Ijcp feb 2017

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Volume 27, Number 9

February 2017, Pages 801–900

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yy American Family Physician yy Cardiology yy Community Medicine yy ENT yy Gastroenterology yy Internal Medicine yy Neurology yy Orthopedics yy Pediatrics

an i c i ys ians

yy Expert’s View

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

Dr KK Aggarwal Group Editor-in-Chief IJCP Group, eMedinewS and eMediNexus

Volume 27, Number 9, February 2017 FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF

805 Budget Reactions

AMERICAN FAMILY PHYSICIAN

807 Diagnosis and Treatment of Atrial Fibrillation

Dr Veena Aggarwal MD, Group Executive Editor

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

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

KK Aggarwal

Cecilia Gutierrez, Daniel G. Blanchard

815 Practice Guidelines 817 Photo Quiz CARDIOLOGY

821 Lipoprotein(a) - A Potential Cardiovascular Risk Factor and Therapeutic Approaches

Pragati Kapoor, Pankaj Kumar, AK Kapoor

COMMUNITY MEDICINE

830 Lead Toxicity Among Automobile Garage Workers in the Vicinity of Nalanda Medical College and Hospital, Patna and Its Adjoining Areas of Patna, Bihar, India

MA Nasar, TF Subhani, RR Sinha

ENT

841 Pyogenic Granuloma of Hard Palate Masquerading as Papilloma: A Case Report

Bhushan Kathuria, Himani Dhingra, Vikrant Kamboj, Samar Pal Singh Yadav

GASTROENTEROLOGY

845 5’-Nucleotidase Activity, Oxidative Stress and Antioxidant Activity in Cirrhotic and Alcoholic Patients

Tarannum Fatima Subhani, Md Abu Nasar, Rajiv Ranjan Sinha, Ijen Bhattacharya

INTERNAL MEDICINE

856 Study of hs-CRP in HIV Patients and Its Correlation with CD4 Count

Arun Viswanath S, Haroon Subhan Khan, Anjum Parvez, Rizwan Hasan Khan

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

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NEUROLOGY

866 Indigenous Axillary Crutch Associated Diparesis

Rajesh Chetiwal, UC Ojha, P Lakhwani, OP Lakhwani

ORTHOPEDICS 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

869 Tubercular Osteomyelitis of Talus in a Child: A Case Report and Review of Literature

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

Ritesh Runu, Mantu Jain, Vidya Sagar, Arnab Sinha, Saurav Kumar, Santosh Kumar

PEDIATRICS

873 Zinc Supplementation During the Growing Years

Copyright 2017 IJCP Publications Ltd. All rights reserved.

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

Shweta Pathak Gupta

EXPERT’S VIEW

875 Which Hypertensive Patients are Most Likely to Benefit from β-blockers?

Editorial Policies

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

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MEDILAW

879 Issuing a Medical Certificate: Guidelines for Medical Practitioners CONFERENCE PROCEEDINGS

882 69th Annual National Conference of Indian Psychiatric Society (ANCIPS 2017) 886 72nd Annual Conference of the Association of Physicians of India (APICON 2017) AROUND THE GLOBE

890 News and Views INSPIRATIONAL STORY

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

895 Begin with a Blank Page LIGHTER READING

896 Lighter Side of Medicine

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FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF

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Group Editor-in-Chief IJCP Group, eMedinewS and eMediNexus

Budget Reactions

T

wo new AIIMS, 5,000 new PG medical seats per annum, action plans for elimination of diseases like kala azar, filariasis and tuberculosis (TB), safe water for areas affected by fluoride and arsenic, transformation of 1.5 lakhs health subcenters into health and wellness centers, separate health cards for elderly, ` 6,000/- aid for every pregnant women, accreditation of colleges and promoting healthcare indirectly by increasing budget for road safety, agricultural, rural health and Swachh Bharat, the current budget is a step forward for improving the healthcare of society. But still more could have been done.

While the proposal to set up two new AIIMS in Gujarat and Jharkhand is a positive development, IMA wants an AIIMS in every state and an overall increase in the budget allocation to 2% of GDP to cover 80% of population who do not avail government health services.

This year's budget makes a commitment towards structural regulatory reforms in medical practice and education as well as digital health. Though more focus could have been given to R&D in healthcare, many of the provisions are worth a mention and a step in the right direction.

In a move to widen the availability of essential drugs across India, an Amendment to the Drugs and Cosmetics Rules has been proposed. This will ensure availability of medicines at reasonable prices and also help people get access to life-saving medicines. New norms will also be formulated for the medical devices sector in order to reduce the cost of such devices and encourage investments.

The Government also plans to add 5,000 PG seats per annum. More qualified doctors being the need of the hour for both urban and rural areas alike; this is a step in the right direction.

The Government has also taken a positive step by deciding to start DNB (Diplomate National Board) courses in many District hospitals across the country, strengthen PG teaching in select ESI and Municipal Corporation Hospitals and encourage reputed Private Hospitals to start DNB courses. But, the country needs more family doctors. All the PG seats that remain vacant may be converted into PG Family Medicine seats.

Action plans to eliminate kala azar and filariasis by 2017, leprosy by 2018, measles by 2020 and TB by 2025 will bring a major relief. Focusing on elderly healthcare, the proposed Aadhaar card-based smart health cards would be a move in the right direction.

The Government also plans to bring down the maternal mortality rate (MMR) to 100 by 2018-2020 and also reduce the infant mortality rate (IMR) to 28 by 2019.

The budget also has provisions for personal income tax as follows: ÂÂ

Existing rate of tax for individuals between ` 2.5 and 5 lakhs reduced to 5% from 10%.

As a result of the combined effect of the new Section 87A rebate and the reduction in the lowest slab tax rate to 5% the tax burden for those with income up to ` 3 lakhs would be zero and tax burden those in the ` 3 lakhs to ` 3.5 lakhs bracket would be ` 2,500.

Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

805

FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF Those earning ` 4.5 lakhs can therefore reduce their tax liability to zero by fully utilizing the tax break under Section 80C combined with these new proposals.

Those falling in the higher income tax slabs will also be eligible for this lower tax rate of 5% on income between ` 2.5 lakhs and ` 5 lakhs. Therefore, those in the higher tax slabs will pay lower tax by ` 12,500 per person.

Individuals earning between ` 50 lakhs and ` 1 crore will have to pay a surcharge of 10% on the total income tax payable by them.

Currently, there was no such surcharge on this category. Only those with income above

` 1 crore were required to pay surcharge of 15%, which continues. ÂÂ

All other categories of tax payers in subsequent brackets will get benefit of ` 12,500.

ÂÂ

Simple one page return for people with annual income of ` 5 lakhs other than business income.

ÂÂ

People filing IT returns for the first time will not come under govt. scrutiny.

ÂÂ

Ten percent surcharge on individual income above ` 50 lakhs and up to ` 1 crore to make up for ` 15,000 crore loss due to cut in personal IT rate.

The 15% surcharge on individual income above 1 crore remains.

■■■■

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Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

AMERICAN FAMILY PHYSICIAN

Diagnosis and Treatment of Atrial Fibrillation CECILIA GUTIERREZ, DANIEL G. BLANCHARD

ABSTRACT Atrial fibrillation is a supraventricular arrhythmia that adversely affects cardiac function and increases the risk of stroke. It is the most common arrhythmia and a major source of morbidity and mortality; its prevalence increases with age. Pulse rate is sensitive, but not specific, for diagnosis, and suspected atrial fibrillation should be confirmed with 12-lead electrocardiography.

Because normal electrocardiographic findings do not rule out atrial fibrillation, home monitoring is recommended if there is clinical suspicion of arrhythmia despite normal test results. Treatment is based on decisions made regarding when to convert to normal sinus rhythm vs. when to treat with rate control, and, in either case, how to best reduce the risk of stroke. For most patients, rate control is preferred to rhythm control. Ablation therapy is used to destroy abnormal foci responsible for atrial fibrillation. Anticoagulation reduces the risk of stroke while increasing the risk of bleeding. The CHA2DS2-VASc scoring system assesses the risk of stroke, with a score of 2 or greater indicating a need for anticoagulation. The HAS-BLED score estimates the risk of bleeding. Scores of 3 or greater indicate high risk. Warfarin, dabigatran, factor Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban), and aspirin are options for stroke prevention. Selection of therapy should be individualized based on risks and poten­tial benefits, cost, and patient preference. Left atrial appendage obliteration is an option for reducing stroke risk. Two implantable devices used to occlude the appendage, the Watchman and the Amplatzer Cardiac Plug, appear to be as effective as warfarin in preventing stroke, but they are invasive. Another percutaneous approach to occlusion, wherein the left atrium is closed off using the Lariat, is also available, but data on its long-term effectiveness and safety are still limited. Surgical treatments for atrial fibrillation are reserved for patients who are undergoing cardiac surgery for other reasons.

Keywords: Atrial fibrillation, supraventricular arrhythmia, cardiac function, risk of stroke, ablation therapy, anticoagulation, left atrial appendage obliteration

A

trial fibrillation is a supraventricular arrhythmia characterized by unco­ ordinated electrical activation of the atria and an irregular, often rapid, ventricular response causing hemody­namic compromise.1,2 As the atria fibrillate, blood pools in the atria, and a clot may form in the atrial appendage, increasing the risk of embolic stroke. Atrial fibrillation is associ­ated with a fivefold increased risk of stroke,3-5 and it is the most common arrhythmia. It worsens heart failure and increases mortal­ity in patients with myocardial infarction, and is an independent risk factor for death.6-8 The prevalence of atrial fibrillation increases with age, and the associated cost of medical care is high.9,10 PATHOPHYSIOLOGY AND DEFINITIONS Micro-reentry and enhanced automaticity in one or more atrial circuits are the most common triggers

CECILIA GUTIERREZ, MD, is a clinical professor in the Department of Family Medicine and Public Health at the University of California, San Diego, School of Medicine.

DANIEL G. BLANCHARD, MD, is a professor of medicine in the Division of Cardiovascular Medicine at the University of California, San Diego, School of Medicine.

Source: Adapted from Am Fam Physician. 2016;94(6):442-452.

for atrial fibrillation.1,2 Key electrocardiographic findings are a loss of P waves and replacement by fibrillatory waves; erratic activation of the ventricles resulting in an irregular, rapid heart rate (usually 90 to 170 beats per minute [bpm]); and a narrow QRS complex, unless other conduction abnormalities coexist (Figure 1). Sympathetic and parasympathetic activation can provoke or worsen atrial fibrillation by shortening the atrial refractory period, which increases susceptibility to reentry and enhanced automaticity.11 Atrial fibrillation results from several dis­ease processes, each with different prognoses. Nonvalvular atrial fibrillation, which occurs in the absence of rheumatic valve disease, a mechanical or bioprosthetic valve, or mitral valve abnormalities, is the most common form of atrial fibrillation.1,2 Paroxysmal atrial fibrillation is episodic and resolves sponta­neously or with intervention within seven days.1,2 Permanent atrial fibrillation indicates a decision to discontinue attempts to restore or maintain sinus rhythm.1,2 Paroxysmal and permanent forms carry the same long-term risk of stroke. Persistent atrial fibrillation lasts more than seven days and causes atrial remodeling, which leads

Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

807

AMERICAN FAMILY PHYSICIAN Table 1. Common Causes of Atrial Fibrillation Cardiac causes

Noncardiac causes

Coronary artery disease

Collagen vascular disease

Myocardial infarction

Diet pills

Myocardial ischemia

Drug toxicity

Epicardial, myocardial, and endocardial diseases (infectious, injury, or drug toxicity) Figure 1. Electrocardiogram showing atrial fibrillation.

Note the absence of distinct P wave, chaotic activity of atria, irregular R-R intervals with narrow QRS complex.

to its perpetua­ tion.1,2,12 Atrial fibrillation caused by valvular disease carries a higher risk of stroke than nonvalvular atrial fibrillation. When due to noncardiac disease, it is referred to as second­ary atrial fibrillation; treating its cause often resolves the arrhythmia. Table 1 lists common causes of atrial fibrillation.

DIAGNOSIS Patients with atrial fibrillation may present with mild or no symptoms, heart failure, myocardial infarction, stroke, or hemody­namic collapse. A systematic review con­cluded that pulse rate is 94% sensitive and 72% specific for diagnosis (positive likelihood ratio = 3.4; negative likelihood ratio = 0.08).13 Suspected atrial fibrillation based on evalua­tion of pulse rate should always be confirmed with 12-lead electrocardiography.

However, a normal test result does not completely rule out the presence of atrial fibrillation because electrocardiography may not capture a par­ oxysmal arrhythmia. When clinical suspicion of atrial fibrillation persists despite normal electrocardiography results, a Holter monitor (24-hour recording) or event monitor (seven-to 30-day recording) may be required.

The history and physical examination are focused on identifying risk factors, comor­bidities, and physical findings of atrial fibrillation. Cardiac and noncardiac etiolo­gies must be considered. Onset and duration of arrhythmia, aggravating and alleviating factors, and severity of associated symptoms should be elicited.

Common symptoms include fatigue, palpitations, chest pain, syncope, dizziness, dyspnea, and orthop­nea.

Sleep apnea, thyroid disease, recent ill­nesses, and the use of any new medications or supplements must be considered. Physi­cians also should inquire about use of illicit drugs, alcohol, and diet pills. The physical examination should assess blood pressure, heart rate, presence of cardiac murmurs (such as aortic or mitral

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Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

Heart failure Iatrogenic condition Postablation therapy Postcardiac catheterization Postcardiac device implant Postcardiac surgery Structural heart disease (congenital or acquired) Atrial septal defect Dilated cardiomyopathy Ebstein anomaly (anomaly of tricuspid valve) Valvular disease Ventricular hypertrophy

Antiarrhythmics Beta agonist inhalers Drugs that increase QT interval Lithium Electrolyte abnormalities Hypothermia Illicit drugs Infiltrative disease Pulmonary disease Chronic obstructive pulmonary disease Cor pulmonale Pneumonia Pulmonary embolism Sleep apnea Thyroid disease

stenosis), and evi­dence of heart failure (pulmonary rales, S3 gallop, peripheral pulses, and jugular venous distension). Initial blood tests include a complete blood count, an electrolyte panel, thyroid-stimulating hormone, and liver and kidney function tests. Imaging requirements for all patients include two-dimensional transthoracic echocardiography to evaluate cardiac structure and function, and chest radiogra­phy to assess for pulmonary disease.1,2 Addi­ tional testing may be necessary depending on the patient’s history and risk factors. These may include stress echocardiogra­phy, nuclear perfusion imaging, or cardiac catheterization to evaluate for ischemia or coronary artery disease; drug screening in selected cases; and a sleep study if sleep apnea is suspected.

TREATMENT In patients who are hemodynamically unstable, immediate evaluation and treat­ment are warranted, including emer­gency cardioversion, if necessary.

In stable patients, treatment depends on the dura­tion of atrial fibrillation and the presence of underlying cardiac disease or other comor­ bidities. Atrial fibrillation treatment poses three main therapeutic

AMERICAN FAMILY PHYSICIAN dilemmas. Physicians must determine how to best control ventricular rate; whether a procedure to convert the rhythm back to normal sinus rhythm is safe and advisable; and whether an anticoagulant should be started, and which medication to use, if so.

All therapeutic decisions should include discussions with the patient and their families about risks and benefits. Figure 2 presents an algorithm showing the key decision-making points in the process.1,2,14-16

Rate Control Rate control is an essential part of atrial fibrillation treatment in acute and chronic settings. It promotes hemodynamic function by slowing ventricular response, improving diastolic ventricular filling, reducing myo­cardial oxygen demand, and improving cor­onary perfusion and mechanical function. Given the challenges of achieving and main­taining normal sinus rhythm and the delete­rious effects of antiarrhythmic

Evaluation and Treatment of Atrial Fibrillation Assess hemodynamic stability and need for emergent cardioversion Initial evaluation: Physical examination, electrocardiography, chest radiography, two-dimensional echocardiography, complete blood count, electrolytes, liver and kidney function tests, and thyroid-stimulating hormone test Additional testing may be required: Event or Holter monitoring, cardiac function testing, polysomnography, additional laboratory tests All patients need evaluation for possible cardioversion, rate vs. rhythm control, and anticoagulation Cardioversion Rate control

Emergent

Nonemergent

Use beta blockers or nondihydropyridine calcium channel blockers as first-line agents to achieve target heart rate (< 80 bpm resting or < 110 bpm in asymptomatic patients with normal left ventricular function)

Electric direct current

Initiate anticoagulation and continue for four weeks

Anticoagulation

Perform if duration of atrial fibrillation is < 48 hours; if duration unknown, anticoagulate for four weeks before electric direct current or pharmacologic* cardioversion and continue for four weeks after

Assess risk of stroke with CHA2DS2VASc score and risk of bleeding with HAS-BLED score

Consider adding digoxin

Discuss anticoagulation risks and benefits with patient and make recommendations

Amiodarone may be used if firstline options do not work

If CHA2DS2-VASc = 0: no; = 1: may consider; ≥ 2: yes If HAS-BLED ≥ 3: reconsider

Pre-cardioversion anticoagulation not required if transesophageal echocardiography shows no thrombus in the left atrium

Ablation therapy

Discuss risks and benefits of therapy with patients and engage in shared decision making

Initiate anticoagulation, based on shared decision making?

Consider in selected patients undergoing invasive cardiac surgery for other reasons or in those who cannot take oral anticoagulants

Consider in patients with refractory atrial fibrillation who are symptomatic or intolerant to drug therapy; younger patients with no structural heart disease; and patients 65 years and older

No

Yes

LAA obliteration

Discuss options, risks and benefits, adverse effects, monitoring

Patient declines or has contraindications

Offer aspirin or aspirin plus clopidogrel

Warfarin

DOACs:

International normalized ratio: 2 to 3

Dabigatran

Monthly monitoring

Apixaban

*Pharmacologic options are amiodarone, flecainide, dofetilide, propafenone, and intravenous ibutilide.

Rivaroxaban Edoxaban

Figure 2. Algorithm for the evaluation and treatment of a patient with atrial fibrillation.

BPM = Beats per minute; CHA2DS2-VASc = Congestive heart failure; hypertension; age 75 years or older [doubled]; diabetes mellitus; stroke, transient ischemic attack, thromboembolism [doubled]; vascular disease; age 65 to 74 years; sex category; DOACs = Direct oral anticoagulants; HAS-BLED = Hypertension, abnormal renal function and liver function, stroke, bleeding, labile international normalized ratio, elderly [older than 65 years], drugs and alcohol; LAA = Left atrial appendage.

Information from references 1, 2, and 14 through 16.

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AMERICAN FAMILY PHYSICIAN drugs, most patients with atrial fibrillation are treated with rate control.17-19 Beta blockers (e.g., metoprolol, esmolol, propranolol) or nondihydro­pyridine calcium channel blockers (e.g., diltiazem, verapamil) are used to achieve heart rate goals (less than 80 bpm during rest and less than 110 bpm during exercise).1,2 More lenient rate control to achieve a resting rate less than 110 bpm is reasonable in asymp­tomatic patients with normal left ventricular function.20 Beta blockers and calcium chan­nel blockers are contraindicated in patients with preexcitation (WolffParkinson-White syndrome). Non-cardioselective beta block­ers are also contraindicated in patients with acute heart failure, severe chronic obstruc­tive pulmonary disease, and asthma. Digoxin is no longer considered a first-line agent or recommended as monotherapy, but it can be added to therapy with beta blockers or calcium channel blockers.1,2 Amiodarone offers another choice for rate control when beta blockers and calcium channel blockers do not work, but its delayed action, poten­tial toxicity, and drug interactions severely limit its use.

It may also cause acute cardio­version, which could lead to a stroke if anti­coagulation therapy has not been properly administered.1,2

Cardioversion The main indication for cardioversion is unstable or poorly tolerated atrial fibrilla­tion that is unresponsive to drug therapy.1,2 Unless done emergently, or when the dura­tion of the arrhythmia is known to be less than 48 hours, four weeks of pre- and post-cardioversion anticoagulation is required.1,2 Cardioversion can be attempted electrically or pharmacologically. Electrical cardiover­sion is usually successful in the short term, but often not in the long term. If transesoph­ageal echocardiography shows no thrombus in the left atrium, it is safe to omit pre-cardioversion anticoagulation.1,2 Electrical cardioversion delivers a direct-current electric shock in synchrony with the QRS complex to avoid triggering ventricular fibrillation. One or more shocks of 200 to 300 joules may be necessary.1,2 Pharmacologic cardioversion uses intravenous ibutilide, flecainide, dofetilide, propafenone, or amiodarone.1,2 Cardioversion and mainte­nance of normal sinus rhythm using medication are challenging because of the limited long-term effectiveness of antiarrhythmics, the risk of triggering ventricular arrhyth­mias, and long-term adverse effects. In gen­ eral, maintenance of normal sinus rhythm with oral medications is more successful in patients

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Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

65 years and younger with structur­ally normal hearts, as well as patients who have only recently developed atrial fibrilla­tion.1,2 Contraindications to either form of cardioversion include known atrial throm­bus, digitalis toxicity, multifocal atrial tachy­cardia, and suboptimal anticoagulation.

Ablation Therapy Electrophysiologic radiofrequency ablation is a nonoperative, catheter-based procedure used to isolate and possibly destroy abnor­mal foci responsible for atrial fibrillation. Specific foci that cause atrial fibrillation have been found at or near the pulmonary vein ostia in the left atrium; locating these sites allows targeted ablation.

Some trials have shown that radiofrequency ablation is supe­rior to antiarrhythmics in selected patients, including patients with paroxysmal atrial fibrillation who are symptomatic but with­ out structural heart disease, patients who are intolerant of antiarrhythmics, and patients with inadequate pharmacologic rhythm control.21,22 However, data on the long-term effectiveness and safety of radiofrequency ablation are limited. Atrial fibrillation may recur after ablation, and a repeat procedure may be required in approximately 20% of cases. Ablation of the accessory pathway is the optimal treatment for patients with WolffParkinson-White syndrome and atrial fibrillation.1,2 The procedure is contraindi­ cated in patients who cannot be anticoagulated one month before and at least several months after the procedure. Atrioventricular nodal ablation with pacemaker implantation may be ben­eficial for older patients with tachycardia-induced cardiomyopathy and persons with refractory ventricular rate control despite maximal medical therapy.1,2 Longterm anticoagulation is usually required following this procedure.1,2

Surgery and Percutaneous Left Atrial Appendage Isolation Surgical treatments for atrial fibrillation are invasive, high risk, and should be considered only in patients undergoing cardiac surgery for other reasons.1,2 The primary surgical therapies for treating atrial fibrillation are the maze procedure and left atrial appendage (LAA) obliteration. The maze procedure aims to eliminate atrial fibrillation through the use of incisions in the atrial wall to inter­rupt arrhythmogenic wavelet pathways and reentry circuits.23 LAA obliteration reduces stroke risk by percutaneous ligation or surgical removal of the LAA.24,25

AMERICAN FAMILY PHYSICIAN LAA obliteration does not correct the underlying atrial fibrillation; however, because approximately 90% of cardiac thrombi occur in the appendage, it decreases the subsequent risk of stroke. Two percuta­ neously inserted devices, the Watchman and the Amplatzer Cardiac Plug, can be used to achieve occlusion of the LAA, although the latter is not available in the United States. Both are non-inferior to warfarin in stroke risk reduction.26,27 A newer device, the Lariat, is available to ligate the LAA, but data on its long-term effectiveness and safety are limited.27 ANTICOAGULATION Anticoagulation is an essential part of atrial fibrillation management. It significantly reduces the risk of embolic stroke, but increases the risk of bleeding. Although the benefit of anticoagulation exceeds the risk of bleeding for most patients, discussions about stroke prevention vs. risk of bleeding remain challenging. Tools to aid in the assessment of the risks of stroke and bleeding are avail­able and are useful in making decisions with patients about therapeutic options.

