduced blood flow to their limbs. Currently surgeons may need to wait days or weeks to see how successful the surgery has been. Findings of this study funded by British Heart Foundation (BHF) and carried out at St Thomas’ Hospital, London, are published in the scientific journal JACC.

Edited Stem Cells Future of Precision Therapy for Blindness Findings from a research are showing a possibility of treating blinding eye diseases using the patient’s own corrected cells as replacement tissue. Using the muchtalked about CRISPR/Cas9 gene editing, a joint team of ophthalmologists from University of Iowa and Columbia University Medical Center have corrected a blindnesscausing gene mutation in stem cells derived from the patient. The research was published in January 27 issue of Scientific Reports.

Immunosuppressant Shown to Provide Better Kidney Transplant Survival Rates vs. Standard of Care According to a worldwide study led by UC San Francisco and Emory University investigators, for the first time, an immunosuppressive agent has shown better organ survival in kidney transplant recipients versus a calcineurin inhibitor, the current standard of care. The drug in focus is belatacept, and the research appears in the January 28 issue of the New England Journal of Medicine. “Belatacept is potentially a transformational drug in kidney transplantation because unlike the currently used calcineurin inhibitor drugs cyclosporine and tacrolimus, it is not toxic to the kidney,” said lead author Flavio Vincenti, a UCSF Health Kidney and pancreas transplant specialist.

AROUND THE GLOBE New Clinical Guidelines on Diagnostic Imaging for Chest Pain Published The Journal of the American College of Radiology and the Journal of the American College of Cardiology have simultaneously published new clinical guidelines from the American College of Cardiology (ACC) and American College of Radiology (ACR) to address the appropriate use of diagnostic imaging for chest pain in the emergency department (ED). The guidelines provide appropriate imaging recommendations that capture a large number of patients who come to the ED with chest pain into a set of clinical scenarios. Chest pain represents one of the most common reasons why patients come to the ED, yet it encompasses a broad variety of problems, ranging from benign to life-threatening. One of the most important key components of the guideline document is tables which summarize 20 clinical scenarios that distill down the recommendations into their bare bones.

FDA Approves First Prefilled Insulin Pen Device of U-500 Strength The US FDA has approved the first prefilled pen device containing concentrated U-500 strength insulin (Humulin R U-500 KwikPen [insulin human injection] 500 units/mL, Eli Lilly) for diabetes patients who require more than 200 units/day. Each KwikPen holds 1,500 units of insulin (3 mL, with each mL containing 500 units), the amount contained in five U-100 insulin pens. However, it is the same size as other Lilly KwikPens and dials in 5 unit increments. This FDA approval is the first in the world for the Humulin R U-500 KwikPen. Humulin R U-500 insulin is currently only approved and marketed in the United States (FDA).

Elbasvir/Grazoprevir for Chronic Hepatitis C Elbasvir/grazoprevir has been approved by FDA for chronic hepatitis C virus (HCV) genotypes 1 and 4 infections, another cure that does not require concomitant use of interferon with all its harsh adverse events. Both are indicated with or without ribavirin for adults with either genotype of HCV. Genotype 1 is the most common, while genotype 4 is one of the least common. These two drugs are now expected to compete headto-head with ones already in use for HCV genotype 1 including ledipasvir plus sofosbuvir, and ombitasvir, paritaprevir, ritonavir, plus dasabuvir. (FDA).

AAP Guidelines on Procedural Pain in Newborns A new policy statement has been released by the American Academy of Pediatrics (AAP) on the procedural pain in newborns. The statement

recommends that healthcare facilities both minimize the number of painful procedures performed on newborns and routinely assess and treat pain in these patients. The policy’s first statement was made in 2006 followed by the updated guidelines published online on January 25 and in February issue of the journal Pediatrics. According to the AAP Committee on Fetus and Newborn and the AAP Section on Anesthesiology and Pain Medicine, “Neonates are frequently subjected to painful procedures, with the most immature infants receiving the highest number of painful events.”