For many years, the CHADS2 (congestive heart failure; hypertension; age 75 years or older; diabetes mellitus; prior stroke, tran­sient ischemic attack, or thromboembolism [doubled]) scoring system was used to esti­mate risk of stroke in patients with atrial fibrillation. Anticoagulation was recom­mended for patients with a CHADS2 score of 2 or more, unless a contraindication was present.28 More recently, the CHA2DS2-VASc (congestive heart failure; hypertension; age 75 years or older [doubled]; diabetes; prior stroke, transient ischemic attack, or throm­boembolism [doubled]; vascular disease; age 65 to 74 years; sex category) scoring system (Table 21) has supplanted CHADS2 because it is superior in identifying stroke risk.29-31 Anticoagulation is recommended for patients with a score of at least 2 who have no con­traindications.

CHA2DS2-VASc significantly increases the number of patients eligible for anticoagulation compared with CHADS2.

Similar clinical tools are available to assess anticoagulation bleeding risk.32-34 The HAS-BLED (hypertension, abnormal renal func­tion and liver function, stroke, bleeding, labile international normalized ratio, elderly [older than 65 years], drugs and alcohol) scoring system has been well validated, with a score of 3 or more indicating that a patient has a high likelihood of hemorrhage.14,34,35 A tool for calculating a patient’s HAS-BLED score is available

at https://www.qxmd.com/calculate/calculator_106/ bleeding-risk-in-atrial-fibrillation-has-bled-score.

Warfarin lowers the risk of thrombo­embolic events,36-39 but it has a narrow therapeutic range, multiple drug and food interactions, and requires frequent blood monitoring of the international normal­ized ratio. Even with optimal compliance, patients using warfarin are within the thera­peutic range (2 to 3 for nonvalvular atrial fibrillation) only 55% to 66% of the time.40,41 Studies have shown that low-intensity warfarin in atrial fibrillation (international normalized ratio of approximately 1.5) is not effective in preventing stroke.42 Aspirin alone or in combination with clopidogrel is an option for patients who decline or are unable to tolerate anticoagulants, or who are at low risk of stroke as indicated by a CHA2DS2-VASc score of 0 or 1.1,2 Direct oral anticoagulants, including a direct thrombin and several factor Xa inhibitors, are available.40,41,43-45 Their main advantages compared with warfarin include fixed dosing, no food interactions, fewer drug interactions, and no need for interna­tional normalized ratio monitoring. Their major drawbacks are higher costs, diffi­culty reversing their effect in emergency situations, and the lack of simple blood tests to check drug levels. A specific antidote for dabigatran is available, and factor Xa inhibitor antidotes are in the late stages of development.46-48 The oral direct thrombin inhibitor dabi­ gatran is as effective as warfarin in pre­venting stroke and systemic emboli. Major bleeding events were similar to those of warfarin, with fewer intracranial bleeds (0.30% vs. 0.74% per year, number needed to treat [NNT] = 227), but increased gas­trointestinal hemorrhage (1.51% vs. 1.02% per year, number needed to harm = 204).40 Factor Xa inhibitors include rivaroxaban, apixaban, and edoxaban.41,43,44 Compared with warfarin, rivaroxaban and edoxaban are noninferior in preventing stroke and systemic thromboembolic events, although edoxaban has a lower rate of major bleeding.41 Apixaban is slightly superior to warfarin in stroke prevention (1.27% vs. 1.60% per year, NNT = 303) and has a lower bleeding risk (2.13% vs.

3.09%, NNT = 104).43 These oral anticoagulants also have a slightly lower risk of intracranial hemor­ rhage compared with warfarin (0.6% vs. 1.2% per year, NNT = 166),15 but require dose adjustment in patients with renal dis­ease.

Table 3 outlines the pharmacologic properties of direct oral anticoagulants and warfarin16; none are

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AMERICAN FAMILY PHYSICIAN Table 4. Risks and Benefits of Direct Oral Anticoagulants Compared with Warfarin Apixaban, 5 mg twice daily

Dabigatran, 150 mg twice daily

Edoxaban, 60 mg daily

Rivarobaxan, 20 mg daily

HR (95% CI); NNT per 2 years

RR (95% CI); NNT or NNH per 2 years

HR (95% CI); NNT or NNH per 3 years

HR or RR (95% CI); NNT or NNH per 3 years

Stroke or systemic emboli

HR = 0.79 (0.66 to 0.95); NNT = 168

RR = 0.66 (0.53 to 0.82); NNT = 91

HR = 0.79 (0.63 to 0.99); NNT = 141

HR = 0.79 (0.65 to 0.95) NNT = 134

Intracranial bleed

HR = 0.51 (0.35 to 0.75); NNT = 238

RR = 0.26 (0.14 to 0.49); NNT = 182

HR = 0.54 (0.38 to 0.77); NNT = 172

HR = 0.67 (0.47 to 0.93); NNT = 247

Major bleed

HR = 0.69 (0.60 to 0.80); NNT = 79

RR = 0.93 (0.81 to 1.07); nonsignificant

HR = 0.80 (0.71 to 0.91); NNT = 66

HR = 1.04 (0.90 to 1.20); nonsignificant

HR = 0.89 (0.70 to 1.15); nonsignificant

RR = 1.50 (1.19 to 1.89); NNH = 100

HR = 1.23 (1.02 to 1.50); NNH = 167

RR = 1.45; NNH = 101

HR = 0.89 (0.80 to 0.99); NNT = 132

RR = 0.88 (0.77 to 1.00); nonsignificant

HR = 0.92 (0.83 to 1.01); nonsignificant

HR = 0.85 (0.70 to 1.02); nonsignificant

Selected clinical outcome

Gastrointestinal bleed Any cause of death

CI = Confidence interval; HR = Hazard ratio; NNH = Number needed to treat for a specific time to cause an adverse event; NNT = Number needed to treat for a specific time to prevent an outcome; RR = Relative risk.

Information from references 40, 41, 43, 45, and 49.

recommended for patients on hemodialysis, nor are they approved for use during pregnancy or in patients with valvular atrial fibrillation or advanced kidney disease. Table 4 compares some of the risks and benefits of direct oral anticoagulants vs. warfarin.40,41,43,45,49 Although current practice has been to use heparin or low-molecular-weight hepa­rin to bridge anticoagulation when patients taking warfarin need surgery or invasive procedures, a recent randomized trial in patients with atrial fibrillation who were undergoing surgery and who were at low or moderate bleeding risk found that these patients had worse outcomes if bridged than those who had their anticoagulation stopped during the perioperative period. Patients with a very high risk of stroke or thrombo­ embolism and those undergoing cardiac, spinal, or intracranial surgery were excluded from the study.50 The treatment of nonvalvular atrial fibrillation must be individualized to each patient’s condition, which can change over time.

REFERRAL Referral to a cardiologist is warranted for patients with complex cardiac disease; those who cannot tolerate atrial fibrillation despite rate control; those who need rhythm con­trol, require ablation therapy, or may benefit from surgical treatment; and those who need a pacemaker or defibrillator because of another rhythm abnormality.1 Note: For complete article visit: www.aafp.org/afp.

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REFERENCES 1. January CT, Wann LS, Alpert JS, et al.; ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society [published correction appears in Circulation. 2014; 130(23):e272-274]. Circulation.

2014;130(23):e199-e267.

2. Camm AJ, Lip GY, De Caterina R, et al.; ESC Commit­tee for Practice Guidelines. 2012 focused update of the ESC Guidelines for the management of atrial fibril­lation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association [published corrections appear in Eur Heart J. 2013;34(10):790, and Eur Heart J. 2013; 34(36):2850- 2851]. Eur Heart J. 2012;33(21):2719-2747.

3. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke.

1996;27(10):1760-1764.

4. Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol. 1998;82(8A):2N-9N. 5. Go AS, Mozaffarian D, Roger VL, et al.; American Heart Association Statistics Committee and Stroke Sta­tistics Subcommittee. Heart disease and stroke statis­tics—2014 update: a report from the American Heart Association.

Circulation. 2014;129(3):e28-e292.

6. Wang TJ, Larson MG, Levy D, et al. Temporal rela­tions of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study.

Circulation. 2003;107(23):2920-2925.

AMERICAN FAMILY PHYSICIAN 7. Pedersen OD, Abildstrøm SZ, Ottesen MM, et al.; TRACE Study Investigators. Increased risk of sudden and nonsudden cardiovascular death in patients with atrial fibrillation/flutter following acute myocardial infarction.

Eur Heart J. 2006;27(3):290-295.

8. Vidaillet H, Granada JF, Chyou Po, et al. A populationbased study of mortality among patients with atrial fibrillation or flutter. Am J Med. 2002;113(5):365-370.

9. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001;285(18):2370-2375.

10. Miller PS, Andersson FL, Kalra L. Are cost benefits of anticoagulation for stroke prevention in atrial fibrillation underestimated? Stroke. 2005;36(2):360-366.

with atrial fibrillation. N Engl J Med. 2010;362(15): 1363-1373.

21. Cappato R, Calkins H, Chen SA, et al. Updated world­wide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophysiol. 2010;3(1):32-38.

22. Arbelo E, Brugada J, Hindricks G, et al.; Atrial Fibril­lation Ablation Pilot Study Investigators. ESC-EURObservational Research Programme: the Atrial Fibrillation Ablation Pilot Study, conducted by the European Heart Rhythm Association. Europace. 2012;14(8):1094-1103.

23. Damiano RJ Jr, Gaynor SL, Bailey M, et al. The long-term outcome of patients with coronary disease and atrial fibrillation undergoing the Cox maze procedure. J Tho­rac Cardiovasc Surg. 2003;126(6):2016-2021.

11. He B, Scherlag BJ, Nakagawa H, Lazzara R, Po SS. The intrinsic autonomic nervous system in atrial fibrillation: a review. ISRN Cardiol. 2012;(2012):490674.

24. Holmes DR Jr, Doshi SK, Kar S, et al. Left atrial appendage closure as an alternative to warfarin for stroke prevention in atrial fibrillation: A patient-level meta-analysis. J Am Coll Cardiol. 2015;65(24):2614-2623.

12. Nattel S, Burstein B, Dobrev D. Atrial remodeling and atrial fibrillation: mechanisms and implications. Circ Arrhythm Electrophysiol. 2008;1(1):62-73.

25. Alli O, Asirvatham S, Holmes DR Jr. Strategies to incorporate left atrial appendage occlusion into clinical practice. J Am Coll Cardiol. 2015;65(21):2337-2344.

13. Cooke G, Doust J, Sanders S. Is pulse palpation help­ful in detecting atrial fibrillation? A systematic review. J Fam Pract. 2006;55(2):130-134.

26. Sick PB, Schuler G, Hauptmann KE, et al. Initial worldwide experience with the WATCHMAN left atrial appendage system for stroke prevention in atrial fibrillation. J Am Coll Cardiol. 2007;49(13):1490-1495.

14. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5): 1093-1100.

15. Chatterjee S, Sardar P, Biondi-Zoccai G, Kumbhani DJ. New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation. JAMA Neurol.

2013;70(12):1486-1490.

16. Steinberg BA, Piccini JP. Anticoagulation in atrial fibrillation. BMJ. 2014;348:g2116.

17. Hagens VE, Ranchor AV, Van Sonderen E, et al.; RACE Study Group. Effect of rate or rhythm control on quality of life in persistent atrial fibrillation. Results from the Rate Control Versus Electrical Cardioversion (RACE) Study.

J Am Coll Cardiol. 2004;43(2):241-247.

18. Van Gelder IC, Hagens VE, Bosker HA, et al.; Rate Control versus Electrical Cardioversion for Persis­tent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med. 2002;347(23):1834-1840.

19. Olshansky B, Rosenfeld LE, Warner AL, et al.; AFFIRM Investigators. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: approaches to control rate in atrial fibrillation. J Am Coll Cardiol. 2004;43(7):1201-1208.

20. Van Gelder IC, Groenveld HF, Crijns HJ, et al.; RACE II Investigators. Lenient versus strict rate control in patients

27. Bartus K, Han FT, Bednarek J, et al. Percutaneous left atrial appendage suture ligation using the LARIAT device in patients with atrial fibrillation: initial clinical experience.

J Am Coll Cardiol. 2013;62(2):108-118.

28. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22): 2864-2870.

29. Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. The value of the CHA2DS2-VASc score for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0-1: a nationwide cohort study. Thromb Haemost. 2012;107(6):1172-1179.

30. Lip GY. Implications of the CHA2DS2-VASc and HASBLED Scores for thromboprophylaxis in atrial fibrillation.

Am J Med. 2011;124(2):111-114.

31. Mason PK, Lake DE, DiMarco JP, et al. Impact of the CHA2DS2-VASc score on anticoagulation recommendations for atrial fibrillation. Am J Med. 2012; 125(6):603.e1-603.e6.

32. Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol. 2011;58(4):395-401.

33. Gage BF, Yan Y, Milligan PE, et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J. 2006;151(3):713-719.

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AMERICAN FAMILY PHYSICIAN 34. Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. Performance of the HEMORR(2)HAGES, ATRIA, and HAS-BLED bleeding risk-prediction scores in patients with atrial fibrillation undergoing anticoagulation: the AMADEUS (evaluating the use of SR34006 compared to warfarin or acenocoumarol in patients with atrial fibrillation) study. J Am Coll Cardiol. 2012;60(9):861-867.

35. Roldán V, Marín F, Fernández H, et al. Predictive value of the HAS-BLED and ATRIA bleeding scores for the risk of serious bleeding in a “real-world” population with atrial fibrillation receiving anticoagulant therapy. Chest.

2013;143(1):179-184.

36. Aguilar MI, Hart R. Oral anticoagulants for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks.

Cochrane Database Syst Rev. 2005;(3):CD001927.

37. Connolly S, Pogue J, Hart R, et al.; ACTIVE Writing Group of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006;367(9526):1903-1912.

38. Aguilar MI, Hart R, Pearce LA. Oral anticoagulants ver­sus antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no history of stroke or transient ischemic attacks. Cochrane Database Syst Rev. 2007;(3):CD006186.

39. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955-962.

40. Connolly SJ, Ezekowitz MD, Yusuf S, et al.; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation [published correction appears in N Engl J Med. 2010;363(19):1877].

N Engl J Med. 2009;361(12):1139-1151.

41. Patel MR, Mahaffey KW, Garg J, et al.; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891.

fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet. 1996;348(9028):633-638.

43. Granger CB, Alexander JH, McMurray JJ, et al.; ARIS­ TOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992.

44. Weitz JI, Connolly SJ, Patel I, et al. Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost. 2010;104(3):633-641.

45. Giugliano RP, Ruff CT, Braunwald E, et al.; ENGAGE AF-TIMI 48 Investigators. Edoxaban ver­sus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-2104.

46. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idaru­cizumab for dabigatran reversal. N Engl J Med. 2015;373(6): 511-520.

47. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects.

Circulation. 2011;124(14):1573-1579.

48. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373(25):2413-2424.

49. Kovacs RJ, Flaker GC, Saxonhouse SJ, et al. Practical management of anticoagulation in patients with atrial fibrillation. J Am Coll Cardiol. 2015;65(13):1340-1360.

50. Douketis JD, Spyropoulos AC, Kaatz S, et al.; BRIDGE Investigators. Perioperative bridging anti­coagulation in patients with atrial fibrillation. N Engl J Med. 2015;373(9):823-833.

51. Snow V, Weiss KB, LeFevre M, et al. Management of newly detected atrial fibrillation: a clinical practice guideline from the American Academy of Family Phy­sicians and the American College of Physicians. Ann Intern Med. 2003;139(12):1009-1017.

52. Gutierrez C, Blanchard DG. Atrial fibrillation: diagnosis 42. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial and treatment. Am Fam Physician. 2011;83(1):61-68.

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Practice Guidelines ACIP UPDATES INFLUENZA VACCINATION RECOMMENDATIONS FOR 2016-2017 The Centers for Disease Control and Preven­tion’s Advisory Committee on Immuniza­tion Practices (ACIP) has released its annual recommendations for routine influenza vac­cination in the 2016-2017 season. Updates this year include the antigenic composition of seasonal influenza vaccines available in the United States; information on influenza vaccines expected to be available this season, including newly licensed products (Table 1); a recommendation against the use of live attenuated influenza vaccine (LAIV); and revised recommendations for vaccination of persons with egg allergy.

Routine annual influenza vaccination is recommended for all persons six months and older who do not have contraindica­tions. No single vaccine is preferred over others in persons for whom more than one product is appropriate (Table 2). The composition of influenza vaccines typically changes from season to season, with one or more vaccine strains replaced annually to provide protection against viruses that are anticipated to circulate during the upcom­ing season. Clinical trials have shown that protection against viruses that are antigeni­cally similar to those in the vaccine extends at least for six to eight months, particularly in nonelderly populations. Influenza strains contained in this year’s trivalent vaccines include an A/California/7/2009 (H1N1)-like virus, an A/Hong Kong/4801/2014 (H3N2)- like virus, and a B/Brisbane/60/2008–like virus (Victoria lineage). Quadrivalent vac­cines will include an additional strain, a B/Phuket/3073/2013–like virus (Yamagata lineage). These vaccines include a change in the H3N2 virus and the lineage of the influ­enza B viruses.

ACIP recommends that quadrivalent LAIV not be used this season because of its low effectiveness in recent years. However, it remains a licensed vaccine that, if available, some clinicians may elect to use; for this reason, previous recommendations for its use are provided in Table 2 for informational purposes.

Source: Adapted from Am Fam Physician. 2016;94(8):668-671.

Although the precise timing of the onset, peak, and end of influenza activity var­ies from one season to the next, annual epidemics of seasonal influenza typically occur in the United States between October and April.

Ideally, vaccination should occur before the onset of influenza activity in the community. Clinicians should offer vac­cination by the end of October, if possible.

Children six months to eight years of age who have not received influenza vaccina­tion before require two doses for the first season. They should receive their first dose as soon as vaccine becomes available, fol­lowed by a second vaccination no earlier than four weeks later.

In recent years, some clinicians have received their initial ship­ments of vaccine as early as July. This has raised questions about the ideal timing of vaccination because early availability and administration of vaccine—particularly in older adults—may contribute to reduced protection against influenza later in the season. Conversely, delaying vaccination may confer greater immunity later in the season, but may also result in missed opportunities to vaccinate.

Persons of all ages are susceptible to seasonal influenza, but complications, hospitalizations, and deaths are typically greatest among persons 65 years and older, children younger than five years (especially those younger than two years), and persons of any age who are immunosuppressed or have certain medical conditions, such as chronic cardiovascular, pulmonary, or renal disease. Vaccination is particularly important in these populations. When vaccine supply is limited, vaccina­tion efforts should target the following persons: ÂÂ

Children six to 59 months of age

ÂÂ

Children and adolescents six months to 18 years of age who are receiving long-term aspirin therapy and may be at risk of Reye syndrome after influenza virus infection

ÂÂ

Pregnant women

ÂÂ

Adults 50 years and older

ÂÂ

Residents of nursing homes and long-term care facilities

ÂÂ

American Indians/Alaska Natives

ÂÂ

Persons with a body mass index of 40 kg per m or greater

ÂÂ

Adults and children with chronic pulmonary, cardiovascular, renal, hepatic, neurologic,

2

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AMERICAN FAMILY PHYSICIAN hematologic, or metabolic disorders, such as asthma and diabetes mellitus ÂÂ

Persons with immunosuppression.

Severe allergic reactions, including anaphylaxis, can occur in response to components of all vaccines; however, these reactions are rare. Not all reactions are related to egg proteins, but the possibility of reactions to influenza vaccines in persons with egg allergy may be of concern. With the exceptions of recombinant trivalent influenza vaccine and cell culture–based quadrivalent inactivated influenza vaccine, currently available influenza vaccines are prepared by propagation of virus in embryonated eggs. However, evidence indicates that severe allergic reactions are unlikely. Therefore, ACIP recommends that persons with a history of egg allergy who have experienced only hives after exposure to egg should receive any of the recommended influenza vaccines appropriate for the recipient’s age and health status. Persons who have had reactions to egg

involving symptoms other than hives (e.g., angioedema, respiratory distress, lightheadedness, recurrent emesis) or who required epinephrine or another emergency medi­cal intervention may receive the cell culture–based or recombinant influenza vaccines appropriate for the recipient’s age and health status. The selected vaccine should be administered in an inpatient or outpatient setting and should be supervised by a clinician who is able to recognize and manage severe allergic conditions.

A previous severe allergic reaction to influenza vaccine is a contraindication to future receipt of the vaccine.

ACIP has removed its previous recommendation that persons allergic to eggs should be observed for 30 minutes after receipt of influenza vaccine. However, clinicians should consider observing all patients— whether or not they are allergic to egg—for 15 minutes postvac­cination to decrease the risk of injury if they experience syncope.

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

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Photo Quiz FEVER AND RASH IN A PATIENT WITH HIV INFECTION A 28-year-old man with a history of human immunodeficiency virus (HIV) infection and AIDS presented to the emergency department with fever and a widespread, severely painful, pruritic rash. The cutaneous eruption began on his chest and rapidly spread to his face, left lower eyelid, neck, trunk, genitalia, and upper and lower extremities. His CD4 cell count was 6 per mm3 (0.01 × 109 per L) with a viral load of 768,970 copies per mL. He was not compliant with highly active antiretroviral therapy. His white blood cell count, liver function, and kidney function were normal. He reported having chickenpox as a child.

On examination, he had vesicles and pus­tules, some umbilicated, overlying an erythematous base in a generalized distribution (Figure 1). His skin was tender, but the mucosal surfaces were unaffected.

Ophthal­mologic evaluation revealed no intraocular involvement.

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

A. Cutaneous Mycobacterium avium-intracellulare complex infection.

B. Disseminated cryptococcosis.

C. Disseminated herpes simplex virus infection.

D. Disseminated varicella-zoster virus infection.

E. Secondary syphilis.

Discussion The answer is D: disseminated varicella-zoster virus infec­tion. A swab of a vesicle base was positive for varicella-zoster virus antigen. Hematoxylin-eosin stain of a skin biopsy revealed classic findings of herpes infection, which may be caused by herpes simplex virus, cytomegalovirus, or varicella virus. These

Source: Adapted from Am Fam Physician. 2016;94(8):658-660.

Figure 1.

findings include nuclear inclu­sions (Cowdry bodies) and multinucleation. Skin cultures were negative for bacteria, fungi, and acid-fast bacilli.

Unusual presentations of HIV-associated varicella-zoster virus infection include multidermatomal, ulcerative, verrucous, and disseminated rashes with ful­minant visceral involvement.1 Cutaneous dissemination alone is an atypical presentation and is defined as more than 20 vesicles outside a dermatomal distribution.2 Most disseminated cases begin in a dermatomal distribution, then generalize or disseminate to the liver and spleen.

The patient presented with widespread vesicles and pustules similar to a primary varicella infection without the visceral involvement that usually occurs with disseminated varicella-zoster virus infection.

Disseminated varicella-zoster virus infection should be considered in patients with HIV infection or AIDS who have a CD4 cell count of less than 500 per mm3 (0.50 × 109 per L).1 Diagnostic workup starts with a detailed history, including previous varicella infection or recent varicella-zoster immunization. Infected epithelial cells from a vesicle base may be sent for rapid diagnosis via a Tzanck test or direct fluorescent antibody test.1 Direct fluorescent antibody testing differentiates herpes simplex virus and varicella-zoster

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AMERICAN FAMILY PHYSICIAN Summary Table Condition

Characteristics

Cutaneous Mycobacterium avium-intracellulare complex infection

May present as a variety of skin lesions: papules, nodules, pustules, ulcers, abscesses, folliculitis, panniculitis, soft tissue swelling

Disseminated cryptococcosis

May present as a variety of skin lesions: umbilicated or ulcerated papules (most common), subcutaneous abscesses, vesicles, plaques, purpura, acne, draining sinuses, bullae

Disseminated herpes Scattered papules, vesicles, and pustular simplex virus infection lesions in different stages of evolution Disseminated varicella-zoster virus infection

Vesicles, pustules, and papules in a dermatomal distribution with more than 20 vesicles outside the dermatomal distribution

Secondary syphilis

Widespread maculopapular rash, usually includes palms and soles

virus infections.3 A skin biopsy may also be obtained for histology and viral culture. Varicella-zoster DNA found in epithelial cells from a vesicle base or scabs from skin lesions can be identified on polymerase chain reaction testing, which is rapid and highly sensitive.3 Polymerase chain reaction testing from other specimens, such as blood or cerebro­spinal fluid, is less desirable. Treatment with antivirals is effective if given within 72 hours of the onset of the rash or radicular pain. Treatment should be continued until all skin lesions have scabbed and any organ involvement has resolved.

Cutaneous Mycobacterium avium-intracellulare com­plex infection is a concern if the CD4 cell count is less than 50 per mm3 (0.05 × 109 per L).1,4 Patients appear very ill because disseminated disease usually involves the lungs, blood, bone marrow, spleen, and lymph nodes before the skin.

Disseminated cryptococcosis is a concern if the CD4 cell count is less than 250 per mm3 (0.25 × 109 per L).

It presents as a papular eruption with umbilicated or ulcerated centers.1,5 Cryptococcosis typically affects the lungs and central nervous system before the skin.

Although rare, disseminated herpes simplex virus infection can manifest solely as cutaneous involvement, appearing as scattered papules, vesicles, and pustular lesions in different stages of evolution.6 In patients who are immunocompromised, disseminated herpes simplex virus infection usually involves visceral organs.

It may present as fulminant hepatitis, encephalitis, or pneumonia.

Secondary syphilis presents four to eight weeks after a primary chancre with widespread macules and papules, usually including the palms and soles.7 It is usually accompanied by fever, malaise, arthralgias, myalgias, pharyngitis, and nontender lymphadenopathy.

REFERENCES 1. Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. St. Louis, Mo.: Elsevier/Saunders; 2012:1285-1302.

2. McCrary ML, Severson J, Tyring SK. Varicella zoster virus.

J Am Acad Dermatol. 1999;41(1):1-14.

3. Roush SW, Baldy LM, eds. Manual for the Surveillance of Vaccine-Preventable Diseases. Atlanta, Ga.: Centers for Disease Control and Prevention; 2008. http://www.cdc. gov/vaccines/pubs/surv-manual/chpt17-varicella.html.

Accessed October 25, 2015.

4. Endly DC, Ackerman LS. Disseminated cutaneous mycobacterium avium complex in a person with AIDS. Dermatol Online J. 2014;20(5):22616.

5. Bennett JE, Dolin R, Douglas RG, Mandell GL, Blaser MJ, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, Pa.: Elsevier/Saunders; 2015:2934-2948.e5.

6. Fancher W, Marsch A, Landers J, Scribner J. Disseminated herpes sim­plex virus presenting as crusted papules on the palms and soles of an immunosuppressed patient.

Dermatol Online J. 2014;20(9).

7. Watts PJ, Greenberg HL, Khachemoune A. Unusual primary syphilis. Int J Dermatol. 2016;55(7):714-728.

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2017

CARDIOLOGY

Lipoprotein(a) - A Potential Cardiovascular Risk Factor and Therapeutic Approaches PRAGATI KAPOOR*, PANKAJ KUMAR†, AK KAPOOR‡

ABSTRACT Lipoprotein(a) also called as Lp(a) has been shown to be an independent, causal, genetic risk factor for cardiovascular disease and aortic stenosis by genetic and numerous epidemiological studies. High Lp(a) levels is an important risk factor for coronary heart disease, cerebrovascular disease, atherosclerosis, thrombosis and stroke. The physiological functions, the mechanism and sites of Lp(a) catabolism, and pathophysiological details are not well-understood though several mechanisms of Lp(a) participation in atherogenesis have been proposed. The goal of therapy is to bring down elevated Lp(a) levels to below 50 mg/dL. Both statins and estrogens are not used for therapy of elevated Lp(a) levels. Niacin and aspirin are two relatively safe, easily available and inexpensive drugs, which significantly reduce raised Lp(a) levels. A variety of other medications that are in various stages of development are dealt with including miscellaneous agents whose role has not been clinically verified.

Keywords: Lipoprotein(a), atherogenesis, therapeutic approaches

L

ipoprotein(a) [also called as Lp(a) or LPA] is a lipoprotein subclass. Lipoprotein is an independent, causal, genetic risk factor for cardiovascular disease (CVD).1 Genetic studies and numerous epidemiological studies have also identified Lp(a) as a risk factor for atherosclerotic diseases such as coronary heart disease (CHD) and stroke.2-5 Lp(a) was discovered in 1963 by Kare Berg.6 Interestingly, Lp(a) is present only in humans, apes and old world monkeys.

STRUCTURE The chemical structure of Lp(a) consists of a lowdensity lipoprotein (LDL)-like particle and the specific apolipoprotein (a) [apo(a)], which is covalently bound to the apoB-100 of the LDL-like particle via one disulfide bridge.7,8 Thus, Lp(a) is composed of

*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 Pragati Kapoor Assistant Professor Dept. of Cardiothoracic Surgery Nizam Institute of Medical Sciences, Hyderabad, Andhra Pradesh E-mail: drpragatikapoor@gmail.com

apoB-100 and apo(a). Lp(a) is a spherical macromolecular complex with a diameter of approximately 25 nm, and density ranging from 1.05 g/mL to 1.12 g/mL.7 Its concentrations are not significantly affected by dietary or environmental effects. Lp(a) plasma concentrations are highly heritable and mainly controlled by the apo(a) gene (LPA) located on chromosome 6 q 26-27. Probably, LPA gene may be responsible for 91% of the variation in Lp(a) concentration, of these 69% are due to the number of kringle IV (KIV) type 2 repetitions. Lp(a) plasma concentration ranges from <1 mg to >1,000 mg/dL. It is worth mentioning that individuals without Lp(a) or with very low Lp(a) levels seem to be healthy.

Apo(a) proteins vary in size due to a size polymorphism (KIV-2 VNTR), which is caused by a variable number of so called KIV repeats in the LPA gene. This size variation at the gene level is expressed on the protein level as well, resulting in apo(a) proteins with 10 to >50 KIV repeats.8,9 These variable apo(a) sizes are known as apo(a) isoforms. Generally, there is inverse correlation between the size of the apo(a) isoforms and the Lp(a) plasma concentration.10 As smaller apo(a) isoforms can be generated more quickly per unit time, hence small isoforms are associated with higher plasma Lp(a) levels. Age and sex have little influence on Lp(a) levels though racial factor has important influence on Lp(a) levels. The half-life of Lp(a) in the circulation is about 3-4 days. There are 6 different alleles for Lp(a). The protein apo(a) is highly homologous (similar) to

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CARDIOLOGY plasminogen, one of the proteins of the fibrinolytic system, though apo(a) has important differences compared with plasminogen.

SYNTHESIS AND METABOLISM The synthesis and metabolism of Lp(a) have not been completely clarified and are totally independent from LDL synthesis and metabolism in spite of structural similarities between Lp(a) and LDL. Lp(a) is synthesized in the liver. Apo(a) is expressed by liver cells (hepatocytes). There is no coordination between the synthetic pathways of apo(a) and of apoB-100, as there is no coordination between synthesis of Lp(a) and of plasminogen, its structural analog.7 Further, Lp(a) levels are not related to lipoprotein lipase activity.

The mechanism and sites of Lp(a) catabolism are also not well-defined. Moreover, the way cellular uptake occurs is also not well-established.7 Uptake via LDL receptor is not a major pathway of Lp(a) metabolism11 and that the role of LDL receptor or isoforms size in that process is limited since only a small fraction of Lp(a) binds to hepatoma cells via LDL receptors. Probably, kidneys may play a role in Lp(a) clearance from plasma.12 Other receptors, such as asialoglycoprotein receptors, megalin receptors and macrophage scavenger receptors may be involved in Lp(a) uptake.13 METHODOLOGY TO DETERMINE LP(A) Lp(a) is commonly estimated by determining the apo(a) concentration by using monoclonal anti-apo(a) antibodies. It may be mentioned, there are difficulties in standardizing the methodology to determine Lp(a) for accurate comparison between different studies. Presently, there are a variety of methods for determining Lp(a). A standardized reference material accepted by the World Health Organization (WHO) Expert Committee on Biological Standardization and the International Federation of Clinical Chemistry and Laboratory Medicine has been notified towards standardizing results. Moreover, a test with simple quantitative results may not provide a complete assessment of risk. Therefore, these assays must be validated with reference standard.

Lipoprotein(a) - Lp(a): ÂÂ

Desirable: <14 mg/dL

ÂÂ

Borderline risk: 14-30 mg/dL

ÂÂ

High risk: 31-50 mg/dL

ÂÂ

Very high risk: >50 mg/dL.

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Lp(a) Concentration and Populations The racial factor has an important influence on Lp(a) levels. There is two- to threefold higher Lp(a) plasma concentration in populations of African descent compared to Asian, Oceanic or European populations,14 but these levels are not related to coronary artery disease (CAD) in Africans.

Physiological Function The physiological function of Lp(a)/apo(a) is still unknown. The data till date did not show a physiological function for Lp(a) in lipid transportation or metabolism regulation.7 Its role within the coagulation system seems plausible owing to high similarity between apo(a) and plasminogen.8 Apo(a) has potent lysine binding domains similar to those on plasminogen and binds to damaged endothelial cells and exposed or injured subendothelial matrix proteins, delivers cholesterol for cell membrane growth. The other functions may be related to recruitment of inflammatory cells through interaction with Mac-1 integrin, angiogenesis, wound healing, innate immunity and infection.

Pathophysiology There are 4 major categories of lipid abnormalities in human beings:1 a) A raised LDL cholesterol, b) a low high-density lipoprotein (HDL) cholesterol, c) elevated triglycerides and d) elevated Lp(a). Of these, LDL cholesterol, HDL cholesterol and triglycerides levels are modulated by diet. In contrast, Lp(a) plasma levels are mediated largely by the LPA gene locus present on chromosome 6 q 22-23 and is minimally affected by diet.15 Presently, Lp(a) remains conceptually only a ‘pathogenic lipoprotein.’ Lp(a) levels >50 mg/dL is typically considered to be elevated for clinical biomarkers. Transient increases in Lp(a) levels are noted in the presence of inflammatory processes or tissue damages, such as those occurring with other acute phase proteins (haptoglobin, α1-antitrypsin and C-reactive protein).15 This can be seen with an episode of acute myocardial infarction, wherein Lp(a) levels are considerably increased in first 24 hours, returning to base values in approximately 30 days. Lp(a) levels are also increased in chronic inflammatory disease, such as rheumatoid arthritis, systemic lupus erythematosus and acquired immune deficiency syndrome and following heart transplantation, pulmonary arterial hypertension and chronic renal failure.16 In contrast, liver diseases and abusive use of steroid hormones decrease Lp(a) levels.16 The relationship between Lp(a) and diabetes have not

CARDIOLOGY been well-defined. Contrary views have been expressed in type 1 diabetes mellitus. Similarly, conflicting results have been reported for type 2 diabetes as well.

Lp(a) concentrations have a hereditary character, tending to remain constant throughout the life and are not altered by environmental factors. Elevated Lp(a) levels is a risk factor for CHD, CVD, atherosclerosis, thrombosis and stroke, though, association between Lp(a) levels and stroke is not as strong as that between Lp(a) and CVD.2 Several mechanisms have been proposed for Lp(a) participation in atherogenesis. The structure of Lp(a) is similar to plasminogen and tissue plasminogen activator (tPA), it might lead to interference with fibrinolysis cascade since it competes with plasminogen for its binding site, causing reduced fibrinolysis. Lp(a) stimulates secretion of plasminogen activator inhibitor-1 (PAI-1), it leads to thrombogenesis. Lp(a) also carries cholesterol and thus contributes to atherosclerosis.17 The mechanisms linking thrombogenesis and atherogenesis with plasma lipoproteins via Lp(a) has thrilled the scientific community.

The probable sequence of events are as follow: Lp(a) would interfere with fibrinolytic system thus Lp(a) competes with plasminogen for binding sites of endothelial cells, inhibiting fibrinolysis and promoting intravascular thrombosis.18 Additionally, Lp(a) transports the more atherogenic proinflammatory oxidized phospholipids, which attract inflammatory cells to vessel walls,19,20 and leads to smooth muscle cell proliferation.21 Probably, the major effect of Lp(a) is on advanced plaque development and destabilization rather than thrombosis.1 An elevated Lp(a) is clearly proatherogenic.22 The participation of Lp(a) in atherogenesis could be multifaceted. One mechanism of atherogenicity is through the LDL component. However, apo(a) alone and Lp(a) as lipoprotein have additional potential contributions,23 including increasing endothelial cell permeability and expression of adhesion molecules, promoting smooth muscle cell proliferation, enhancing monocyte entry and retention in the vessel wall, macrophage foam cell formation, promoting release of proinflammatory interleukin (IL)-8 levels, and antifibrinolytic effects, as a carrier of proinflammatory and proatherogenic oxidized phospholipids (OxPL).24 A recent study has reported that Lp(a) and OxPL mediate macrophage apoptosis in endoplasmic reticulum.

Since, macrophage apoptosis is a key component of plaque vulnerability, these data provide supporting

evidence of Lp(a) as a risk factor for the development of advanced, clinically relevant atherosclerotic lesions.1 Lp(a) levels also predict severity of coronary atherosclerosis in clinically symptomatic patients. A key component of atherogenicity of Lp(a) has been the contribution of OxPL. OxPL are immunogenic and accumulate in atherosclerotic lesions and mediate plaque destabilization. Thus, raised OxPL on apoB are linked with the presence and progression of CAD and peripheral artery disease (PAD) and predict new CVD events in prospective studies.1 Another proatherogenic mechanism relates to direct deposition of Lp(a) on arterial wall similar to that which happens with LDL and oxidized LDL as Lp(a) being more prone to oxidation than LDL.7 This might facilitate uptake of macrophages via scavenger receptor.13 This is the most universal mechanism of atherogenesis. Yet, another proatherogenic mechanism of Lp(a) refers to the inverse correlation between lipoprotein levels and vascular reactivity, wherein increase in Lp(a) plasma levels will induce endothelial dysfunction.25 A prime feature of atherosclerosis is chronic inflammation and accumulation of proinflammatory substances in the vessel wall, modified and oxidized products of apoB-containing lipoprotein, are key mediators of such proinflammatory responses that contribute to clinical manifestations of CVD. Helgadottir et al26 has observed the independent residual risk of Lp(a) in mediating CVD is substantial and this can provide an opportunity and a potential target of therapy in reducing the overall risk of CVD even further. Helgadottir et al26 suggested that LPA variants rs 10455872 and rs 3798220, defined as LPA risk score by combining their effects, are associated with angiographically determined earlier onset of CAD (p = 4.8 × 1012), PAD (p = 2.9 × 1014), aortic aneurysm (p = 6.0 × 105) and ischemic stroke subtype large artery atherosclerosis (p = 6.7 × 104).

Further, investigators have observed associations between Lp(a) and inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), IL-6 and monocyte chemoattractant protein-1 (MCP-1).27,28 In addition to a reduction in fibrinolysis, it may involve platelet aggregation, induction of the expression of adhesion molecules, vascular remodeling via changes in the proliferative and migratory capacity of endothelial cells and resident smooth muscle cells, oxidative modification and formulation of foam cells.7 In brief, Lp(a) may be atherothrombotic through its LDL moiety, but also through apo(a), including its ability to be retained in vessel well and mediate proinflammatory and

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CARDIOLOGY proapoptopic effects including those potentiated by its content of OxPL, and antifibrinolytic effects.1

Lp(a) as Cardiovascular Risk Factor A number of cross-sectional studies have confirmed the association between Lp(a) levels and risk of developing CAD, regardless of other risk factors. Risk being 2.3 times higher in patients with Lp(a) levels over 50 mg/ dL. Riches et al28 noted risk as twice greater for Lp(a) levels over 20 mg/dL. Rhoads et al29 and Murai et al30 confirmed the relationship between Lp(a) and CAD and cerebral infarction. Rhoads et al29 also noted that with advancing age the risk decreased, and in the age group over 70 years risk became 1.2 times. In the Brazilian population, Maranhao et al,31 have reported a risk of developing CAD 2.3 times greater when Lp(a) levels were over 25 mg/dL. In Korean population with CAD, a raised Lp(a) has been labeled as an independent risk factor.32 A meta-analysis of 27 prospective studies has clearly identified an independent association between Lp(a) and CAD.5 A Danish prospective study involving more than 9,000 individuals over 10 years follow-up has observed that very high Lp(a) levels (>120 mg/dL) increased 3 to 4 times the risk of CAD.33 Most studies and meta-analyses have shown an increase in CVD risk starting at Lp(a) >25 mg/dL. A majority of prospective studies reported Lp(a) is really an independent risk factor for CVD though conflicting results, ranging from strong positive associations to complete lack of association between Lp(a) and CVD are in the literature. Yet, high Lp(a) levels enhanced the potency as risk factors of both hypercholesterolemia and low HDL cholesterol concentration.34 High Lp(a) levels predicts risk of early atherosclerosis independently of other cardiac risk factors, including LDL. In patients of advanced CVD, Lp(a) indicates a coagulant risk of plaque thrombosis. Elevated Lp(a) levels may augment the CHD risk from increased LDL cholesterol concentrations as has been demonstrated in patients with familial hypercholesterolemia.35 A consensus paper issued by the European Atherosclerosis Society in 2010 describes Lp(a) as a causal risk factor for CHD and CVD. The possibility that Lp(a) may become functionally altered in patients with CAD has been put forward by Tsironis et al36 on the basis of mass and specific activity of Lp(a) as mediator of plateletactivating factor acetylhydrolase activity, an enzyme that hydrolyzes oxidized phospholipids. The mean Lp(a) concentrations are markedly high in black individuals, 2 to 3 times greater than in Caucasian and Oriental individuals,14 but these levels are nonpredictive of CVD in black individuals.

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Additionally, high Lp(a) is also a risk factor for atherosclerosis in other arterial beds, such as in ischemic cerebral disease where risk gets escalated with Lp(a) levels, over 30 mg/dL. Further, in a 13-year long follow-up in 14,000 participants, a prospective study has shown a higher incidence of ischemic cerebral disease with raised Lp(a) level.37 Similarly, in another study involving 50,000 individuals it was also shown that a raised Lp(a) levels are associated with ischemic cerebrovascular accidents.5 In a meta-analysis of 40 prospective studies involving 58,000 individuals, a 2 times increase in the risk for developing CAD and cerebrovascular accident was noted in individuals with smaller apo(a) isoforms, regardless of the Lp(a) concentration and classical risk factors.38 In recent years, a number of studies have reported that elevated Lp(a) levels are independently and linearly predictive of future CVD though, the mechanisms linking Lp(a) to atherogenesis are still unclear and that studies proving the therapeutic decrease of Lp(a) reduces the number of events still lack. The influence of Lp(a) levels on carotid intima-media thickness is still controversial. An inverse association in Japanese population has been observed while no relationship between that thickness and Lp(a) levels has been noted in Spaniards.

Regarding implication of gender, it was observed that a raised lipoprotein level leads to more significant risk repercussions in female sex compared to male sex.39 A more recent Atherosclerosis Risk in Communities (ARIC) study has reported differences in LP(a) concentrations between sexes, which is higher in females.40 Although most studies have shown no difference between sexes in Lp(a) concentrations.

In postmenopausal women, an elevated Lp(a) and triglyceride level are predictive of the presence of CAD. Investigators have observed that predictive utility of Lp(a) is markedly attenuated among women taking hormone replacement therapy and that the relationship of high Lp(a) levels with increased CVD is modified by hormone replacement therapy.41 Atherogenesis is a common causal factor of abdominal aortic aneurysm and that Lp(a) levels are elevated in abdominal aneurysm showing the association between lipoprotein and atherogenesis. Recent events suggest that genetic variation in the LPA locus-mediated by Lp(a) concentration may also predict aortic valve stenosis.42 This can well explain why heart valve calcification may run in families. A causal relationship between Lp(a) and calcific aortic valve disease has also been demonstrated. Nongenetic risk factors for aortic valve calcification include advanced age, high blood

CARDIOLOGY pressure, obesity, high cholesterol levels and smoking.

Development of novel targeted medications in future might slow the progression of disease. Statins have not been shown to reduce aortic valve calcification.

High Lp(a) levels predict risk of early atherosclerosis independently of other cardiac risk factors, including LDL and that Lp(a) concentrations also associate significantly with the severity of coronary atherosclerosis. In addition, Lp(a) appears to be an independent risk factor in both primary and secondary settings though there is a paucity of information on the predictive valve of Lp(a) in patients with stable CVD.43 The authors observed that Lp(a) represents a significant risk factor for recurrent events. In patients of advanced CVD, Lp(a) indicates a coagulant risk of plaque thrombosis. In the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study, baseline Lp(a) was associated with future CVD and CHD. The authors observed that baseline Lp(a) concentration was associated with total CHD events (p < 0.001), total CVD events (p = 0.002) and coronary events (p = 0.03).