Colchicine for Prevention of Cardiovascular Events Hemkens et al have stated that colchicine may have substantial benefits in reducing myocardial infarction in selected high-risk populations but uncertainty about the size of the effect on survival and other cardiovascular outcomes is high, especially in the general population from which most of the studies in the review were drawn. Colchicine is associated with gastrointestinal side effects based on low-quality evidence. The researchers conducted randomized controlled trials (parallel-group or cluster design or first phases of crossover studies) comparing colchicine over at least 6 months versus any control in any adult population to evaluate potential cardiovascular benefits and harms of a continuous long-term treatment with colchicine in any population, and specifically in people with high cardiovascular risk (Cochrane Database Syst Rev. 2016 Jan 27;1).

Tocilizumab plus Methotrexate in RA In rheumatoid arthritis (RA) patients with an inadequate response to methotrexate, adding tocilizumab to the regimen is more effective than simply switching to tocilizumab, according to Japanese researcher, Dr Tsutomu Takeuchi and the team from Keio University School of Medicine, Tokyo. They stated that methotrexate “is an anchor drug in the management of RA because of its long-term effectiveness and safety profile.” The paper has been published in January 5 issue of the Annals of the Rheumatic Disease. The researchers randomized 223 patients with moderate-to-high disease activity to add-on tocilizumab or a switch to tocilizumab. At 24 weeks, DAS28 remission rates were significantly greater in the add-on group than in switchers (70% vs. 55%, p = 0.02) among the 193 patients who completed the study. However, by week 52 rates were comparable (72% vs. 70%, p = 0.86).

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AROUND THE GLOBE USAID Extends Funding for Projects for TB-free India

Aggression and Suicide Risk Doubled in Children by Antidepressants

To support India’s efforts to end tuberculosis, US development agency USAID today announced grants aimed at scaling up innovative solutions for combating the disease in a country where an estimated 2.2 million such cases are reported annually. “We have made great strides towards ending TB in India, but much more work remains. Partnerships, technology and innovations are essential tools to find low-cost, sustainable solutions to address public health challenges, including TB,” US Ambassador to India, Richard R Verma, said after the US Agency for International Development’s (USAID) announcement. As part of the Tuberculosis Health Action Learning Initiative (THALI) project, USD 7.5 million has been awarded to the World Health Partners (WHP) for implementing activities in Kolkata while another USD 7.5 million has been awarded to Karnataka Health Promotion Trust (KHPT) for work in Bangalore, Hyderabad, and Pune… (PTI - Jan 29)

Adolescents and children have double the risk of suicide and aggression during antidepressant treatment, while in adults, there was no significant increase in all four outcomes of mortality, suicidality, aggressive behavior and akathisia. The systematic review and meta-analysis conducted in Denmark University of Copenhagen is published in (BMJ. 2016;352:i65) and included 70 trials (64,381 pages of clinical study reports) with 18,526 patients.

Angiography may Predict Very Late Stent Thrombosis The ADAPT-DES substudy published online in the journal Catheterization and Cardiovascular Interventions found that it may be possible to predict very late stent thrombosis following drug-eluting stent (DES) implantation using angiographic clues. Philippe Généreux, MD, of New York-Presbyterian Hospital/ Columbia University Medical Center in New York, and coauthors observed: “Anatomically complex lesions and the presence of thrombus are strong predictors of 2-year stent thrombosis in the DES era.”

Proton Radiotherapy has Acceptable Toxicity A nonrandomized, open-label, single-center, phase 2 trial concluded that proton radiotherapy for pediatric medulloblastoma has acceptable toxicity and had similar survival outcomes to those noted with conventional radiotherapy, suggesting that the use of the treatment may be an alternative to photon-based treatments. The trial enrolled patients aged 3-21 years who had medulloblastoma and were given craniospinal irradiation of 18–36 Gy radiobiological equivalents (GyRBE) delivered at 1·8 GyRBE per fraction followed by a boost dose. The findings are published in The Lancet Oncology. Published online: January 29, 2016.