For events after 1 year, an increase in Lp(a) at 1 year was associated with adverse outcomes for total CHD events and total CVD events (p = 0.002 each). It was demonstrated that a rising Lp(a) level is associated with cardiovascular events.43 THERAPEUTIC APPROACHES FOR ELEVATED LP(A) LEVELS The European Atherosclerosis Society currently recommends that patients with a moderate or high risk of cardiovascular risk having one of the following risk factors such as premature CVD, familial hypercholesterolemia, family history of premature CVD, family history of elevated Lp(a), recurrent CVD despite statin treatment, >3% 10-year risk of fatal CVD according to the European guidelines, >10% 10-year risk of fatal and or nonfatal CVD according to US guidelines should be screened for their Lp(a) levels.2 If the Lp(a) levels are raised, treatment should be started with a goal of bringing the level below 50 mg/dL. In addition, the patientâ&#x20AC;&#x2122;s other cardiovascular risk factors (including LDL levels) should be optimally managed.2 Besides, Lp(a) plasma concentration, the apo(a) isoforms might be an important risk parameter as well. Moreover, a better understanding of the basic mechanism of production and metabolism of Lp(a) and apo(a) is important to correlate the effect of future therapeutic agents. Major gaps in clinical medicine are: Lowering Lp(a) levels leads to clinical benefit have not been documented; in majority of studies, Lp(a)

levels were lowered in conjunction with changes in other lipoprotein thus complexing the outcomes and the underlying mechanisms of Lp(a)-lowering of these agents are not fully clarified.1 EFFECTS OF DRUGS ON LP(A) CONCENTRATION Currently, there is no specifically targeted definitive therapy to decrease Lp(a) levels and that specific and effective agents do not exist without affecting other lipoproteins. Traditional lipid-lowering agents such as statins or fibrates do not consistently decrease Lp(a) concentrations. Statins either have no effect or increase Lp(a) levels, sometimes significantly. The use of atorvastatin at a dose of 20 mg/day for 24 weeks caused no effect on Lp(a) levels. In a double-blind study with placebo, using doses of 10 or 40 mg/day of atorvastatin for 12 weeks, the Lp(a) concentration had significantly decreased.44 A recent meta-analysis published in 2012, suggests that atorvastatin may lower Lp(a) levels.45 In respect to lovastatin, simvastatin and gemfibrozil, the latter has shown greater efficacy in reducing Lp(a).46 Ezetimibe decreases Lp(a) levels approximately 29%;47 however, ezetimibe is commonly used with simvastatin, which does not have any additive effect to that of ezetimibe in regard to Lp(a) levels.

Presently, more commonly simple treatment which is relatively safe and independent for raised Lp(a) levels is niacin and aspirin.

Niacin High dose niacin 1-3 g/day generally in an extendedrelease form is preferred. The Lp(a) levels are reduced by 20-30%,48 while 4 g/day of niacin leads to 38% reduction in Lp(a) levels though at lower dose 1 g/day niacin has not shown that effectiveness. High dose niacin is widely used in the treatment of dyslipidemia because in addition to reducing LDL cholesterol levels, it increases HDL cholesterol levels and decreases Lp(a) levels.49 The European Atherosclerosis Society Consensus Panel have suggested use of niacin for Lp(a) and CVD risk reduction. Further, extendedrelease niacin has also reduced Lp(a) levels in diabetic patients with dyslipidemia. Etofibrate, a hybrid drug combining niacin and clofibrate, at a dose of 1 g/day decreases Lp(a) levels by 26% in type II dyslipidemic patients.50 Patients with type IIa and IIb hyperlipidemia being treated with neomycin alone leads to a decrease in Lp(a) concentration by 24%, while the neomycinniacin association in high doses has resulted in a 45% reduction.51

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CARDIOLOGY It may be mentioned that high doses of niacin are associated with adverse effects, such as migraine, flushing, diarrhea, vomiting, tachycardia and liver toxicity, though, administration of aspirin 30 minutes prior to niacin can relieve some of these adverse effects.

Aspirin Another commonly used cheap drug aspirin may be beneficial. Japanese patients with elevated Lp(a) levels (>300 mg/dL) have shown a 20% reduction in Lp(a) levels even with low doses of aspirin (81 mg/day).52 Women with high Lp(a) levels and an apo(a) polymorphic allele seem to have benefited more from treatment with aspirin than those who lack that allele.53 Thus, aspirin has been found useful only in patients that carry the apolipoprotein(a) gene minor allele variant (rs 3798220).53

Estrogen Replacement Estrogens lower Lp(a) up to 30%; although estrogen replacement therapy in postmenopausal women has beneficial effects on Lp(a) and other plasma lipids, yet it is studded with controversies regarding increased risk of certain malignant neoplasias and thromboembolic accidents. At present, estrogen is not indicated for treatment of elevated Lp(a). Tamoxifene and raloxifene have not been shown to reduce levels.

The precise underlying mechanisms of Lp(a)-lowering of these agents are not fully defined. A variety of agents belonging to different chemical groups are in various stages of development or undergoing clinical trials that may reduce Lp(a) concentrations and in future may open the doors to new avenues of therapy include:

reduction in body weight and minimal effects on skeletal mass. The agent reduces fat mass without increasing food intake and controls dyslipidemia, without causing deleterious effects on heart or bone mass.55 ÂÂ

KB-141 is another THRβ agonist, which is 10 times more selective for stimulating metabolic rate and 30 times more selective for cholesterol-lowering than for increase in heart rate.55 KB-141 has been shown to cause weight reduction as well as reduction of cholesterol and Lp(a).56

ÂÂ

Eprotirome: It is also a THRβ selective compound, causes 40% reduction in total and LDL cholesterol after 14 days treatment probably owing to an increase in bile acid synthesis.55 In humans, data from a clinical trial of 98 hyperlipidemic patients, eprotirome was shown to cause 25% reduction in LDL, apoB, along with 37% decrease in Lp(a) at 100 µg/day after 16 weeks. At 200 µg/day, there was 45% decrease in Lp(a). Triglycerides also decreased significantly. No cardiac, bone or muscle effects were observed, though mild transient elevation in liver enzymes was seen. Moreover, selective thyromimetics may have additive LDL cholesterollowering when used in combination with statins in animal models.

Cholesteryl Ester Transfer Protein Inhibitors

It is a combination of L-lysine and ascorbate may also reduce LPA levels.54 A more effective treatment is the Linus Pauling protocol, 6-18 g/day ascorbic acid, 6 g/day L-lysine and 2 g/day L-proline. This protocol may reduce Lp(a) two- to fivefold over a few months.

These agents reduce risk of atherosclerosis by improving plasma lipid levels. They substantially increase HDL, lower LDL and reverse the transport of cholesterol.

A few of these agents namely torcetrapib, dalcetrapib, evacetrapib have failed in clinical trials. However, anacetrapib and TA-8995 have shown encouraging phase II clinical trials results.57 Cholesteryl ester transfer protein (CETP) inhibitors inhibit CETP, which normally transfer cholesterol from HDL cholesterol to very LDL (VLDL) or LDL. Inhibition of this process results in higher HDL levels and reduces LDL levels.

CETP inhibitors do not reduce rates of mortality, heart attack or stroke in patients already taking statins.

Thyromimetics

Antisense Oligonucleotides to ApoB

The development of selective thyromimetics having specific liver selectivity (affinity to THRβ isoforms) provide an opportunity for the treatment of dyslipidemia, obesity or for weight loss, nonalcoholic fatty liver disease and may play a role in decreasing Lp(a) levels.55

Mipomersen, a second-generation antisense oligonucleotide injectable drug approved by the Food and Drug Administration (FDA) to be used in homozygous familial hypercholesterolemia in January 2013, might be a promise to decrease Lp(a) levels.58 Mipomersen is a polynucleotide of 20 bases that is complementary in sequence to a segment of human apoB-100 mRNA. It specifically binds to apoB-100 mRNA, blocking the translation of the gene product.58

L-carnitine

ÂÂ

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Sobetirome, a selective thyromimetic compound reduced LDL cholesterol by 41% at 100 µg/day and in primates caused increase in oxygen consumption,

Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

CARDIOLOGY A reduction in the synthesis of apoB-100 decreases the hepatic production of VLDL, consequently decreasing circulating levels of atherogenic VLDL remnants, intermediate-density lipoprotein (IDL), LDL and Lp(a) particles.58 Thus, mipomersen reduces all apoB-containing atherogenic lipoproteins and that it consistently and effectively reduces Lp(a) levels in patients with a variety of lipid abnormalities and cardiovascular risk. It has been recently demonstrated that a specific antisense oligonucleotide directed to KIV-11 repeats lowers apo(a) mRNA and apo(a) plasma levels by 85% in apo(a) transgenic mice, with minor effects on other lipoproteins. Mipomersen’s mode of action differs from traditional enzymes or protein-targeting drugs such as statins. It has no dependency on cytochrome P450 metabolism, hence minimal interaction with statins, ezetimibe, bile acids binding resins or other lipid-lowering medications with which it might be combined. Lp(a) levels are decreased in conjunction with changes in other lipoproteins. However, the safety of its use has not been well-established.

Farnesoid X Receptor Agonists Farnesoid X receptor (FXR, also referred to as NR1H4) is a member of the nuclear receptor superfamily of ligand-regulated transcription factors that plays critical role in the regulation of bile acid, triglyceride and cholesterol homeostasis. However, its impact on cholesterol homeostasis is less clear. Bile acids, the endproduct of cholesterol catabolism, are physiological ligand for FXR. Activation of FXR leads to downregulation of CYP7A1, the rate limiting enzyme in bile acid synthesis, resulting in reduced cholesterol catabolism. WAY-362450 is a potent synthetic FXR agonist, which decreases serum triglyceride levels with efficacy comparable to fenofibrate. It also reduced serum cholesterol levels via reductions in LDL cholesterol, VLDL cholesterol and HDL cholesterol lipoprotein fractions and may be of clinical utility in the treatment of mixed dyslipidemia. Synthetic FXR ligands have been demonstrated to regulate apolipoprotein CII (apoCII) and apolipoprotein CIII (apoCIII), cofactors involved in lipoprotein lipase (LPL)-mediated lipolysis and down modulate sterol regulatory element-binding protein 1c (SREBP-1c), the master regulator of the triglyceride synthetic pathway. Evans et al59 demonstrated that orally active FXR ligand WAY-362450 potently lowers serum triglyceride levels and VLDL cholesterol in multiple rodent models of dyslipidemia along with consistent-lowering of circulating serum cholesterol levels. The mechanism of action of WAY-362450 is

probably through modulation of genes involved in both lipolysis and lipogenesis.

Anti-proprotein convertase, subtilisin/Kexin type 9 (anti-PCSK-9) inhibitors, monoclonal antibodies, protein responsible for degrading LDL receptor; and anti-tocilizumab antibody, that can block IL-6-signaling are still in experimental phase. In severe cases, such as familial hypercholesterolemia, or treatment-resistant hypercholesterolemia lipid apheresis may lead to dramatic reductions in Lp(a) levels in more than 50% of patients.

Miscellaneous Agents ÂÂ Methotrexate: An immunosuppressive and anti-inflammatory drug used in the treatment of rheumatoid arthritis, may also reduce Lp(a) levels.60 ÂÂ Gingko biloba may be beneficial, but has not been clinically verified. Coenzyme Q-10, pine-bark extract and pharmacological amounts of fish oil supplements may be helpful to lower the levels of Lp(a) but none of these are clinically proven.

Interactions Lp(a) has been shown to interact with calnexin, fibronectin and fibrinogen beta chain.

CONCLUSION New novel, targeted therapeutic agents that can specifically and definitely reduce Lp(a) plasma concentrations are still being sought. In general, in the absence of well-tolerated drugs that effectively decrease Lp(a) concentrations, levels over 25-30 mg/dL should lead to a more strict control of other risk factors for CAD. However, the presumption that lowering Lp(a) levels leads to clinical benefits such as decreased risk of CVD needs confirmation.

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2012;60(8):716-21.

2. Nordestgaard BG, Chapman MJ, Ray K, Borén J, Andreotti F, Watts GF, et al; European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31(23):2844-53.

3. Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG. Lipoprotein(a) and risk of myocardial infarction - genetic epidemiologic evidence of causality. Scand J Clin Lab Invest. 2011;71(2):87-93.

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CARDIOLOGY 4. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies.

Circulation. 2000;102(10):1082-5.

20. Tsimikas S, Witztum JL. The role of oxidized phospholipids in mediating lipoprotein(a) atherogenicity. Curr Opin Lipidol. 2008;19(4):369-77.

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21. Ichikawa T, Unoki H, Sun H, Shimoyamada H, Marcovina S, Shikama H, et al. Lipoprotein(a) promotes smooth muscle cell proliferation and dedifferentiation in atherosclerotic lesions of human apo(a) transgenic rabbits. Am J Pathol.

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8. McLean JW, Tomlinson JE, Kuang WJ, Eaton DL, Chen EY, Fless GM, et al. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature.

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9. Utermann G, Menzel HJ, Kraft HG, Duba HC, Kemmler HG, Seitz C. Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma. J Clin Invest. 1987;80(2):458-65.

10. Sandholzer C, Hallman DM, Saha N, Sigurdsson G, Lackner C, Császár A, et al. Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups. Hum Genet. 1991;86(6):607-14.

11. Rader DJ, Mann WA, Cain W, Kraft HG, Usher D, Zech LA, et al. The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans. J Clin Invest. 1995;95(3):1403-8.

12. Albers JJ, Koschinsky ML, Marcovina SM. Evidence mounts for a role of the kidney in lipoprotein(a) catabolism. Kidney Int. 2007;71(10):961-2.

13. Argraves KM, Kozarsky KF, Fallon JT, Harpel PC, Strickland DK. The atherogenic lipoprotein Lp(a) is internalized and degraded in a process mediated by the VLDL receptor. J Clin Invest. 1997;100(9):2170-81.

14. Cobbaert C, Kesteloot H. Serum lipoprotein(a) levels in racially different populations. Am J Epidemiol.

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15. Maeda S, Abe A, Seishima M, Makino K, Noma A, Kawade M. Transient changes of serum lipoprotein(a) as an acute phase protein. Atherosclerosis. 1989;78(2-3):145-50.

16. De Lima JJ, Maranhão RC, Latrilha Mda C, Diament J, Romão JE, Krieger EM, et al. Early elevation of lipoprotein(a) levels in chronic renal insufficiency. Ren Fail. 1997;19(1):145-54.

17. Sotiriou SN, Orlova VV, Al-Fakhri N, Ihanus E, Economopoulou M, Isermann B, et al. Lipoprotein(a) in atherosclerotic plaques recruits inflammatory cells through interaction with Mac-1 integrin. FASEB J. 2006;20(3):559-61.

18. Hajjar KA, Gavish D, Breslow JL, Nachman RL. Lipoprotein(a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis.

Nature. 1989;339(6222):303-5.

19. Gouni-Berthold I, Berthold HK. Lipoprotein(a): current perspectives. Curr Vasc Pharmacol. 2011;9(6):682-92.

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22. Hobbs HH, White AL. Lipoprotein(a): intrigues and insights. Curr Opin Lipidol. 1999;10(3):225-36.

23. Koschinsky ML, Marcovina SM. Structure-function relationships in apolipoprotein(a): insights into lipoprotein(a) assembly and pathogenicity. Curr Opin Lipidol. 2004;15(2):167-74.

24. Taleb A, Witztum JL, Tsimikas S. Oxidized phospholipids on apoB-100-containing lipoproteins: a biomarker predicting cardiovascular disease and cardiovascular events. Biomark Med. 2011;5(5):673-94.

25. Wu HD, Berglund L, Dimayuga C, Jones J, Sciacca RR, Di Tullio MR, et al. High lipoprotein(a) levels and small apolipoprotein(a) sizes are associated with endothelial dysfunction in a multiethnic cohort. J Am Coll Cardiol.

2004;43(10):1828-33.

26. Helgadottir A, Gretarsdottir S, Thorleifsson G, Holm H, Patel RS, Gudnason T, et al. Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism. J Am Coll Cardiol. 2012;60(8):722-9.

27. Ramharack R, Barkalow D, Spahr MA. Dominant negative effect of TGF-beta1 and TNF-alpha on basal and IL-6-induced lipoprotein(a) and apolipoprotein(a) mRNA expression in primary monkey hepatocyte cultures.

Arterioscler Thromb Vasc Biol. 1998;18(6):984-90.

28. Riches K, Porter KE. Lipoprotein(a): cellular effects and molecular mechanisms. Cholesterol. 2012;2012:923289.

29. Rhoads GG, Dahlen G, Berg K, Morton NE, Dannenberg AL. Lp(a) lipoprotein as a risk factor for myocardial infarction. JAMA. 1986;256(18):2540-4.

30. Murai A, Miyahara T, Fujimoto N, Matsuda M, Kameyama M. Lp(a) lipoprotein as a risk factor for coronary heart disease and cerebral infarction. Atherosclerosis.

1986;59(2):199-204.

31. Maranhäo R, Arie S, Vinagre CG, Guimarães JB, Strunz C, Pileggi F. Lipoprotein (a) plasma levels in normal subjects and patients with coronary disease confirmed by coronary cineangiography. Arq Bras Cardiol. 1991;56(2):121-5.

32. Kwon SW, Lee BK, Hong BK, Kim JY, Choi EY, Sung JM, et al. Prognostic significance of elevated lipoprotein(a) in coronary artery revascularization patients. Int J Cardiol.

2013;167(5):1990-4.

33. Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a) levels and improved cardiovascular risk prediction. J Am Coll Cardiol. 2013;61(11):1146-56.

CARDIOLOGY 34. Cantin B, Gagnon F, Moorjani S, Després JP, Lamarche B, Lupien PJ, et al. Is lipoprotein(a) an independent risk factor for ischemic heart disease in men? The Quebec Cardiovascular Study. J Am Coll Cardiol. 1998;31(3): 519-25.

35. Nenseter MS, Lindvig HW, Ueland T, Langslet G, Ose L, Holven KB, et al. Lipoprotein(a) levels in coronary heart disease-susceptible and -resistant patients with familial hypercholesterolemia. Atherosclerosis. 2011;216(2):426-32.

36. Tsironis LD, Katsouras CS, Lourida ES, Mitsios JV, Goudevenos J, Elisaf M, et al. Reduced PAF-acetylhydrolase activity associated with Lp(a) in patients with coronary artery disease. Atherosclerosis. 2004;177(1):193-201.

37. Ohira T, Schreiner PJ, Morrisett JD, Chambless LE, Rosamond WD, Folsom AR. Lipoprotein(a) and incident ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) study. Stroke. 2006;37(6):1407-12.

38. Erqou S, Thompson A, Di Angelantonio E, Saleheen D, Kaptoge S, Marcovina S, Danesh J. Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants. J Am Coll Cardiol. 2010;55(19):2160-7.

39. Frohlich J, Dobiásová M, Adler L, Francis M. Gender differences in plasma levels of lipoprotein (a) in patients with angiographically proven coronary artery disease.

Physiol Res. 2004;53(5):481-6.

40. Virani SS, Brautbar A, Davis BC, Nambi V, Hoogeveen RC, Sharrett AR, et al. Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2012;125(2):241-9.

41. Suk Danik J, Rifai N, Buring JE, Ridker PM. Lipoprotein(a), hormone replacement therapy, and risk of future cardiovascular events. J Am Coll Cardiol. 2008;52(2):124-31.

42. Thanassoulis G, Campbell CY, Owens DS, Smith JG, Smith AV, Peloso GM, et al; CHARGE Extracoronary Calcium Working Group. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013;368(6):503-12.

43. Nestel PJ, Barnes EH, Tonkin AM, Simes J, Fournier M, White HD, et al. Plasma lipoprotein(a) concentration predicts future coronary and cardiovascular events in patients with stable coronary heart disease. Arterioscler Thromb Vasc Biol. 2013;33(12):2902-8.

44. Hernández C, Francisco G, Ciudin A, Chacón P, Montoro B, Llaverias G, et al. Effect of atorvastatin on lipoprotein (a) and interleukin-10: a randomized placebo-controlled trial.

Diabetes Metab. 2011;37(2):124-30.

47. Nozue T, Michishita I, Mizuguchi I. Effects of ezetimibe on remnant-like particle cholesterol, lipoprotein (a), and oxidized low-density lipoprotein in patients with dyslipidemia. J Atheroscler Thromb. 2010;17(1):37-44.

48. Boden WE, Sidhu MS, Toth PP. The therapeutic role of niacin in dyslipidemia management. J Cardiovasc Pharmacol Ther. 2014;19(2):141-58.

49. Pan J, Van JT, Chan E, Kesala RL, Lin M, Charles MA. Extended-release niacin treatment of the atherogenic lipid profile and lipoprotein(a) in diabetes. Metabolism.

2002;51(9):1120-7.

50. Sposito AC, Mansur AP, Maranhão RC, RodriguesSobrinho CR, Coelho OR, Ramires JA. Etofibrate but not controlled-release niacin decreases LDL cholesterol and lipoprotein (a) in type IIb dyslipidemic subjects. Braz J Med Biol Res. 2001;34(2):177-82.

51. Gurakar A, Hoeg JM, Kostner G, Papadopoulos NM, Brewer HB Jr. Levels of lipoprotein Lp(a) decline with neomycin and niacin treatment. Atherosclerosis.

1985;57(2-3):293-301.

52. Akaike M, Azuma H, Kagawa A, Matsumoto K, Hayashi I, Tamura K, et al. Effect of aspirin treatment on serum concentrations of lipoprotein(a) in patients with atherosclerotic diseases. Clin Chem. 2002;48(9):1454-9.

53. Chasman DI, Shiffman D, Zee RY, Louie JZ, Luke MM, Rowland CM, et al. Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis. 2009;203(2): 371-6.

54. Parhofer KG. Lipoprotein(a): medical treatment options for an elusive molecule. Curr Pharm Des. 2011;17(9):871-6.

55. Kapoor P, Kumar P, Kapoor AK. Thyroid, obesity and thyromimetic compounds. IJCP. 2016;26(9):836-45.

56. Galofre JC, Fruhbeck G, Salvador J. Obesity and thyroid function: Pathophysiological and therapeutic implications. Hot Thyroidol. 2010;6:1-22.

57. Hovingh GK, Kastelein JJ, van Deventer SJ, Round P, Ford J, Saleheen D, et al. Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet. 2015;386(9992):452-60.

58. Toth PP. Emerging LDL therapies: Mipomersenantisense oligonucleotide therapy in the management of hypercholesterolemia. J Clin Lipidol. 2013;7(3 Suppl):S6-10.

45. Takagi H, Umemoto T. Atorvastatin decreases lipoprotein(a): a meta-analysis of randomized trials. Int J Cardiol. 2012;154(2):183-6.

59. Evans MJ, Mahaney PE, Borges-Marcucci L, Lai K, Wang S, Krueger JA, et al. A synthetic farnesoid X receptor (FXR) agonist promotes cholesterol lowering in models of dyslipidemia. Am J Physiol Gastrointest Liver Physiol.

2009;296(3):G543-52.

46. Ramires JA, Mansur AP, Solimene MC, Maranhão R, Chamone D, da Luz P, et al. Effect of gemfibrozil versus lovastatin on increased serum lipoprotein(a) levels of patients with hypercholesterolemia. Int J Cardiol.

1995;48(2):115-20.

60. Hjeltnes G, Hollan I, Førre O, Wiik A, Lyberg T, Mikkelsen K, et al. Serum levels of lipoprotein(a) and E-selectin are reduced in rheumatoid arthritis patients treated with methotrexate or methotrexate in combination with TNFα-inhibitor. Clin Exp Rheumatol. 2013;31(3):415-21.

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Lead Toxicity Among Automobile Garage Workers in the Vicinity of Nalanda Medical College and Hospital, Patna and Its Adjoining Areas of Patna, Bihar, India MA NASAR*, TF SUBHANI†, RR SINHA*

ABSTRACT In India, particularly in state of Bihar, there are numerous small-scale and medium industries, which use lead-based raw materials that may pose health risks to workers. There are no workplace regulations for lead exposure. Moreover, there are no studies carried out on the blood lead levels (BLLs) of workers or on the contribution of common workplace practices to lead poisoning. A cross-sectional study on the BLLs of 45 automobile garage workers and 40 non-garage workers was carried out in the vicinity of Nalanda Medical College and Hospital, Patna, India. In addition to BLL analysis, data on some risk factors such as smoking, and chewing tobacco (gutka and pan parag) were gathered through structured questionnaires and interviews and data analysis was performed using SPSS (Version 16). The t-test was used to compare mean BLLs of study groups.

The analysis of variance (ANOVA), Kruskal-Wallis, Pearson chi-square and odds ratio tests were used to investigate the associations between specific job type, smoking and/or tobacco chewing, service years and occurrence of nonspecific symptoms with BLLs. The mean BLL of the automobile garage workers was found to be significantly greater than that of the controls.

The BLLs of all the lead-exposed individuals were found to be over 10 μg/dL, and 53% of them had BLLs ranging 12-20 μg/ dL, with the remaining 47% having over 20 μg/dL. The BLL of the workers increased with the duration of working in an automobile garage. Individuals involved in manual car painting comprise a larger percentage (58%) of those with the highest BLLs (≥20 μg/dL). Lead accumulation in individuals who chew tobacco in the work place was found to be faster than in those who are not used to chewing tobacco. The findings of the study have clearly demonstrated that the BLLs of automobile garage workers in Patna, Bihar are considerably high with a range of 11.73-36.52 μg/dL and the workers are in danger of impending lead toxicity. The BLLs of the workers are influenced by their occupational practices, chewing tobacco at the workplace, and the time spent working in an automobile garage.

Keywords: Lead, garage workers, blood lead level, tobacco, gutka

L

ead is one of the most widely distributed toxins in our environment. Although its toxic effects have been known for centuries, occupational exposure to lead that results in poisoning, be it moderately or clinically symptomatic, is still common in many countries of the world.1,2 Excessive occupational exposure over a brief period of time can cause a

syndrome of acute lead poisoning. Clinical findings in this syndrome include abdominal colic, constipation, fatigue and central nervous system dysfunction. With even greater doses, acute encephalopathy with coma and convulsions may occur, whereas in cases of milder exposures, headaches and personality changes may be the only signs of neurologic toxicity.3

*Dept. of Biochemistry Nalanda Medical College, Patna, Bihar †Dept. of Biochemistry NC Medical College, Panipat, Haryana Address for correspondence Dr MA Nasar Assistant Professor Dept. of Biochemistry Nalanda Medical College, Patna, Bihar

Children are particularly susceptible to lead intoxication that causes various neurological and behavioral problems, ranging from raised hearing threshold to reduction in intelligence quotient (IQ) at low blood lead concentrations. Although no threshold has been determined for the harmful effects of lead in children, a 1991 Centers for Disease Control and Prevention (CDC) Report of UK has put the blood lead level (BLL) of concern in children at 10 μg/dL. The level of concern

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COMMUNITY MEDICINE has changed over the past few decades, from 60 μg/dL (1960), to 30 μg/dL (1970), to 25 μg/dL (1985), to 10 μg/dL (1991).4 Occupational lead exposure in many developing countries is entirely unregulated, often with no monitoring of exposure.5 In India, although there are numerous small-scale and large industries which use lead-based raw materials that may pose health risks to workers, there are no workplace regulations for lead exposure and no data are available with the labor departments among the workers of small-scale lead-based units with regard to lead poisoning. Many people working for different manufacturing or service rendering organizations such as battery manufacturing workers, gas-station attendants, radiator repair workers, solderers of lead products and welders, are involved in jobs, which expose them to gradual health risks from exposure to lead without having any idea about the materials they are handling. Due to lack of awareness about their exposure, workers usually eat, smoke or drink while at work and such workplace practices may aggravate their exposure.6,7 In India and in some other developing countries, tobacco chewing at the workplace is a common practice.

The dried leaves of tobacco are chewed for their stimulating effects. After chewing the leaves, people may swallow the juice and throw away the residue or swallow whatever they chewed. In many work areas, the workers who chew tobacco (gutka) do so at the workplace. This is typically done by putting them into the mouth from time to time while performing duties.

Whatever the material that the workers are handling, they do not wash their hands each time they cut the packet and put them into their mouth. As a result, various toxic substances, including lead, that have stuck to the hands of these workers might easily get transferred onto the tobacco leaves surface and then ingested with the tobacco by the workers.

Relating the concentration of heavy metals, such as lead, in humans to an environmental and occupational level is crucial in order to determine areas of health risk. Most toxicology studies rely on BLL as the measure of exposure.8-10 Lead in shed deciduous teeth is sometimes quoted being regarded as a record of past lead exposure.11,12 Other materials that have been used to estimate the amount of lead in human beings include hair,13-15 urine and feces.16,17 Auto-garage workers in India are involved in car painting, soldering, welding and other repairing activities. The garage compounds in which the workers

carry out their daily activities are usually filled with fuel exhaust from automobiles entering or leaving the garage’s compounds. Moreover, workplace tobacco chewing is common practice for many auto-garage workers. Most of the workers have no idea about the toxic metals they might be exposed to; as a result, they pay little attention to protecting themselves from the possible inhalation or ingestion of such toxic substances, nor are they made aware of this or advised to take the necessary protective measures. Despite this fact, no study has been conducted to assess the BLLs of people working in auto-garages or of workers in other industries that are expected to pose health risks to workers. However, a single cross-sectional study on the occupational lead exposure of 51 workers in lead acid battery repair units of transport service enterprises at New Delhi, using δ-Aminolevulinic acid (δ-ALA) levels in the urine and serum as a biomarker, has been reported.18 According to data obtained, there are other smallscale industries involved in furniture production, food processing, metal and woodwork, bakery and pastry, flour-making and coffee processing. There are no large-scale industrial activities in the town, which are expected to expose workers to lead pollution. It could also be assumed in Patna that, despite the continued use of lead free petroleum, a situation where lead emissions from motor vehicles would constitute a serious risk to public health is not anticipated. Such a conclusion, however, would not be valid without evidence of completed work.

There are around more than 200 automobile garages in the city of Patna, each of which has an average of 15 workers. All of these garages offer multiple autorepair services in a single compound. Within this compound, all workers carry out their specific jobs near other colleagues engaged in other activities, moving around to share tools and help one another. Therefore, all the workers are exposed virtually to the same extent to the toxic substances resulting from all the services offered in the auto-garage. The problem of exposure may be further compounded with the chewing of tobacco (gutka) at the work place. Preliminary observations have revealed that the automobile garage workers who are used to chewing gutka, while at work are taking the gutka under poor hygienic conditions and they have no idea about the possible toxic substances they might ingest with the gutka or inhale from the surrounding air. As a result, they use no protective devices to minimize exposure.

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COMMUNITY MEDICINE Therefore, the BLLs of automotive garage workers around Patna might be higher than other people who are not occupationally exposed. On top of this, autogarage workers who are used to workplace gutka chewing and smoking might have higher BLLs than their colleagues who are not used to practicing these habits while at work. This study was therefore aimed at investigating the BLLs and associated health problems of automotive garage workers in Patna and relating the data to workplace practices of chewing gutka and smoking.

METHODS

Study Subjects and Study Design The study was a cross-sectional BLL survey that included blood lead sampling from 45 occupationally exposed garage workers (44 males, 1 female) and 40 controls (36 males, 4 females). The occupationally exposed group included individuals who were mainly involved in manual auto spray-painting or welding for a duration of around 5-15 years in the auto-garages, where excessive usage of petrol and petroleum by-products takes place with a daily exposure of 8-12 hours. The occupationally nonexposed group members were school and university students and teachers who had apparently no history of lead exposure, were non-smokers, nontobacco chewers and nonalcoholics.

Reagents and Laboratory Ware Analytical standard solutions of lead were prepared by serially diluting a 1,000 mg/L stock calibration standard solution (Spectro ECON). All chemicals and reagents used were of analytical grade purchased from Merck or Sigma Chemical Co.

Blood Sample Collection Venous blood samples (4 mL each) were collected from the 45 garage workers and, 40 apparently healthy nongarage workers using carefully labeled vacutainer tubes containing 7.2 mg K2EDTA by qualified medical laboratory professionals. All samples were then preserved at 4°C. Blood specimen collection was carried out using separate sterilized needles and gloves for each individual. All used needles and gloves were packed in appropriately labeled disposable bags and taken to the Nalanda Medical College and Hospital, Patna waste disposal unit.

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Sample Preparation The blood specimens were heated in a hot water bath at 37°C for 25 minutes and homogenized by shaking for 1 minute. Accurately measured 3 mL of each of the blood samples was transferred into a Pyrex test tube. A 3:1 mixture of trichloroacetic acid (TCA 5%) and perchloric acid solution (2 M) was added to each test tube and centrifuged for 25 minutes at 3,000 rpm.

The supernatant from each sample was decanted into a labeled sample bottle and the precipitate was further digested with 3.0 mL 2 M perchloric acid and centrifuged for 15 minutes. The supernatant from each centrifuged sample was decanted and mixed with its corresponding supernatant from the first digestion.

Finally, the digests were stored at 4°C until dispatched for analysis.

BLL Analysis The concentration of lead in the blood samples was determined by Flame Atomic Absorption Spectrometer (NovAA 300) at 283.3 nm after optimizing the various instrument parameters. Triplicate samples were analyzed in each determination and averages of triplicate measurements were taken for each sample.

Instrument drift was controlled by running standards after analyzing 10 samples. Quantification of lead in blood was carried out with the help of a standard lead solution.

Data Collection In addition to determining the concentration of lead in blood samples, data on some risk factors for lead poisoning such as: addiction to alcohol, smoking, tobacco chewing and eating and/or drinking habits at the workplace, were gathered through questionnaires and interviews. A standardized structured questionnaire, designed to yield information on associated risk factors with the observed BLL, was prepared in English and administered after obtaining consent from the participants of the study. Each item in the questionnaire was interpreted into the local language Hindi for those who do not understand English. In addition to the questionnaire, participants were interviewed privately on further points. The interviews included detailed demographic information, exposure history and the presence and nature of lead-related symptoms.

Statistical Analysis Statistical analyses of results were basically performed by using SPSS (Version 16). Comparison of mean BLLs of study groups was carried out using a t-test. One-way

COMMUNITY MEDICINE analysis of variance (ANOVA) was used to investigate the variation in BLL with the specific job types of the autogarage workers. The Pearson chi-square statistic and the odds ratio test were used to investigate the associations between BLL and service years, and BLL and occurrence of nonspecific symptoms, respectively.

The Kruskal-Wallis test was used to investigate the dependence of BLL on smoking and/or tobacco chewing habit in the workplace. All data were expressed as mean ± SD and the level of significance was determined at p < 0.05.

Ethical Consideration The study was conducted upon obtaining ethical clearance from the Institutional Ethics Committee of Nalanda Medical College and Hospital, Patna. The purpose of the study was clearly explained to the study participants following a pre-developed procedure and oral consent was obtained from each of the participating individuals and the auto-garage owners.

Blood specimen collection was carried out using a separate sterilized needle and glove for every individual. All used needles and gloves were packed in appropriately labeled disposable bags and taken to the Nalanda Medical College and Hospital waste disposal unit.

RESULTS

job categories 20.30 ± 4.52. The observed differences; however, were not statistically significant (p > 0.05). The BLLs of the garage workers were all >10 μg/dL, while 41% of the controls had BLLs lower than this value.

The remaining 59% of the controls had BLLs ranging 10-16 μg/dL. Among the garage workers, 53% had BLLs ranging from 12 to 20 μg/dL and the remaining 44% of them had 20 to 27 μg/dL. One person among the garage workers had a relatively higher BLL, 36.52 μg/dL and the person was identified to be an alcoholic, smoker, tobacco chewer and had served for 25 years in autogarages. The female garage worker who participated in the study had a BLL of 15.87 μg/dL. She had served for over 10 years, and did not chew tobacco, smoke or drink alcohol. The mean BLL of the 4 females among the controls was 10.13 μg/dL (95% CI: 9.36-10.90, median: 9.96 μg/dL; range: 9.38-11.22 μg/dL).

BLLs of Occupationally Exposed Group Relative to Service Years The proportion of individuals with BLLs <15, 15-20 or above 20 μg/dL among the garage workers with service years between 1-3, 3-6 and above 6 years are given in Figure 1. The figure clearly shows a steady increase in the proportion of individuals with higher BLLs with an increase in service years. The chi-square test has revealed that the dependence of BLL on service

BLLs of Occupationally Exposed and Nonexposed Groups

The BLLs of the auto-garage workers were found to vary with the specific job type they are involved in.

The mean BLL of the workers involved in manual auto-painting was 21.12 ± 5.59 μg/dL, that of welders 19.19 ± 4.08 μg/dL and that of workers involved in both

3-6 years

Above 6 years

60 No of individuals (%)

The mean lead concentrations of the garage workers and controls are given in Table 1. According to the t-test the difference between the mean BLL of the garage workers, 19.76 μg/dL (95% confidence interval [CI]: 18.45-21.06, median: 19.75 μg/dL; range: 11.7336.52 μg/dL), and that of the controls, 10.73 μg/dL (95% CI: 10.05-11.41, median: 10.40 μg/dL; range: 5.615.64 μg/dL) is significant (p < 0.05).

1-3 years 70

50 40 30 20 10 0 Below 15 µg/dL

15-20 µg/dL

Above 20 µg/dL

Blood lead level range

Figure 1. Proportion of the garage workers with BLLs <15 μg/dL, between 15-20 μg/dL and above 20 μg/dL in the 1-3, 3-6 and above 6 years of service categories.

Table 1. BLLs of the Garage Workers and Controls Mean Pb conc (μg/dL ± SD)

95% CI (μg/dL)

Range (μg/dL)

% BLL ≥10 μg/dL

Garage workers

19.75 ± 4.46

18.45-21.06

11.73-36.52

100

Controls

10.73 ± 2.22

10.05-11.41

5.6-15.64

56

Category

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COMMUNITY MEDICINE However, those who were nonsmokers but habituated to gutka chewing had a mean BLL of 20.19 ± 4.06 μg/dL (n = 7). Six of the seven gutka chewers had BLLs above 18 μg/dL and only one individual had a BLL of 13.89 μg/dL. The fact that both the gutka chewers and nonchewers are not smokers and that the BLLs of the nongutka chewers is significantly lower than that of the gutka chewers indicates that gutka chewing either accelerates lead accumulation or is an additional source of lead intake.

years is statistically significant (p < 0.05). Among the individuals in the 1-3 service years group, the relative number of individuals with BLLs of <15 μg/dL is greater than that of individuals with BLLs ranging from 15 to 20 μg/dL or above 20 μg/dL. Forty-six percent of the garage workers with service between 1-3 years and 14% of those with service between 3-6 years were found to have BLLs <15 μg/dL. Among the workers with more than 6 years of service, 68% had BLLs above 20 μg/ dL, 32% in the range from 15 to 20 μg/dL and none of them had <15 μg/dL. Individuals with more than 10 years of service comprise a larger percentage (88%) of those with BLLs above 20 μg/dL. This clearly shows the direct relationship between BLL and service years.

A similar difference between the two groups was not observed in the BLLs of the individuals with more than 3 years of service in the auto-garages. The impact of gutka chewing on lead accumulation steadily decreased with service years, and in individuals with more than 10 years of service its impact was not visible.

BLL and Smoking/Tobacco (Gutka) Chewing Habits The mean BLL of the total garage workers who were neither smokers nor tobacco chewers was 16.58 ± 3.5 μg/dL (n = 14) and that of the tobacco chewing nonsmokers was 20.17 ± 3.11 μg/dL (n = 25). According to the Kruskal-Wallis test, the observed BLL difference between the two groups is significant (p < 0.05). Table 2 illustrates the mean BLLs of the garage workers who were gutka chewers but not smokers and, non-gutka chewers and nonsmokers in the service year ranges of 1-3, 3-6 and above 6 years. As shown in this table, among the 11 individuals with service years ranging 1-3 years, the mean BLL of those who were habituated neither to gutka chewing nor to smoking had a mean BLL of 12.57 ± 0.88 μg/dL (n = 4).

Lead Toxicity Symptoms The odds ratio of the reported nonspecific symptoms in the garage workers in relation to the controls was calculated and the results obtained are shown in Table 3. The results clearly show that among the reported nonspecific symptoms, the occurrence of wrist drop, tingling and numbness in fingers and hands, nausea and decreased libido in the auto-garage workers are significantly greater than in the controls.

The proportion of individuals affected by the nonspecific symptoms among the individuals with BLLs: <16, 16-20 or above 20 μg/dL, was assessed and the results obtained are illustrated in Figure 2.

Table 2. Relationship of BLL with Smoking, Tobacco Chewing and/or Smoking Habit and Service Years Service years 1-3 years

3-6 years

Above 6 years

Tobacco (gutka) chewing

Smoking

n

Mean BLL (μg/dL)

Range (μg/dL)

Median (μg/dL)

CI (p = 0.05) (μg/dL)

×

×

4

12.57

11.73-13.8

12.37

11.69-13.45

√

√

-

-

-

-

√

×

7

20.19

13.89-27.1

19.91

×

√

-

-

-

-

×

×

2

18.51

16.51 & 20.51*

-

14.59-22.43

√

√

1

21.99

-

-

-

√

×

4

22.04

18.21-25.94

22

18.87-23.21

×

√

-

-

-

-

-

×

×

8

18.94

15.87-21.68

19.61

17.25-20.63

√

√

3

25.46

19.58-36.52

20.29

14.63-36.3

√

×

14

19.63

15.66-23.69

19.06

18.29-20.97

×

√

2

25.16

24.08 & 26.23*

-

23.06-27.26

n = Number of workers, × = Not smoking or tobacco chewing, √ = Smoking or tobacco chewing. *Where n = 2, both blood lead concentrations are given in place of the range.

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Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

COMMUNITY MEDICINE Table 3. Reported Symptoms Among the Occupationally Exposed (n = 45) and the Controls (n = 40) and the Ratio of their Odds No of ‘Yes’ response for symptom Symptom

Cases

Controls

Odds ratio

P value

Depression

28

7

7.76*

0.00

Memory impairment

13

6

2.30

0.21

Sleep disturbance

23

9

3.60*

0.01

Concentration difficulty

9

11

0.66

0.32

Headaches

17

14

1.13

0.91

Wrist drop

25

1

48.75*

0.00

Tingling and numbness in fingers/hands

12

1

14.18*

0.01

Lack of appetite

12

5

2.55

0.18

Nausea

10

1

11.14*

0.02

Constipation

10

3

3.52

0.13

Abdominal discomfort

16

8

2.21

0.17

Decreased libido

21

3

10.79*

0.00

*Significant relative risk of occurrence in the auto-garage workers at p < 0.05.

<16 µg/dL

80

16-20 µg/dL

≥20 µg/dL

70

No of individuals (%)

60 50 40 30 20 10 0 Depression

Memory Imp.

Headache

Wrist drop

Ting. & numbness

Lack of appetite

Nausea

Decr. in libido

Type of nonspecific symptom

Figure 2. Nonspecific symptoms observed at different BLL.

The results clearly indicated an increase in the prevalence of all the symptoms with an increase in BLL. Among the symptoms assessed, depression, wrist drop and decreased libido were the most prevalent ones in the individuals with BLLs ≥20 μg/dL. About 80% of the garage workers in this BLL range reported having symptoms of depression, 75% for wrist drop and 58% for decreased libido.

Results of the odds ratio test for the relative occurrence of the nonspecific symptoms between the garage

workers with BLLs of <20 μg/dL (n = 25) and the controls (n = 40) are given in Table 4. The results clearly show that the occurrence of most of the symptoms in the garage workers is significantly greater than in the controls (p < 0.05). This could be a clear indication for the negative health impacts of BLLs as low as 10 μg/dL. During interviews, the garage workers reported some nonspecific symptoms, which were not included in the questionnaire. Among the workers, 15 (33.3%) reported having developed a feeling of metallic taste in their

Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

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COMMUNITY MEDICINE Table 4. Reported Symptoms Among the Auto-Garage Workers with BLLs <20 μg/dL (n = 25) and the Controls (n = 40) and the Ratio of their Odds Yes responses for symptoms Symptoms

Cases

Controls

Odds ratio

P value

Depression

28

7

5.11*

0.02

Memory impairment

13

6

1.08

0.61

Sleep disturbance

23

9

3.18*

0.01

Concentration difficulty

9

11

0.50

0.55

Headaches

17

14

0.66

0.52

Wrist drop

25

1

26.00*

0.00

Tingling and numbness in fingers/hands

12

1

7.43*

0.04

Lack of appetite

12

5

2.20

0.06

Nausea

10

1

5.32*

0.04

Constipation

10

3

2.25

0.16

Abdominal discomfort

16

8

1.88

0.29

Decreased libido

21

3

8.22*

0.00

*Significant relative risk of occurrence in the auto-garage workers at p < 0.05.

mouth, 9 (20%) reported having blurred vision and 11 (24.4%) had dry white scars in one or two areas on their heads.

DISCUSSION Occupationally related BLL assessment has not previously been carried out in any part of Patna.

However, in a cross-sectional study carried out in New Delhi on lead exposure among storage battery repair workers by measuring urinary aminolevulinic acid levels, higher levels of urinary aminolevulinic acid were found in the storage battery repair workers and the possible parallel rise in BLLs of the workers was predicted. The results obtained in our study have shown that auto-garage workers have significantly greater BLL than the nongarage workers (p < 0.05).

This clearly indicates that auto-garage workers are more likely to be exposed to lead due to occupational incidences than the general population. Furthermore, the results obtained in our study are consistent with the results of other studies carried out on the determination of the BLLs of: Ninety-seven occupationally and nonoccupationally exposed individuals in Nigeria,19 workers involved in various types of jobs in the United Arab Emirates,20 31 male nonsmoking industrial workers in Iran21 and apprentices working in leadrelated industries in Turkey.6 Among the lead-exposed garage workers, the mean BLL of individuals who were mainly involved in manual auto-painting (21.12 ± 5.59 μg/dL) was slightly higher than that of the mechanics

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Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

(19.19 ± 4.08 μg/dL). Comparison of the mean values by using a t-test has shown that the observed difference was not; however, statistically significant. A study done in Bangkok on 52 mechanics, 27 dye sprayer and 20 controls, reported mean BLLs of 8.7 μg/dL, 12.02 μg/dL and 6.63 μg/dL, respectively.22 The mean BLLs obtained by these researchers for all the three groups were much lower than those obtained in our study. The relative difference between the BLLs of the mechanics and the auto-painters in their study (27.6%); however, is greater than that of the difference obtained in our study (9.1%). The observed higher BLL in the painters than in the mechanics might indicate a greater exposure of the dye sprayers relative to the mechanics.

The painters, in addition to the oral exposure routes, are more likely exposed to inhalation of lead fumes found in the dyes than those workers engaged in other autorepairing activities. This could be a possible reason for the observed BLL difference between the two groups.

The garage workers were found to exhibit significantly higher levels of the nonspecific symptoms, which included: Depression, sleep disturbance, wrist drop, tingling and numbness in fingers and hands, nausea and decrease in libido relative to the controls. Moreover, the prevalence of these symptoms was higher in the workers with higher service years than in those with lower service years. Comparison of the prevalence of the nonspecific symptoms between the occupationally exposed individuals with BLLs <20 μg/dL (n = 25) with that of the controls (n = 40) has also revealed that

COMMUNITY MEDICINE there is a significantly greater prevalence of most of the symptoms in the garage workers. The Association of Occupational and Environmental Clinics (AOEC) has revealed the health effects of various BLLs on lead-exposed adults, and according to this document, the nonspecific symptoms such as: Headache, sleep disturbance, fatigue and decreased libido are shown to occur in the BLL range between 20 and 39 μg/dL. However, the findings of our study suggest that these symptoms are exhibited by lead-exposed individuals at lower BLLs (10-20 μg/dL) than indicated in the AOEC document. Our report on the variations of the nonspecific symptoms between the two groups is entirely from what the two groups revealed in the questionnaires and interviews. Although this may be suggestive of the adverse effects of lead (Pb) on the exposed individuals relative to the nonexposed, a close medical investigation is required to affirm that the epidemiologic variations between the two groups are exclusively results of the difference in the BLLs of the groups.