TEP as the Procedure of Choice in Primary Inguinal Hernia Surgery Endoscopic total extraperitoneal repair (TEP) may be the procedure of choice in the surgical treatment of primary inguinal hernia, reports a study published in the Annals of Surgery. 2016; 63(2):240-3. Patients operated with TEP experienced less long-term postoperative pain and less limitation in their ability to exercise than those operated with Lichtenstein using local anesthesia.

Two-year Outcome of Surgical Treatment of Severe Ischemic Mitral Regurgitation

CHMP Recommends Coagadex to Manage

In a randomized 2-year outcome study of surgical treatment of severe ischemic mitral regurgitation (MR) in 251 patients reported in N Engl J Med. 2016; 374:344-53, no significant between-group difference in left ventricular reverse remodeling or survival at 2 years was observed in patients undergoing mitral-valve repair replacement or repair for severe ischemic MR. However, MR recurred more frequently in the repair group, resulting in more heart-failure–related adverse events and cardiovascular admissions.

Antihemorrhagic factor X concentrate (Coagadex, Bio Products Laboratory Limited) has been recommended by the European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) for the treatment, prophylaxis and perioperative management in patients with hereditary factor X deficiency. The injectable product, which was designated as an orphan medicinal product in 2007 and evaluated under accelerated assessment, will be available as 250 IU and 500 IU powder and solvent for solution.

Deficiency of Factor X

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INSPIRATIONAL STORY

Determination and Persistence

his is a real life story of engineer John Roebling building the Brooklyn Bridge in New York, USA back in 1870. The bridge was completed in 1883, after 13 years. In 1883, a creative engineer named John Roebling was inspired by an idea to build a spectacular bridge connecting New York with the Long Island. However, bridge building experts throughout the world thought that this was an impossible feat and told Roebling to forget the idea. It just could not be done. It was not practical. It had never been done before. Roebling could not ignore the vision he had in his mind of this bridge. He thought about it all the time and he knew deep in his heart that it could be done. He just had to share the dream with someone else. After much discussion and persuasion he managed to convince his son Washington, an up and coming engineer, that the bridge in fact could be built. Working together for the first time, the father and son developed concepts of how it could be accomplished and how the obstacles could be overcome. With great excitement and inspiration, and the headiness of a wild challenge before them, they hired their crew and began to build their dream bridge. The project started well, but when it was only a few months underway a tragic accident on the site took the life of John Roebling. Washington was also injured and left with a certain amount of brain damage, which resulted in him not being able to talk or walk. “We told them so.” “Crazy men and their crazy dreams.” “It’s foolish to chase wild visions.” Everyone had a negative comment to make and felt that the project should be scrapped since the Roebling’s were the only ones who knew how the bridge could be built. In spite of his handicap, Washington was never discouraged and still had a burning desire to complete the bridge and his mind was still as sharp as ever. He tried to inspire and pass on his enthusiasm to some of

his friends, but they were too daunted by the task. As he lay on his bed in his hospital room, with the sunlight streaming through the windows, a gentle breeze blew the flimsy white curtains apart and he was able to see the sky and the tops of the trees outside for just a moment. It seemed that there was a message for him not to give up. Suddenly an idea hit him. All he could do was move one finger and he decided to make the best use of it. By moving this, he slowly developed a code of communication with his wife. He touched his wife’s arm with that finger, indicating to her that he wanted her to call the engineers again. Then he used the same method of tapping her arm to tell the engineers what to do. It seemed foolish but the project was under way again. For 13 years Washington tapped out his instructions with his finger on his wife’s arm, until the bridge was finally completed. Today the spectacular Brooklyn Bridge stands in all its glory as a tribute to the triumph of one man’s indomitable spirit and his determination not to be defeated by circumstances. It is also a tribute to the engineers and their team work, and to their faith in a man who was considered mad by half the world. It stands too as a tangible monument to the love and devotion of his wife who for 13 long years patiently decoded the messages of her husband and told the engineers what to do. Perhaps this is one of the best examples of a never-saydie attitude that overcomes a terrible physical handicap and achieves an impossible goal. Often when we face obstacles in our day-to-day life, our hurdles seem very small in comparison to what many others have to face. The Brooklyn Bridge shows us that dreams that seem impossible can be realized with determination and persistence, no matter what the odds are.