The BLLs of the workers are influenced by their occupational practices and roughly paralleled with the duration of occupational lead exposure. Workplace gutka chewing and lack of awareness about the ill health effects of lead and the routes through which it enters the human body has contributed to the easy entry of lead into the body of the workers and the resulting elevated BLL. Further large-scale screening and regular monitoring of automobile-garage workers is urgently needed to reduce long-term adverse effects of lead exposure.

Tobacco chewing has been found to enhance lead accumulation in the first 1-3 years of service in the occupationally exposed individuals. The mean BLL of the gutka chewers in the 1-3 service year range was 61% higher than the mean BLL of the nonchewers in the same service year range. The observed elevated level of lead in the gutka chewers could most likely be due to oral ingestion. The garage workers are chewing gutka at the workplace. Moreover, they chew the gutka while carrying out their work and do not wash their hands each time they cut the packets and put them in their mouth. This makes lead entry into the digestive system easier, thereby increasing BLL.

3. Landrigan PJ. In: Rosenstock L, Cullen MR (Eds.).

Textbook of Clinical Occupational and Environmental Medicine. Saunders: Philadelphia; 1994. pp. 745-54.

Several potential limitations of our study may have affected the analysis. The records of environmental Pb exposure in the proximity of the auto-garages were not available because monitoring of Pb in air was not enforced. Any observed difference in response to occupational and environmental Pb exposure may, therefore, be attributed to a degree of exposure to Pb. The participants in the control group were selected from university students and teachers. As a result, absence of some epidemiological symptoms in this group might not be exclusively attributed to lower BLL relative to the automotive-garage workers.

REFERENCES 1. Vaglenov A, Creus A, Laltchev S, Petkova V, Pavlova S, Marcos R. Occupational exposure to lead and induction of genetic damage. Environ Health Perspect. 2001;109(3): 295-8.

2. Bhagwat VR, Patil AJ, Patil JA, Sontakke AV. Occupational lead exposure and liver functions in battery manufacture workers around Kolhapur (Maharashtra). Al Ameen J Med Sci. 2008;1(1):2-9.

4. Centers for Disease Control and Prevention. Preventing Lead Poisoning in Young Children: A Statement by the Centers for Disease Control. US Department of Health and Human Services, Public Health Service, Atlanta; 1991.

5. Lovei M. Eliminating a silent threat: World Bank support for the global phase-out of lead from gasoline. In: George AM (Eds.). Proceedings of the International Conference on Lead Poisoning Prevention and Treatment. Bangalore, India: The George Foundation; 1999. pp. 169-80.

6. Pala K, Turkkan A, Gucer S, Osman E, Aytekin H. Occupational lead exposure: blood lead levels of apprentices in Bursa, Turkey. Ind Health. 2009;47(1):97-102.

7. Grandjean P, Hollnagel H, Olsen NB. Occupationally related lead exposure in the general population.

A population study of 40-year-old men. Scand J Work Environ Health. 1981;7(4):298-301.

8. Baloh RW. Laboratory diagnosis of increased lead absorption. Arch Environ Health. 1974;28(4):198-208.

9. Landrigan PJ, Whitworth RH, Baloh RW, Staehling NW, Barthel WF, Rosenblum BF. Neuropsychological dysfunction in children with chronic low-level lead absorption. Lancet. 1975;1(7909):708-12.

CONCLUSION

10. Ratcliffe JM. Developmental and behavioural functions in young children with elevated blood lead levels. Br J Prev Soc Med. 1977;31(4):258-64.

The BLLs of automotive-garage workers in Patna are noticeably high with a range of 11.73-36.52 μg/dL and the workers are in danger of impending lead toxicity.

11. Needleman HL, Gunnoe C, Leviton A, Reed R, Peresie H, Maher C, et al. Deficits in psychologic and classroom performance of children with elevated dentine lead levels.

N Engl J Med. 1979;300(13):689-95.

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COMMUNITY MEDICINE 12. Gloag D. A cooler look at lead. Br Med J (Clin Res Ed).

1983;286(6376):1458-9.

13. Pihl RO, Parkes M. Hair element content in learning disabled children. Science. 1977;198(4313):204-6.

14. Phil RO, Drake H, Vrana F. Hair analysis in learning and behaviour problems. In: Brown AC, Crounse RG (Eds.). Hair, Trace Elements and Human Illness. Praeger Publications; 1980. pp. 128-43.

18. Ahmed K, Ayana G, Engidawork E. Lead exposure study among workers in lead acid battery repair units of transport service enterprises, Addis Ababa, Ethiopia: a cross-sectional study. J Occup Med Toxicol (London, England). 2008;3:30.

19. Fatoki OS, Ayoade D. Lead assay in blood of occupationally and non-occupationally exposed donors. Int J Environ Health Res. 1996;6(3):195-200.

15. Thatcher RW, Lester ML, McAlaster R, Horst R. Effects of low levels of cadmium and lead on cognitive functioning in children. Arch Environ Health. 1982;37(3):159-66.

20. Bener A, Almehdi AM, Alwash R, Al-Neamy FR. A pilot survey of blood lead levels in various types of workers in the United Arab Emirates. Environ Int. 2001;27(4):311-4.

16. Chisolm JJ. Current status of lead exposure and poisoning in children. South Med J. 1976;69(5):529-31.

21. Aliasgharpour M, Hagani H. Impact of occupational lead exposure on industrial workers health condition in Tehran-Iran. Eastern J Med. 2005;10:20-3.

17. Hammond PB, Clark CS, Gartside PS, Berger O, Walker A, 22. Suwansaksri J, Teerasart N, Wiwanitkit V, Chaiyaset T. Michael LW. Fecal lead excretion in young children as High blood lead level among garage workers in Bangkok, related to sources of lead in their environments. Int Arch public concern is necessary. Biometals. 2002;15(4):367-70.

Occup Environ Health. 1980;46(3):191-202.

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Countrywide Pulse Polio Program for 2017 Launched by the President The Pulse Polio program for 2017 was launched by the President of India by administering polio drops to children less than 5 years old, at the Rashtrapati Bhawan. Union Minister of Health & Family Welfare Shri JP Nadda and Ministers of State (Health) Shri Faggan Singh Kulaste and Smt Anupriya Patel were also present on the occasion. Around 17 crore children of less than 5 years across the country will be given polio drops as part of the drive of Government of India to sustain polio eradication from the country.

The Union Minister for Health & Family Welfare Shri JP Nadda stated that polio-free certification of the entire South-East Asia Region of WHO including India on 27th March 2014 is a huge accomplishment in the history of public health. He added that as the risk of importation still persists from remaining three countries (Pakistan, Afghanistan and Nigeria) where poliovirus is still circulating, the need still persists for the country to maintain the population immunity and sensitive surveillance till global polio eradication happens. This is maintained through National and Sub National Polio rounds along with sustained high quality polio surveillance …

(Press Information Bureau, Ministry of Health and Family Welfare, 28th January, 2017)

Tight Glycemic Control in Critically-ill Children Offers no Advantage in Outcomes Children who were critically ill with hyperglycemia did not benefit from tight glycemic control targeted to a blood glucose level of 80-110 mg/dL compared with a level of 150-180 mg/dL, according to findings of the HALFPINT trial released at the Society of Critical Care Medicine Annual Congress in Honolulu, Hawaii and online January 24 by the New England Journal of Medicine. Children in whom hyperglycemia was tightly controlled also had higher rates of health care-associated infections and severe hypoglycemia (blood glucose level below 40 mg/dL). The trial was stopped early due to a low likelihood of benefit and evidence of the possibility of harm.

A New Online Hub for Affordable Insulin Initiative The American Diabetes Association (ADA) has unveiled a new online hub, makeinsulinaffordable.org, as part of its Stand Up for Affordable Insulin Initiative, which was launched in November 2016. The site houses key resources, including the Association's national petition for insulin affordability. The Association's petition calls for all entities in the insulin supply chain to increase transparency and ensure that no person with diabetes is denied affordable insulin, and for Congress to hold hearings with these entities to identify the reasons for the dramatic increases in insulin prices and take action to protect Americans with diabetes… (ADA, January 25, 2017)

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Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

2017

ENT

Pyogenic Granuloma of Hard Palate Masquerading as Papilloma: A Case Report BHUSHAN KATHURIA*, HIMANI DHINGRA†, VIKRANT KAMBOJ‡, SAMAR PAL SINGH YADAV#

ABSTRACT Pyogenic granuloma is a kind of reactive inflammatory hyperplasia mostly seen in the oral cavity. Gingiva is the most common site of involvement (75%), other extragingival sites involved are lips, tongue and buccal mucosa. Here we discuss a case of pyogenic granuloma of hard palate in a 4-year-old female child, which we find very interesting because of an unusual age and site of presentation; this was initially considered as a case of papilloma of hard palate but later on, it was confirmed to be pyogenic granuloma after surgical excision and histopathological examination.

Keywords: Pyogenic granuloma, papilloma, hard palate, histopathological examination

P

yogenic granuloma is primarily an oral disease which appears in the mouth as an overgrowth of tissue considered to be non-neoplastic, inflammatory hyperplasia due to chronic irritation, physical trauma or hormonal factors.1 On the other hand, oral squamous papillomas are benign proliferating lesions induced by human papillomavirus (HPV). Gingiva is the predominant site followed by lips, tongue, buccal mucosa and hard plate. Extragingival pyogenic granuloma of hard palate in a adult is already reported in literature.2

50 years, and sometimes can occur before the age of 10 years.3 Although pyogenic granuloma may occur in all ages, it is predominant in the second decade of life in young adult females, possibly because of the vascular effects of female hormones.4 Papillomatous lesion can occur in pediatric age group due to known etiopathogenic factors like HPV infection. But pyogenic granuloma is a very rare presentation in this age group.

Clinically, these lesions are asymptomatic, painless and slowly growing masses. As an oral lesion, these raise concern because of their clinical appearance.

These lesions commonly occur between age 30 and

A 4-year-old female child presented to us with 4-month history of swelling over hard palate. Clinical history revealed that the growth had started as a small nodule, which gradually increased to the present size with history of occasional bleeding from the lesion that prompted the patient bystander to seek treatment.

No other complaints of pain or any feeding difficulty were present. Family and medical history revealed no abnormalities.

*Resident Dept. of Otolaryngology and Head and Neck Surgery Pt. BD Sharma PGIMS, Rohtak, Haryana †Resident Dept. of Pediatric KEM Hospital, Parel, Mumbai, Maharashtra ‡Resident Dept. of Otolaryngology and Head and Neck Surgery Kasturba Medical College, Mangalore, Karnataka #Senior Professor and Head Dept. of Otolaryngology and Head and Neck Surgery Pt. BD Sharma PGIMS, Rohtak, Haryana Address for correspondence Dr Bhushan Kathuria Resident Dept. of Otolaryngology and Head and Neck Surgery Pt. BD Sharma PGIMS, Rohtak, Haryana E-mail: kathuriabhushan56@gmail.com

CASE REPORT

On intraoral examination, a single, well-defined, exophytic, pedunculated lesion was evident in the mid-palatal region, measuring around 0.8 × 1.2 cm in size with irregular margins and lobulated surfaces and it was purplish red in color. The lesion was firm in consistency, nontender to touch with smooth lobulated surfaces and having a wide pedunculated base. The lesion was surrounded by ulcerated mucosa anteriorly with evidence of bleeding from lesion (Fig. 1). The oral hygiene status was fair. Clinically, lesion was considered as papilloma of hard palate and

Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

841

ENT DISCUSSION

Figure 1. A exophytic mass over hard palate with ulcerated mucosa anteriorly.

Figure 2. Stratified squamous orthokeratinized epithelium covering cellular connective tissue, lobular arrangement of multiple capillaries lined by endothelial cells, and edematous stroma with inflammatory cell infiltration and fibroblast proliferation.

it was planned to excise it. Systemic examination did not reveal any abnormal finding. An excisional biopsy was done under general anesthesia and specimen was sent for histopathological examination.

Histopathological examination of the specimen revealed stratified squamous orthokeratinized epithelium covering the cellular connective tissue with a lobular arrangement of multiple capillaries lined by endothelial cells, and edematous stroma with inflammatory cell infiltration and fibroblast proliferation in routine hematoxylin and eosin (H&E)-stained sections of formalin-fixed, paraffin-embedded materials. There was no evidence of atypia or malignancy. Since histopathologically, there was presence of capillaries with lobular arrangement and there was evidence of inflammation, a diagnosis of pyogenic granuloma was considered over clinically papillomatous lesion (Fig. 2).

Patient was on regular follow-up; at 18-month, there was no evidence of any recurrence.

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Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

Pyogenic granuloma is a misnomer as the lesion is not associated with pus formation and histologically the lesion is not composed of granulation tissue.

Clinically, the lesions show necrotic white material which resembles pus, that impelled clinicians to refer to these lesions as pyogenic granulomas.1 Gingiva is the predominant site followed by lips, tongue, buccal mucosa and hard plate.3 Intraorally, it can present with a wide array of clinical appearances, ranging from a sessile lesion to an elevated mass. Pyogenic granulomas generally are soft, painless and deep red to reddishpurple in color depending on the age of the lesion.5 Because of a wide array of clinical appearances of these lesions and sometime unusual site of presentation, it is very difficult to reach a confirmatory diagnosis clinically. Differential diagnosis of such lesions firstly should be squamous papilloma; the clinical presentation of the lesion as a single papillomatous painless mass gave the clue towards papilloma. Other differentials which should be included are peripheral giant cell granuloma, peripheral ossifying fibroma, metastatic cancer, hemangioma, pregnancy tumor, conventional granulation tissue hyperplasia, Kaposi's, sarcoma, bacillary angiomatosis and non-Hodgkin's lymphoma.6,7 Excision and biopsy of such type of lesions is the recommended line of treatment, unless it would produce a marked deformity and in such a case incisional biopsy is recommended. The histopathological examination is an important tool to make a proper diagnosis of such an atypical presentation and its adequate management. These patients should be followed up for long duration for early detection of any recurrence, because of notorious nature of these lesion for higher recurrences. There are various studies in literature that have reported recurrence rate ranging from 5% to 16%; incomplete excision, failure to remove etiologic factors or repeated trauma contributes to recurrence of these lesions.5,8,9 We followed our patient for 36 months; there was no evidence of recurrence. But still there is chance of recurrence during puberty and pregnancy since patient is a female, which is a very high risk factor for recurrence. Now-a-days, various other treatment modalities such as use of Nd:YAG laser, carbon dioxide laser, flash lamp pulse dye laser, cryosurgery, electrodessication, sodium tetradecyl sulfate sclerotherapy and use of intralesional steroids have been used for treatment of pyogenic granulomatous lesions with minimal or no recurrence rate by various clinicians.10,11

ENT CONCLUSION The clinical diagnosis of such an uncommon presentation can be quite challenging as they sometimes may mimic more serious lesions such as malignancies. We would like to conclude that though pyogenic granulomas of hard palate are less common in pediatric age group, but their possibility should always be kept in mind whenever dealing with the swellings of hard palate as there are various treatment modalities with no or minimal recurrence. If the surgical excision with cold knife is planned for such lesions, it should always be followed by histopathological examination and patient should be closely followed up for long duration for diagnosis of early recurrence and their adequate management.

REFERENCES 1. Bouquot JE, Nikai H. Lesions of the oral cavity. In: Gnepp DR (Ed.). Diagnostic Surgical Pathology of Head and Neck. Philadelphia: WB Saunders; 2001. pp.

141-233.

2. Patil K, Mahima VG, Lahari K. Extragingival pyogenic granuloma. Indian J Dent Res. 2006;17(4):199-202.

4. Ojanotko-Harri AO, Harri MP, Hurttia HM, Sewón LA. Altered tissue metabolism of progesterone in pregnancy gingivitis and granuloma. J Clin Periodontol.

1991;18(4):262-6.

5. Bhaskar SN, Jacoway JR. Pyogenic granuloma - clinical features, incidence, histology, and result of treatment: report of 242 cases. J Oral Surg. 1966;24(5):391-8.

6. Kamal R, Dahiya P, Puri A. Oral pyogenic granuloma: Various concepts of etiopathogenesis. J Oral Maxillofac Pathol. 2012;16(1):79-82.

7. Eversole LR. Clinical Outline of Oral Pathology: Diagnosis and Treatment. 3rd Edition, Hamilton: BC Decker; 2002. pp. 113-4.

8. Al-Khateeb T, Ababneh K. Oral pyogenic granuloma in Jordanians: a retrospective analysis of 108 cases. J Oral Maxillofac Surg. 2003;61(11):1285-8.

9. Vilmann A, Vilmann P, Vilmann H. Pyogenic granuloma: evaluation of oral conditions. Br J Oral Maxillofac Surg.

1986;24(5):376-82.

10. Parisi E, Glick PH, Glick M. Recurrent intraoral pyogenic granuloma with satellitosis treated with corticosteroids.

Oral Dis. 2006;12(1):70-2.

11. Sacchidanand S, Purohit V. Sclerotherapy for the treatment of pyogenic granuloma. Indian J Dermatol. 2013;58(1): 3. Jafarzadeh H, Sanatkhani M, Mohtasham N. Oral pyogenic granuloma: a review. J Oral Sci. 2006;48(4):167-75.

77-8.

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New IDSA Guidelines on Diagnosis of TB in Adults and Children A task force supported by the American Thoracic Society (ATS), Centers for Disease Control and Prevention (CDC) and Infectious Diseases Society of America (IDSA) has published new guidelines on the diagnosis of tuberculosis (TB) and latent TB infection (LTBI) in adults and children.

The guidelines published in the January 2017 issue of the Clinical Infectious Diseases journal include 23 evidencebased recommendations about diagnostic testing for LTBI, pulmonary TB and extrapulmonary TB. The six strong recommendations include: ÂÂ

An interferon-gamma release assay (IGRA) rather than a tuberculin skin test (TST) should be done in individuals 5 years or older who are likely to be infected with Mtb, who have a low or intermediate risk of disease progression, and in whom it has been decided that testing for LTBI is warranted.

ÂÂ

Acid-fast bacilli (AFB) smear microscopy is recommended in all patients suspected of having pulmonary TB.

ÂÂ

Rapid molecular drug susceptibility testing for rifampin with or without isoniazid is recommended using the respiratory specimens of persons who are either AFB smear positive or Hologic Amplified MTD positive and who meet one of the following criteria: (1) have been treated for TB in the past; (2) were born in or have lived for at least 1 year in a foreign country with at least a moderate TB incidence (≥20 per 1,00,000) or a high primary multidrug-resistant TB prevalence (≥2%); (3) are contacts of patients with multidrug-resistant TB, or (4) are HIV-infected.

ÂÂ

Mycobacterial cultures should be done on specimens collected from sites of suspected extrapulmonary TB.

ÂÂ

Genotyping should be done on one culture isolate from each mycobacterial culture-positive patient.

Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

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GASTROENTEROLOGY

5’-Nucleotidase Activity, Oxidative Stress and Antioxidant Activity in Cirrhotic and Alcoholic Patients TARANNUM FATIMA SUBHANI*, MD ABU NASAR†, RAJIV RANJAN SINHA†, IJEN BHATTACHARYA*

ABSTRACT Background: The present study was undertaken to estimate the 5’-nucleotidase (5’-NT) enzyme in liver cirrhosis and alcoholics.

The oxidative stress, antioxidants and their correlation with 5’-NT was also included in this study. Material and methods: The blood samples of 25 subjects (age- and sex-matched) each from Group I (control), Group II (alcoholic) and Group III (cirrhotic) was taken and centrifuged for separation of plasma for analysis of 5’-NT. The separated cells were washed thrice with 0.9% w/v cold normal saline and used for the analysis of glutathione, malondialdehyde and superoxide dismutase. Results: The activity of serum 5’-NT was significantly increased in both cirrhotics and alcoholics. The levels of malondialdehyde were also significantly increased in both cirrhotic and alcoholic patients. The levels of glutathione and superoxide dismutase were significantly decreased in both cirrhotics and alcoholics. Conclusions: From these findings, it was concluded that the activity of serum 5’-NT rises consistently in cirrhotic and alcoholics according to the extent of liver damage, hepatobiliary damage and biliary stasis and can be a useful marker for diagnosis of hepatobiliary disorders.

Keywords: Alcoholics, antioxidant effects, cirrhotics, 5’-nucleotidase, oxidative stress

5

’-nucleotidase (5’-NT), an intrinsic membrane glycoprotein, present as an ectoenzyme in a wide variety of mammalian cells, hydrolyzes 5’-nucleotides to their corresponding nucleosides.1 Elevations in the 5’-NT serum levels appear to be restricted to intrahepatic or extrahepatic obstructive disease with no change in other organs disease.2 It is measured as an indicator of liver damage resulting primarily from interference with the secretion of bile.2 Enzyme activity elevates in all diseases including liver cirrhosis, chronic alcoholism, neoplasms of liver and bile ducts, benign biliary disease but reaches its highest level in the presence of biliary stasis.3,4 5’-NT is also a sensitive marker for hepatic metastasis either by itself or in combination with other enzymes. The diagnostic value of 5’-NT has been shown to be superior to

*Dept. of Biochemistry Rama Medical College Hospital and Research Centre, Hapur, Ghaziabad, Uttar Pradesh †Dept. of Biochemistry Nalanda Medical College, Patna, Bihar Address for correspondence Dr Tarannum Fatima Subhani Associate Professor Dept. of Biochemistry Rama Medical College Hospital and Research Centre, Hapur, Ghaziabad, Uttar Pradesh E-mail: drtarannum_fatima@rediffmail.com

other liver enzymes, especially in liver metastasis.

Raised levels of 5’-NT activities are found in 92% of patient with obstructive jaundice, 70% of patients with parenchymal liver disease and 81% of patients with hepatic metastasis.5,6 It is also reported that serum 5’-NT is clinically useful for differential diagnosis of hepatobiliary and osseous diseases, the enzyme activity being increased only in hepatobiliary disease.7 Because, it is a plentiful primary liver enzyme, the 5’-NT may be more readily influenced, by minute areas of obstruction than is the alkaline phosphatase.2,8 Although determination of either oxidants or antioxidant components alone may give information about the oxidative stress, determination of oxidants along with antioxidants is more useful in this context.9 Oxidative stress has been implicated in liver cirrhosis.

Studies suggested that evidence of oxygen free radical is found early in the development of fibrosis and cirrhosis of liver.10 Patients suffering from liver disease either due to nonalcohol or excessive alcohol intake show depletion of antioxidants such as glutathione (GSH) and superoxide dismutase (SOD) and increased concentration of products of lipid peroxidation such as malondialdehyde (MDA).11-19 Depletion of antioxidants such as GSH occurs as a result of decreased production from the diseased liver and consumption of antioxidants due to increased oxidative

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GASTROENTEROLOGY stress. Depletion of antioxidants renders the cell more susceptible to oxidative stress. Antioxidant and stressrelated enzymes might be able to determine the degree of liver damage.16-19 Hepatic fibrogenesis in alcoholic liver cirrhosis is an intricate process, which appears to involve metabolic products of ethanol oxidation; cytochrome P450 induction, enhanced oxidative stress, depletion of antioxidant defenses, lipid peroxidation, generation of aldehydic products, the effects of mitogenic and fibrogenic cytokines and complex interactions between liver parenchymal and nonparenchymal cells, with hepatic stellate cells (Ito cells, hepatic lipocyte or fat storing cell) are now recognized as the primary source of extracellular matrix.20,21 There is evidence that the diseased liver of patients with cholestatic liver disease is exposed to oxidative stress associated with increased lipid peroxidation involving intraorgan generation of reactive oxygen species (ROS), possibly mediated by endotoxins, bile acids and accumulation of degradative products of lipid peroxidation, such as lipid peroxides and MDA.20,22 Alcohol promotes the generation of ROS and/or interferes with the body’s normal defense mechanism against these compounds.23 Studies suggest that evidence of oxygen free radicals is also found early in the development of fibrosis and cirrhosis of liver.10 The present study was therefore undertaken to estimate the 5’-NT enzyme in liver cirrhosis and alcoholics. The oxidative stress, antioxidants and their correlation with 5’-NT was also included in this study.

MATERIAL AND METHODS

Subjects This study was conducted on 3 groups of 25 subjects each in the age group of 35-70 years. Thirteen males and 12 females were used in each group. ÂÂ

Group I: Consisted of 25 healthy individuals (13 males and 12 females) between the age group of 35-70 years having no history of any liver disease and no history of alcohol intake in the past or present, hereafter referred to as ‘control group’.

ÂÂ

Group II: Consisted of 25 individuals (13 males and 12 females) between the age group of 35-70 years with a history of 10 years or more of alcohol intake without any history of liver disease or other hepatobiliary disorders hereafter referred to as ‘alcoholic group’.

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Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

ÂÂ

Group III: Consisted of 25 patients (13 males and 12 females) diagnosed to have cirrhosis of liver with either history of jaundice, alcohol intake or hepatotoxic drug intake, hereafter referred to as ‘cirrhotic group’.

Selection of Cases The test Group III for this study consisting of 25 patients of cirrhosis of liver were taken from the following hospitals in Patna: ÂÂ

Nalanda Medical College and Hospital, Patna, India

ÂÂ

Patna Medical College and Hospital, Patna, India

ÂÂ

Alam Clinic, Patna, India.

The test Group II for the study consisting of 25 individuals with history of alcoholism were taken by personal contact from known alcoholics. While choosing the subject for the test and control groups, care was taken to eliminate subjects with habits like smoking, tobacco chewing, chronic inflammatory diseases like tuberculosis, rheumatoid arthritis, diabetes mellitus and malignancy, all of which play a vital role in contributing to oxidative stress injury.

Care was also taken to eliminate those with any bone disease or any other clinical conditions that might be involved in raised 5’-NT activity. Approval to carry out these studies on human subjects was obtained from Institutional Clinical Ethics Committee of Nalanda Medical College, Patna, India and their guidelines were followed for these studies.

Sample Collection Two milliliters of venous blood was collected in a plain vial for serum separation for the analysis of 5’-NT. Five milliliters of venous blood was collected in separate ethylenediaminetetraacetic acid (EDTA) containers from the median cubital vein or basilic vein of the study subjects under strict aseptic precautions.

From this, 0.2 mL of whole blood was used for GSH estimation; the rest of the sample was centrifuged at 3,000 rpm for 10 minutes within 3-hour of collection.

Plasma was discarded. The sediment was used to prepare the erythrocyte suspension and used for the assay of MDA and SOD. Preparation of Erythrocyte Suspension The sediment separated was washed thrice with 0.9% cold normal saline, after which they were suspended in an equal volume of the same saline solution. This was then stored as 50% cell suspension at 4-5°C and was used for the assay of MDA and SOD.

GASTROENTEROLOGY 5’-Nucleotidase Determination

Glutathione

Serum 5’-NT enzyme was estimated using reported method:5

Whole blood GSH level was measured by the method of Beutler et al.25 To, 0.2 mL of whole blood, 1.8 mL of distilled water was added and mixed; 3 mL of precipitating solution was added, mixed and allowed to stand for 10 minutes at room temperature. This mixture was then centrifuged. To, 2 mL of supernatant, 8 mL of phosphate solution (0.4 M) and 1 mL of DTNB reagent was added. The absorbance was read at 412 nm.

Two test tubes were set up as follows: ÂÂ

Total activity: 0.2 mL of serum was added, 0.1 mL of 0.02 M manganous sulfate and 1.5 mL of 40 mM, pH 7.5 barbitone buffer.

ÂÂ

Nonspecific alkaline phosphatase activity: 0.2 mL of serum was added, 0.1 mL of 0.02 M manganous sulfate, 1.3 mL of 40 mM, pH 7.5 barbitone buffer and 0.2 mL of 0.1 M nickel chloride.

ÂÂ

Both test tubes warmed to 37°C and then 0.2 mL, 10 mM adenosine 5’-phosphate was added to each test tube and incubated at 37°C for 30 minutes. Then 2 mL of 10% trichloroacetic acid (TCA) was added, mixed well and was centrifuged after allowing it to stand briefly. Two milliliters of supernatant were taken (=0.1 mL serum) for estimation of inorganic phosphorous. For the blank and standard, 1 mL of water and 1 mL of the phosphate standard (stock solution containing 6 mM/L) were taken for use, each with 1 mL of TCA added. To all four tubes 3 mL 2 M, pH 4.0 acetate buffer, 0.5 mL of 5% ammonium molybdate and 0.5 mL metol (2 g metol and 10 g sodium sulfite in water made up to 100 mL) were added and mixed, allowed to stand for 10 minutes and then reading was taken using a red filter or at 680 nM.

Malondialdehyde Red cell lipid peroxidation was studied as thiobarbituric acid (TBA) reaction products. The method of Stocks and Dormandy was followed with certain modifications.24 One milliliter of erythrocyte suspension was added to 8.5 mL of 0.9% normal saline and mixed well.

Next 0.5 mL of 0.44 M H2O2 (hydrogen peroxide) was added. From the above mixture, 2.5 mL of aliquot was immediately taken, to which 1 mL of 28% TCA, in 0.1 M sodium metaarsenite was added. This was mixed well and allowed to stand for 10 minutes, after which it was centrifuged.

Three milliliters of the supernatant was then taken to which 1 mL of 1% TBA in 50 mM sodium hydroxide (NaOH) was added. This was then kept in a boiling water bath for 15 minutes and immediately cooled under tap water. The pink chromogen was read at 535 nm in a spectrophotometer. Values were expressed as nanomoles of MDA formed per deciliter of red blood cell (RBC), taking the molar extinction co-efficient as 1.56 × 105.

Superoxide Dismutase The method of Fridovich was followed for estimation of SOD.26 Inhibition of the reduction of nitroblue tetrazolium (NBT) by superoxide radicals, generated by the illumination of riboflavin in the presence of oxygen, an electron donor. Methionine was used as a basis for the assay of SOD. Preparation of Hemolysate This was done by the method of McCord and Fridovich.27 To 1 mL of erythrocytes (washed with 0.9% normal saline) was added 1 mL of deionised water to lyse the cells. To this was added 0.5 mL of distilled ethanol followed by 0.3 mL of chloroform and mixed well. It was allowed to stand for 15 minutes and then 0.2 mL of H2O was added and centrifuged at 40C. The supernatant contains SOD activity and was used for the assay of SOD, after dilution with potassium phosphate buffer (pH 7.8, 0.05 M); 0.1 mL of hemolysate was diluted with 1.9 mL of potassium phosphate buffer.

Finaly, it was the diluted hemolysate that was used in the procedure given below.

Four test tubes were taken and labeled as ‘Test’, ‘Control’, ‘Test blank’ and control blank’, respectively.

To the test 2.9 mL of reaction mixture with NBT containing 149 mg of methionine, 4.93 mL of NBT (1 mg/mL), 0.63 mL of riboflavin (1 mg/mL) and made up to 100 mL with potassium phosphate buffer (pH 7.8/0.05 M) and 0.1 mL of diluted hemolysate was added. To the ‘Test blank’ 2.9 mL of same reaction mixture without NBT and 0.1 mL of diluted hemolysate was added.

To the ‘Control test’ 2.9 mL of the same reaction mixture with NBT and 0.1 mL of potassium phosphate buffer (pH 7.8/0.05 M) was added. To the ‘Control blank’ 2.9 mL of the same reaction mixture without NBT and 0.1 mL of potassium phosphate buffer (pH 7.8/0.05 M) was added. Each of these mixtures were now taken in a 10 mL beaker. The beakers were kept in an aluminum foil lined box fitted with a 15 W fluorescent lamp for 10 minutes. The absorbance was read at 560 nm in a spectrophotometer for all the four beakers.

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GASTROENTEROLOGY Estimation of Hemoglobin The hemoglobin content of erythrocytes was determined by the cyanmethemoglobin method.28 Hemoglobin was treated with a reagent containing potassium ferricyanide, potassium cyanide and potassium dihydrogen phosphate (Drabkin’s Reagent). The ferricyanide oxidizes hemoglobin to methemoglobin, which is converted to cyanmethemoglobin by the cyanide. Absorbance was measured at 540 nm in a spectrophotometer.

Statistical Analysis All the biochemical parameters were compared using Fisher’s ‘F’ test for analysis of variance (ANOVA).

The statistical software “SPSS Version 11” (Statistical Package for Social Sciences) was used for this purpose.

RESULTS AND DISCUSSION In this study, the serum 5’-NT level, the product of lipid peroxidation and antioxidant level were compared between cirrhotic patients, alcoholics and normal individuals taken as controls of the same age group.

5’-Nucleotidase The activity of this enzyme is distinguished from that of a nonspecific alkaline phosphatase by nickel inhibition and the inorganic phosphate released from adenosine monophosphate used as a substrate.29 This method was chosen due to its reliable analytical qualities and is appropriate for routine diagnostics.4 Serum 5’-NT activity in this study was highest in cirrhotic group.

Relatively high but less than cirrhotic and more than control in alcoholic group, and it was found to be lowest in controls (Table 1). The values were statistically highly significant (p < 0.001) on comparison between the three groups.

Its highest level (20.56 ± 2.16 IU/L) in cirrhotic group appeared to be indicative of greater sensitivity for intrahepatic obstruction or liver cell damage.2 Because, it is a plentiful primary liver enzyme, 5’-NT may be

more readily influenced by minute areas of obstruction.

Its high level in cirrhotic group is suggestive of intrahepatic obstruction of bile canaliculi due to fibrosis as a result of liver cell injury. Measurement of 5’-NT has been used in the early detection of pericholangitis in patients with ulcerative colitis.1,2 5’-NT activity is also elevated early in congestive heart failure (CHF) with secondary passive congestion in the liver. 5’-NT, when abnormal in the nonicteric patient with other normal liver function tests, would be highly suggestive of hepatic tumor.1,2 Its relatively higher activity (17.62 ± 1.73 IU/L) in the alcoholic group found support in a previous report that increased nucleic acid catabolism in chronic alcohol toxicity lead to its elevation as the enzyme is related to the breakdown of nucleic acid, especially mRNA. Chronic alcoholism produces a wide spectrum of liver and other organ diseases depending on the amount and duration of alcohol intake. The effect on liver range from fatty change to hepatitis and cirrhosis and the activity of 5’-NT will also be ranging as per the damage done to the liver cells and bile canalicular membranes resulting in mild-to-moderate biliary stasis. 5’-NT enzyme is induced in alcoholism.

Of importance is the fact that increased 5’-NT activity in the serum of patients identified with high probability of the presence of liver disease confirms that any increase in 5’-NT activity is highly specific for hepatobiliary disease.1,2 It has been observed and confirmed by several studies that serum 5’-NT is clinically useful for differential diagnosis of hepatobiliary and osseous diseases, the enzyme activity being increased only in hepatobiliary diseases.2

RBC Malondialdehyde As a measure of oxidative stress, MDA, the end-product of lipid peroxidation was estimated by the TBA method because of the ease with which this method can be used as an indicator of lipid peroxidation and free radical activity in biological samples. RBC of MDA levels in this study were highest in cirrhotic group (749.36 ± 57.77 nmol/100 mL) as shown in Table 2. MDA level was relatively lower in alcoholic group (608.16 ±

Table 1. Mean 5’-nucleotidase Activity of Control, Alcoholic and Cirrhotic Groups Groups

N

Mean (IU/L)

SD

P value

Remarks

Control

25

12.98

1.52

Alcoholics

25

17.62

1.73

<0.001

HS

Cirrhotics

25

22.56

2.16

<0.001

HS

-

Name of the test used-Fishers ‘F’ test → for analyses of variance (ANOVA), N = No. of subjects, SD = Standard deviation, ‘P’ value = Probability, HS = Highly significant.

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Table 2. Mean MDA Levels of Control, Alcoholic and Cirrhotic Groups Groups

N

Mean (nmol/100 mL)

SD

P value

Remarks

Control

25

504.24

95.19

Alcoholics

25

608.16

71.14

<0.001

HS

Cirrhotics

25

749.36

57.77

<0.001

HS

GASTROENTEROLOGY 71.14 nmol/100 mL), and it was found to be lowest in controls (504.24 ± 95.19 nmol/100 mL). The values were statistically highly significant (p < 0.001) on comparison between 3 groups. Its high levels in both cirrhotics and alcoholics were suggestive of increased oxidative stress in patients of cirrhosis of liver as well as in alcoholics.23 These findings agreed with the result of several studies, which have confirmed involvement of free radicals in the pathogenesis of liver injury in case of cirrhosis of liver and chronic alcoholism.30,31

Glutathione and Superoxide Dismutase Blood GSH levels in this study were highest in control group (57.52 ± 5.96 mg/dL), relatively less in alcoholic group (43.75 ± 5.79 mg/dL) and lowest in cirrhotic group (23.23 ± 6.97 mg/dL) as shown in Table 3. The values were statistically highly significant (p < 0.001) when a comparative analysis was done between the 3 groups.

The enzyme SOD activity was measured by the method of Fridovich. The RBC of SOD values were also highest in control group (8075.60 ± 399.85 U/g), relatively less in alcoholic group (6228.72 ± 631.16 U/g) and lowest in cirrhotic group (4945.64 ± 442.44 U/g) as shown in Table 4.

The results were statistically very highly significant (p < 0.001) on comparative analysis.

GSH was chosen in this study because it represents the most abundant natural antioxidant in our body.

GSH is of major importance in the reduction of H2O2 and organic peroxides (e.g., lipid peroxides) in a reaction that is catalyzed by selenium-containing GSH peroxidase and by other proteins that also exhibit GSHS-transferase (GST) activity.32 It is the major endogenous Table 3. Mean Glutathione Level of Control, Alcoholic and Cirrhotic Groups Groups

N

Mean (mg/dL)

SD

P value

Remarks

Control

25

57.52

5.96

Alcoholics

25

43.75

5.79

<0.001

HS

Cirrhotics

25

23.23

6.97

<0.001

HS

Table 4. Mean SOD Level of Control, Alcoholic and Cirrhotic Groups Groups

N

Mean (U/g)

SD

Control

25

8075.60

399.85

P value Remarks

Alcoholics

25

6228.72

631.16

<0.001

HS

Cirrhotics

25

4945.64

442.44

<0.001

HS

antioxidant produced by the cell. It participates directly in the neutralization of free radicals, reactive oxygen compounds and maintains exogenous antioxidants such as vitamins C and E and also plays a role in the detoxification of many xenobiotics.23 It is an essential component of human immune response. It is also involved in the synthesis and repair of DNA. SOD was chosen in this study as it plays a role in the removal of H2O2 formed in red cells and because hemoglobin and SOD have been shown to be in close association in red cells. In addition to this, some studies have documented that SOD is one of the most important enzymes in the front line of defense against oxidative stress and is more effective in protecting the RBCs against damage by exogenous H2O2, especially at higher concentration.

The low levels of GSH and SOD in cellular and extracellular fluids reduce their oxygen-derived free radical (ODFR) scavenging capacity making the tissues more vulnerable to ODFR damage.33 The low level of GSH and SOD in cirrhotics and alcoholics is indicative of increased oxidative stress in patients of liver cirrhosis as well as alcoholics.30 Increased lipid peroxides (MDA) and a decrease in antioxidants (GSH and SOD) in RBC of cirrhotic patients shows an altered oxidant and antioxidant status.30 Several factors contribute to the fall in GSH and SOD level in alcoholics and cirrhotic patients, most important being oxidative stress, which occurred in this study. Depletion of GSH renders the cell more susceptible to oxidative stress.

Decrease of GSH in cirrhotic patients is probably related to a reduced synthesis of the tripeptide by the diseased liver. A greatly increased production of reactive oxygen metabolites might overpower the capacity of the tissue to synthesize or regenerate sufficient amounts of GSH resulting in a decrease in GSH concentration.16,19 Low GSH in the presence of good nutrition in cirrhotics and alcoholics suggest a decreased efflux of GSH from liver.16 Our results show that antioxidant barrier in liver cirrhosis is impaired, associated with decrease of GSH level and also activity of the antioxidant enzyme SOD.18,19 Alcohol has been shown to deplete GSH levels, particularly in the mitochondria, which normally are characterized by high levels of GSH needed to eliminate the ROS generated during activity of the respiratory chain. Mitochondria cannot synthesize GSH, but import it from the cytosol.23

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GASTROENTEROLOGY Reduced GSH in cirrhotics and alcoholics was consistent with other reports.19 This observation may be explained on the basis of: ÂÂ

Its utilization in scavenging the free radicals.

ÂÂ

Its involvement in maintaining non-GSH critical protein sulfhydryls in reduced state.

ÂÂ

Acting as co-factor for GSH during detoxification of xenobiotics including alcohol.

ÂÂ

Oxidation of GSH to its oxidized form by GSH peroxidase in detoxification of H2O2 and/or lipid peroxides.

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Suppression of GSH synthesis by ethanol. Greater degree of reduction in GSH in alcoholic cirrhotics may be because of synergistic action of alcohol and cirrhosis of liver.

Lowest level of GSH found in our study in cirrhotics indicate that GSH antioxidant system in cirrhosis is imbalanced and support the hypothesis that oxidative stress plays an important role in the development of liver cirrhosis.19 Low levels of SOD activity observed in cirrhotics and alcoholics are indicative of oxidative stress that may be responsible for maximal destruction in liver architecture.

A markedly lower SOD activity observed in cirrhotics indicates that the oxidative stress is much profound in cirrhosis of liver than alcoholics, as liver cirrhosis is a common outcome of a variety of chronic liver diseases.22 Significant increase in MDA levels in cirrhotics and alcoholics suggest that cirrhotics and alcoholics are subjected to more oxidative stress. Alcoholic cirrhotics seem to have still greater degree of oxidative stress, which may be due to compounding effect of alcohol.

A decreased level of both GSH and SOD in the present study suggests that with increase in oxidative stress, there is corresponding proportionate decrease in antioxidant defense system in cirrhotics and alcoholics.

Antioxidants and stress-related enzymes might be able to determine the degree of liver damage. The differences between the groups might be based on the type of liver pathology rather than its etiology (i.e., alcohol and nonalcohol related causes).

The implication of oxidative stress in alcoholic liver damage gives a rationale to the clinical application of therapies aimed to prevent or reduce ethanol-induced oxidative damage by antioxidant compounds. The parameters of lipid peroxidation and antioxidant defenses may be useful surrogate markers for monitoring patients with liver disease during hepatoprotective treatment.15 Mapping the broader time structure with age and multifrequency rhythm characteristics of

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antioxidants and pro-oxidants is needed for exploring their putative role as markers in the treatment and management of liver cirrhosis.

In summary, our results show that the antioxidant potential in cirrhosis and alcohol is unbalanced which leads to an increase in ROS action. In cirrhotics and alcoholics, the MDA level is increased, both GSH and SOD levels are decreased. These results are consistent with the finding of several studies already discussed.

The positive significant correlation between MDA and 5’-NT in cirrhotic group suggest that in case of cirrhosis of liver in addition to increased level of MDA due to increased lipid peroxidation as a result of oxidative stress, there is simultaneous consistent increase in the activity of 5’-NT as a result of biliary obstruction due to fibrosis of the canalicular membranes and sinusoids in the liver tissue. There is also positive significant correlation between SOD and 5’-NT in alcoholic group.

This finding may be explained on the basis that in case of alcoholics the SOD activity was relatively lower than controls but more than cirrhotics and the 5’-NT activity was also relatively lower than cirrhotics but more than controls.

From these findings, we can conclude that the activity of 5’-NT rises consistently in cirrhotics and alcoholics according to the extent of damage to the liver and there is an increase in oxidative stress and decrease of antioxidant status in both cirrhosis of liver patients and alcoholics, but the extent of oxidative stress is more profound in cirrhotics than alcoholics.

CONCLUSION This study attempts to establish the extent of rise of serum 5’-NT activity in cirrhotic patients and alcoholic in respect of normal individuals (controls). This study also attempts to establish the extent of oxidative stress and antioxidant status in cirrhotic patients and alcoholics.

The results of the above study can be summarized as follows: ÂÂ

The activity of serum 5’-NT was significantly increased in both cirrhotics and alcoholics, but increase was very high in cirrhotic patients.

ÂÂ

The levels of MDA were significantly increased in both cirrhotics and alcoholics but increase was very high in cirrhotic patients.

ÂÂ

The levels of GSH were significantly decreased in both cirrhotics and alcoholics, but decrease was more in cirrhotic patients.

GASTROENTEROLOGY ÂÂ

The levels of SOD were significantly decreased in both cirrhotics and alcoholics but decrease was more in cirrhotic patients.

From these findings, we can conclude that the activity of serum 5’-NT rises consistently in cirrhotic and alcoholics according to the extent of liver damage, hepatobiliary damage and biliary stasis and can be a useful marker for diagnosis of hepatobiliary disorders. We can also conclude that there is an increase in oxidative stress and decrease of antioxidant status in both cirrhosis of liver patients and alcoholics, but the extent of oxidative stress is more profound in cirrhotics than in alcoholics with or without any history of hepatobiliary diseases.

The parameters of lipid peroxidation and antioxidant defense may be useful markers for monitoring patients with hepatobiliary disorders.

Acknowledgment The authors are grateful to Nalanda Medical College, Patna, India for providing facilities to carry out these studies.

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1975;44:147-59.

31. Ljubuncic P, Tanne Z, Bomzon A. Evidence of a systemic phenomenon for oxidative stress in cholestatic liver disease. Gut. 2000;47(5):710-6.

27. McCord JM, Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein).

J Biol Chem. 1969;244(22):6049-55.

32. Meister A. Selective modification of metabolism. Science. 1983;220(4596):472-7.

glutathione

33. Gupta VK, Mallika V, Gupta Y, Srivastava DK. Oxygen 28. Drabkin DL, Austin JM. Spectrophotometric constants derived free radicals in clinical context. Indian J Clin for common haemoglobin derivatives in human, dog and Biochem. 1992;7(1):3-10. rabbit blood. J Biol Chem. 1932;98:719-33.

■■■■

ACG Clinical Guideline on Treatment of H. pylori Infection The American College of Gastroenterology has published clinical guidelines on the treatment of Helicobacter pylori (H. pylori) infection. History of previous antibiotic exposure should be noted. If a patient received a firstline treatment containing clarithromycin, bismuth quadruple therapy or levofloxacin salvage regimens are the preferred treatment options. If a patient received first-line bismuth quadruple therapy, clarithromycin or levofloxacin-containing salvage regimens are the preferred treatment options. These guidelines were published online January 10, 2017 in the American Journal of Gastroenterology.