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LIGHTER READING

Student: I’d climb a tree.

was safe to leave them with his assistant and left to get a hot dog. He came back to a near riot. He asked his assistant what in the world happened. He said: “Everything was fine ‘until some vendor came by and yelled ‘peanuts’.”

Teacher: If the lion climbs a tree?

BOSSES VERSUS WORKERS

IF A LION IS CHASING YOU Teacher: If a lion is chasing you, what would you do?

Student: I will jump in the lake and swim. Teacher: If the lion also jumps in the water and swims after you? Student: Teacher, are you on my side or on the lion’s? THEY WERE ALL ON THE PHONE A man was in the kitchen making a lot of noise! His wife comes in and asks why he was making so much noise? The man replies: “I am killing flies.” A short time later his wife came back and he was still making lots of noise! She asks: “Well, Mr. Big Shot, how many flies have you killed?” He says: “I have killed seven flies! 4 males and 3 females.”

When I take a long time, I am slow. When my boss takes a long time, he is thorough. When I don’t do it, I am lazy. When my boss doesn’t do it, he’s too busy. When I do it without being told, I’m trying to be smart. When my boss does the same, that is initiative. When I please my boss, that’s brown-nosing. When my boss pleases his boss, that’s co-operating. When I do good, my boss never remembers. When I do wrong, he never forgets.

QUOTES

“Families break up when people take hints you don’t intend and miss hints you do intend.” —Robert Frost “Inventing is the mixing of brains and materials. The more brains you use, the less materials you need.” —Charles F. Kettering

She says: “Right, how can you tell the gender of flies?” He says: “Very easy: the 4 flies in my right hand are males. When I killed them, they were all on beer cans!” Then she asks: “If you are so smart, how can you tell the gender of the females?”

Dr. Good and Dr. Bad SITUATION: A 16-year-old female was diagnosed to have calcific lesions in the ventricles on a CT scan.

He says: “The three in my left hand, they were all on the phone!!!” PEANUTS

This is a typical case of neurocysticercosis

This is not neurocysticercosis

A doctor worked at a mental hospital. He wanted to take some patients to a ballgame, worked months to get them to follow simple commands, and finally decided they were ready. When the star spangled banner played he said: “Stand up nuts” and they stood. When it was over he said: “Sit down nuts” and they sat. When a player got a hit he said: “Cheer nuts” and they cheered. When the umpire made a bad call he said: “Boo nuts” and they booed. He decided it

HUMOR

Lighter Side of Medicine

LESSON: In neurocysticercosis, the calcification is seen only in the parenchyma and not in ventricles or cisterns.

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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. –

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Books

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

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Articles in Books

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Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.

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4.____________ 4.________________

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Asian Journal of Diabetology

Emerging role of Cardiac MRI in Ischemic and Non-ischemic Cardiomyopathy

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Acute Renal Failure and Silent Myocardial Infarction Following Multiple Honey Bee Stings

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Superficial Brachial Artery: Its Embryological and Clinical Significance

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Glucose Tolerance in Nondiabetic Patients after First Attack of Acute Myocardial Infarction and its Outcome

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A Case of Left Atrial Myxoma Presenting as Severe Pulmonary Hypertension

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Double-Chambered Right Ventricle with Transient 2:1 Atrioventricular Block: A Rare Presentation

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Cornary Artery Air Embolism

Volume 17, Number 5

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