New Guideline for Preventive Care in Inflammatory Bowel Disease A new clinical guideline from the American College of Gastroenterology has said that the primary care physician should also be involved in the management of a patient with inflammatory bowel disease (IBD), especially with regard to preventive health maintenance such as vaccinations. The guideline published in the February 2017 issue of the American Journal of Gastroenterology says, “To improve the care delivered to IBD patients, health maintenance issues need to be co-managed by both the gastroenterologist and primary care team. It is equally important to educate the primary care clinician to the unique health maintenance needs of the IBD patient, especially those on immunomodulators and biologic agents.” The guideline includes 14 recommendations to address the preventive care needs of these patients. ÂÂ

Guideline recommends appropriate vaccinations including influenza, pneumococcal, herpes zoster, varicella, Tdap (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis), hepatitis A and B and HPV, as per guidelines.

ÂÂ

Consult an infectious disease specialist prior to travel to endemic areas for yellow fever.

ÂÂ

Household members of immunosuppressed patients can receive live vaccines with certain precautions.

ÂÂ

Women on immunosuppressive therapy should be evaluated for cervical cancer annually.

ÂÂ

All patients should be screened for depression and anxiety.

ÂÂ

Evaluate these patients for melanoma independent of the use of biologic therapy; patients on immunomodulators should be screened for nonmelanoma squamous cell cancer.

ÂÂ

Screen for osteoporosis at the time of diagnosis as well as at regular intervals in at-risk patients.

ÂÂ

Crohn’s disease patients who smoke should be counselled to quit.

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2017

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Study of hs-CRP in HIV Patients and Its Correlation with CD4 Count ARUN VISWANATH S*, HAROON SUBHAN KHAN†, ANJUM PARVEZ†, RIZWAN HASAN KHAN‡

ABSTRACT Objectives: The ever-growing prevalence of human immunodeficiency virus (HIV) infection in developing nations had long called for the need to optimize the health resources spent over HIV patients. In such a scenario, monitoring of disease progression in HIV patients with CD4 estimation biennially is a luxury only few countries can afford. In our study, we evaluated the potential role of high-sensitivity C-reactive protein (hs-CRP) as a cheaper alternative for CD4 estimation by assessing the correlation that exists between the two parameters. Study design: This was an open-labelled, randomized, cross-sectional study. We measured hs-CRP and CD4 counts in 142 HIV patients (16 children and 126 adults) and evaluated the correlation between the two parameters with regards to different patient characteristics. Results: We found a statistically significant negative correlation between the two variables (p < 0.001). This strong negative correlation persisted in different subgroups of the study population formed with respect to age, sex, antiretroviral therapy (ART) status, different ART regimen, hemoglobin status, body mass index, duration and stage of the disease. Only in underweight patients, the negative correlation between hs-CRP and CD4 counts did not reach statistical significance (p > 0.05). Conclusion: hs-CRP does hold the exciting possibility of being the cheaper alternative marker of disease progression in HIV patients pending further studies.

Keywords: Human immunodeficiency virus, high-sensitivity C-reactive protein, cluster of differentiation, immunoturbidimetry

D

espite being the burning topic of clinical research for more than three decades, the cure for human immunodeficiency virus-acquired immune deficiency syndrome (HIV-AIDS) remains elusive till date. Since, the introduction of first antiretroviral drug in late 1990, more than 25 licensed antiretroviral drugs are currently available for the management of HIV infection. These drugs have transformed HIV from a progressive disease with a fatal outcome into a chronic manageable disease.

phase and are having improved mortality rates. This has resulted in overall increase in prevalence of HIV infection even though the incidence of new cases with each passing year is gradually coming down. With widespread increase in prevalence of HIV infection and the growing emphasis on improved healthcare for HIV-infected patients, the overall cost of management of HIV patients has placed a huge economic burden on health infrastructure of every nation, more so for developing countries like India.

With improved antiretroviral therapy (ART) regimens and widespread availability of ART drugs, more and more patients are now entering into chronic disease

This scenario of growing patient population along with limited health resources calls for optimum utilization of available resources for maximizing benefits. In this situation, periodic measurement of CD4 counts for monitoring HIV disease progression is a luxury which many countries can no longer afford, even though CD4 count remains the gold standard tool for monitoring HIV disease progression. This is considered by many experts as a wasteful expenditure in resource poor settings especially for patients with disease stage 1 or 2 on combination ART regimen for at least 2 years with either persistently stable CD4 counts or HIV RNA levels below 50 copies/µL.1 This has resulted in a long-term demand for an alternate marker for monitoring HIV disease progression that could show

*Post PG †Professor Dept. of Medicine Jawaharlal Nehru Medical College and Hospital, AMU, Aligarh, Uttar Pradesh ‡Professor Interdisciplinary Biotechnology Unit, AMU, Aligarh, Uttar Pradesh Address for correspondence Prof Anjum Parvez Flat No. 2, 2nd Floor, Royal Apartments Kela Nagar, Civil Lines, Aligarh - 202 002, Uttar Pradesh E-mail: anjumparvez66@yahoo.com

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INTERNAL MEDICINE reliable correlation with CD4 counts and at the same time cheaper to perform. All the HIV disease-specific markers earlier proposed were costly and least effective when compared to CD4 monitoring. There were few non-HIV-specific markers of inflammation, which have been proposed as a potential replacement marker of CD4 count estimation.

These include:

ÂÂ

Body mass index (BMI) ≥25 kg/m2 (Asian cut-off for obesity).

ÂÂ

Deranged lipid profile: Triglyceride >150; lowdensity lipoprotein [LDL] cholesterol >100 mg/dL.

ÂÂ

History of cardiovascular disease or any long-term medical illness, which requires medication for more than 3 months apart from HIV infection.

ÂÂ

History of smoking (current or past).

ÂÂ

Interleukin (IL)-6

ÂÂ

Soluble CD14

Study Design

ÂÂ

D-dimer

ÂÂ

High-sensitivity C-reactive protein (hs-CRP).

This study was an open-labelled, randomized, crosssectional study. Patients attending our ART center were seen on a first come first serve basis. More than 400 patients attended the ART center during the study period. It included patients who come for 6-monthly laboratory check-up, monthly drugs collection and those newly diagnosed. Each person had an ART number and a patient card. They then wait until their number was called to be seen by the clinician. When the patient arrived, the examining clinician referred him/her to the researcher. The researcher queried their interest in participating in this study. If interested, the researcher reviewed eligibility criteria and explained the purpose of the study, benefits and risks as part of the informed consent. Adequate time was given for the participant to consider participation. A written informed consent was obtained from all individuals who agreed to participate. A study ID number was then allocated. Our study included a total of 142 HIV patients of which 72 were male and 70 were female.

Among the four, measuring IL-6 and soluble CD14 is a costly venture when compared to the cost of measuring CD4. This leaves us with two options. Among the two, earlier studies with D-dimer were highly disappointing.

While studies showing direct correlation of hs-CRP with CD4 counts were lacking. This prompted us to work on this topic. Our primary objective was to estimate the levels of serum hs-CRP in HIV-infected patients and to find out whether any correlation exists between serum hs-CRP levels and CD4 counts of HIV patients.

Our secondary objective was to evaluate whether this correlation holds good in different subgroups.

MATERIAL AND METHODS

Participants We carried out this study within the framework of the National AIDS Control Programme (NACP) with diagnosis and treatment of HIV patients conducted in accordance with recommended procedures. Patients detected to be HIV positive confirmed by western blot attending ART center, JN Medical College and Hospital, AMU, Aligarh, were taken up for the study.

The present study included all patients who attended our ART center from January 2014 up to February 2015. Patients who had confounding factors that could potentially influence hs-CRP levels were excluded from the study. The exclusion criterion included: ÂÂ

Any hospitalized patients or those with history of any acute illness in preceding 2 weeks.

ÂÂ

Patients with World Health Organization (WHO) Stage 4 disease.

ÂÂ

Patients with liver dysfunction. zz

Deranged liver function tests i.e., total bilirubin >1.5 mg/dL and/or liver enzyme levels ≥3 times of upper normal limit

zz

Concomitant viral hepatitis B or C (hepatitis B surface antigen/anti-HCV antibody).

A standard data abstraction tool relating to clinical history was developed and used to abstract required information from the patients files/charts and HIV/ AIDS treatment and monitoring database. The following data were recorded: duration and kind of ART, CD4 cell count, complete blood cell (CBC) count and blood chemistries (viz., creatinine, aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), demographic data such as age and sex, duration and stage of HIV infection according to WHO criteria.2 HIV and ART duration were calculated from the date confirmed HIV positive and date started ART, respectively to the date when blood sample for hs-CRP analysis was taken and age was calculated from the date of birth to the date when blood taken for hs-CRP.

Sample Collection Under aseptic techniques, we performed routine venous puncture. Using a serum separator tube (SST; Becton Dickinson, Franklin Lakes, NJ, USA), 7 mL nonfasting

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INTERNAL MEDICINE whole blood was drawn and left to clot for about 30 minutes, followed by centrifugation for 12-15 minutes.

Complete Blood Cell Count CBC counts were done using Sysmex KX-21 (Sysmex Corporation; Kobe Japan). The machine automatically dilutes a whole blood sample, lyses, counts and gives a printout result of absolute numbers of leukocytes (expressed as number of cells × [109] per liter), erythrocytes (number of cells × [1012] per liter), platelets (number of cells × [109] per liter), lymphocytes (number of cells × [109] per liter), mononuclear cells (number of cells × [109] per liter), granulocytes (number of cells × [109] per liter) and hemoglobin (grams per deciliter).

The quality and accuracy of the technique and the machine was assessed every 6 months.

Renal Function Tests ÂÂ

Blood urea: This was performed by Nessler’s method.

ÂÂ

Serum creatinine: This was estimated by Jaffe’s method.

Liver Function Tests ÂÂ

Total serum bilirubin: Estimated by Van den Bergh method of calorimetry.

ÂÂ

AST/ALT: Serum AST and ALT were estimated by simplified calorimetric test at 505 nm.

ÂÂ

Alkaline phosphatase (ALP): Estimated calorimetrically by the test described by EJ King.

CD4 T Cell Counts Analysis Cluster differential cells (CD4 T cells) were analyzed using a FACSCount Flow cytometer (Becton Dickinson Immunocytometry Systems, San Jose, Calif). In brief, 50 μL of whole blood was mixed and incubated at room temperature for 20 minutes with 20 μL of a test solution. Red blood cells (RBCs) were then lysed by adding 450 μL of fluorescence-activated cell sorter lysing solution. The tubes were incubated at room temperature for 10 minutes, and then analyzed with the FACS Count’s CellQuest software (Becton Dickinson Immunocytometry Systems) within 6 hours. By using quality control (Multi check; Becton Dickinson Immunocytometry Systems), the accuracy of the technique was assessed every 6 months.

Measurement of hs-CRP In our study, hs-CRP was measured by immunoturbidimetry method. It works on the principal of light scattering by interaction with particles in solution.

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Turbidimetry is an analytical technique that uses light scattering principle to measure the concentration of particle in the solution. The photometric signal is generated by a decrease in light intensity as a direct consequence of increasing turbidity in the reaction well. The reaction occurring in the well is the classical antigen-antibody reaction, hence the name immunoturbidimetry. The photometric signal is then detected by a photometer. In our study, serum was separated from patient’s blood samples and stored in separate serotops. The samples were processed in batches with the storage time of each sample not exceeding more than 2 weeks. The kit used in our test was Agape hs-CRP kit and the analysis was performed using a BIOLIS-242 auto analyzer. The hs-CRP levels were measured in mg/L units.

Data Management The principle investigator abstracted and filled the information obtained from the patients file to the abstraction forms. Immediately following completion of abstraction form, the researcher double checked the instruments for completeness and consistency of answers. Completed abstraction forms were then coded by numbers and entered in Microsoft Excel sheet version 2010. Cross-checking and data cleaning was done. During data cleaning and cross-checking missing information were obtained by going back to the abstraction form, HIV treatment and monitoring database and when necessary reviewing the patients on the next visit to the clinics. The data were then transferred to SPSS version 21 software for analysis.

Statistical Analysis All analyses were performed with SPSS software for Windows, version 21 (SPSS Inc., IBM, Version 21.0, USA).

Statistical Tests Applied ÂÂ

Spearman’s bivariate correlation coefficient test.

ÂÂ

Independent sample t-test.

ÂÂ

One way ANOVA with post-hoc analysis done using Tukey’s HSD method, wherever needed.

In our study, we considered patients up to 14 years as pediatric population. No attempt was made from our side to classify patient’s stage of disease. The WHO clinical stage allotted to each patient from the ART center of our institute at the time of sample collection was used as such in our study.2,3 WHO BMI staging for South-East Asian population was used to exclude obese patients with BMI ≥25 kg/m2.4 WHO classification was used to classify patient’s hemoglobin values.5 Patients

INTERNAL MEDICINE taking ART in our study were following one of the three NACO’s (National AIDS Control Organization) ART regimen - Regimen 1, 2 or 2a.6 The American Heart Association (AHA) risk grading of hs-CRP used

by Shikuma et al7 was used in our study to classify patients based on hs-CRP values into 4 groups (Low ≤1 mg/L, Average - 1.1-3 mg/L, High - 3.1-10 mg/L and Outliers - ≥10.1 mg/L). We also made 3 groups based on CD4 counts (≤200, 201 up to 500 and >500).

and another 31 had CD4 count >500 cells/mm3. While 80 patients had CD4 count in the 200-500 cells/mm3 range.

RESULTS

Distribution of study population based on hs-CRP and other baseline characteristics is as shown in Table 1.

Outliers were excluded from all statistical analysis.

Subgroups with less than 10 entries (viz., moderate and severe anemia, regimen 2 subgroups) were also excluded from analysis. First we studied the difference in hs-CRP values in different subgroups formed based on certain characteristics of patient. This was done using independent sample t-test (for parameters with ≤2 patient subgroups) and ANOVA test (for parameters with >2 patient subgroups like BMI, duration of illness and stage of disease). Post-hoc analysis was done using Tukey’s HSD method, wherever needed.

In our study, 200 HIV patients were chosen randomly.

After applying exclusion criteria, 142 patients were selected for measuring hs-CRP. Out of 142, 16 (11%) patients belonged to pediatric age group (≤14 years) and 126 (89%) patients were adults. Among 126 adults, there were 61 (48%) males and 65 (52%) females.

Regarding ART status, 21 (15%) patients were not taking ART, which included 12 males and 9 females.

Rest of the patients (121) were on ART. In our study, 36 (25%) patients had Stage 1 disease, which included 10 males and 26 females. Seventy-four (52%) patients had Stage 2 disease out of which 43 were males and 31 were females. There were 32 (23%) Stage 3 patients in our study, which included 19 males and 13 females. The distribution of study population is depicted in Figure 1.

The mean CD4 count of the study population was 361.8 ± 183. The CD4 count ranged from 27 to 1,402 in our study.

Thirty-one patients had CD4 count ≤200 cells/mm3

The hs-CRP values in the study population ranged from 0.10 to 169.70 mg/L with a mean of 7.9239 ± 23.55 mg/L. Fifty-one patients had low (≤1), 49 had average (1.1 up to 3), 25 had high (3.1 up to 10) hs-CRP values.

Seventeen patients had hs-CRP in the outliers (>10) range.

Results of independent sample t-test and ANOVA were as shown in Tables 2 and 3. Apart from CD4 and hemoglobin subgroups, there was no statistically significant (p > 0.05) difference in hs-CRP values among the other subgroups formed based on different parameters. Post-hoc analysis revealed that statistically

200 randomly selected HIV patients After applying exclusion criteria hs-CRP measured in 142 patients

Age

ART status

Adults 126

Children (≤14 years) 16

Male 61

Female 65

ART naive patients 21 Stage of disease

ART patients 121 Regimen 1 (91) Regimen 2a (25)

Stage 1 (36)

Stage 2 (74)

Stage 3 (32)

Regimen 2 (5)

(Regimen 1 - Zidovudine, Lamivudine, Nevirapine; Regimen 2a - Tenofovir, Lamivudine, Efavirenz; Regimen 2 - Zidovudine, Lamivudine, Efavirenz)

Figure 1. Distribution of study population.

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INTERNAL MEDICINE Table 1. Distribution of Study Population-based on hs-CRP Measurements and Baseline Characteristics Parameter Age

Sex

ART status

Hb level

BMI status

Duration of illness

Stages of disease

ART regimen

CD4 count

Subgroups

Low

Average

High

Outliers

Total

Adults

48

41

21

16

126

Children

41

8

4

1

16

Male

18

33

8

13

72

Female

33

16

17

4

70

Pre-ART

7

2

7

5

21

On-ART

44

47

18

12

121

Normal

42

31

13

5

91

Mild

5

13

10

12

40

Moderate

3

4

2

-

9

Severe

1

1

-

-

2

Underweight

1

8

2

5

16

Normal

39

25

9

11

84

Overweight

11

16

14

1

42

<3 years

26

15

13

13

67

3-5 years

25

23

6

3

48

≥5 years

6

11

6

1

27

1

33

11

5

-

36

2

9

32

11

6

74

3

2

6

9

11

32

Regimen 1

33

36

14

8

91

Regimen 2a

9

9

4

3

25

Regimen 2

2

2

1

-

5

>500

21

10

-

-

31

200-500

29

31

17

4

81

≤200

1

8

8

13

30

Table 2. Results of Independent Sample t-test Parameter Age Sex ART status Hb ART regimen

860

Subgroups

hs-CRP N

Mean

t

df

P

Adults

110

1.96 (1.63)

0.17

123

0.87

Children

15

2.80 (2.64) 0.201

123

0.841

1.394

123

0.166

-3.226

112

0.002

-0.131

104

0.896

Male

59

2.10 (1.70)

Female

66

2.03 (1.88)

ART

109

1.98 (1.63)

Pre-ART

16

2.64 (2.66)

Normal

86

1.78 (1.47)

Mild anemia

28

3.02 (2.47)

Regimen 1

83

1.93 (1.50)

Regimen 2a

23

1.98 (1.41)

Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

INTERNAL MEDICINE significant (p < 0.05) difference in hs-CRP values exists between all the three CD4 subgroups.

10.00

Correlation of hs-CRP with CD4 Count 8.00

hs-CRP

The main objective of our study was to find whether there is any correlation of hs-CRP with CD4 levels. This was done using nonparametric Spearman’s correlation coefficient test. The correlation between hs-CRP and CD4 was also tested in different subgroups.

4.00

Using Spearman’s correlation coefficient test, the correlation coefficient between hs-CRP and CD4 count was found to be -0.555 with a statistically significant p value <0.001. This reflects the presence of statistically significant strong negative correlation between hs-CRP and CD4 count. Figure 2 shows the scatter plot showing the correlation between hs-CRP and CD4 count.

The correlation between hs-CRP and CD4 count was tested separately with respect to different parameters.

The statistically significant (p < 0.05) negative correlation between hs-CRP and CD4 count persisted with respect to different parameters as shown in the Table 4 except in underweight patients. The negative correlation in underweight patients did not reach statistical significance (p > 0.05). However, there were only 11 patients in this category.

2.00

.00 0

In adults (p < 0.001 and cc = -0.570) than in children (p = 0.018, cc = - 0.602)

200

400

600

800

1000

1200

1400

CD4

Figure 2. Scatter plot showing correlation of hs-CRP with CD4 count.

Here the dependent variable (Y axis) is hs-CRP and the independent variable (X axis) is CD4 count. Note the peaking of the plot towards the left side indicating the raising hs-CRP with lower CD4 count. ÂÂ

In female (p < 0.001 and cc = -0.707) than in male (p = 0.004, cc = -0.371).

ÂÂ

In normal BMI subgroup (p < 0.001, cc = -0.640) than in overweight subgroup (p = 0.017, cc = -0.424).

ÂÂ

In ART patients (p < 0.001, cc = -0.557) than in preART patients (p value = 0.025, cc = -0.556).

The negative correlation was stronger ÂÂ

6.00

Table 3. Results of ANOVA Parameter BMI

DOI

Stages

CD4 count

Subgroups

Hs-CRP N

Mean (SD)

F

df

P

Underweight

11

2.02 (0.92)

2.60

2

0.78

Normal

73

1.78 (1.87)

Overweight

41

2.57 (1.75)

<3 years

54

1.96 (1.74)

1.61

2

0.852

3-5 years

45

2.14 (1.96)

>5 years

26

2.15 (1.65)

1

36

1.88 (1.94)

1.328

2

0.269

2

68

1.98 (1.71)

3

21

2.63 (1.77)

<200

17

3.69 (2.65)

14.14

2

<0.001

200-500

77

2.10 (1.61)

>500

31

1.08 (0.71)

Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

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INTERNAL MEDICINE Table 4. Correlation of hs-CRP with CD4 with Respect to Different Parameters Parameters Age Sex ART status Duration of illness

BMI

Stages of disease

ART regimen Hb levels

Subgroup

P value

Spearman’s coefficient

Children

0.018

-0.602

Adults

<0.001

-0.570

Male

0.004

-0.371

Female

<0.001

-0.707

Pre-ART

0.025

-0.556

ART

<0.001

-0.557

<3 years

<0.001

-0.622

3-5 years

<0.001

-0.541

>5 years

0.012

-0.483

Underweight

0.155

-0.460

Normal

<0.001

-0.640

Overweight

0.017

-0.424

1

0.001

-0.548

2

<0.001

-0.649

3

0.010

-0.500

Regimen 1

<0.001

-0.542

Regimen 2a

0.001

-0.649

Normal

<0.001

-0.481

Mild

<0.001

-0.674

ÂÂ

In patients with duration of illness <3 years (p < 0.001, cc = -0.622) and 3-5 years (p < 0.001, cc = -0.541) than in patients with duration of illness >5 years (p = 0.012, cc = -0.483).

ÂÂ

In patients with Stage 1 (p = 0.001, cc = -0.548) and Stage 2 disease (p < 0.001, cc = -0.481) than in patients with Stage 3 disease (p = 0.010, cc = -0.547).

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In patients on Regimen 1 (p < 0.001, cc = -0.542) than in patients on Regimen 2a (p = 0.001, cc = -0.649).

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The correlation between hs-CRP and CD4 count was equally stronger in patients with normal hemoglobin (p < 0.001, cc = -0.481) and mildly anemic patients (p < 0.001, cc = -0.674).

DISCUSSION The AHA defines risk grade in hs-CRP as <1 mg/L (low risk), 1-3 mg/L (average risk), >3-10 mg/L (high risk) and >10 mg/L (Outlier; suggestive of other inflammatory processes). In assessing cardiovascular disease risk, the AHA recommends that hs-CRP >10 mg/L be discarded and repeated because extremely high hs-CRP values may reflect other processes such as acute infection or other inflammatory processes.8 In our study, we followed the same protocol for

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Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

grouping patients based on hs-CRP. Our study had 17 outliers out of the 142 patients. The outliers were excluded from all statistical analysis done in this study.

In our study, there was no statistically significant (p > 0.05) difference in hs-CRP values between the <15 years and >15 years age group. This finding was also observed in a study of 97 HIV patients by Zhou et al published in 2015.9 But, a study from Sao Paulo in Brazil by Riberio (1997) with a sample size of 165 adults and 125 children showed a significant difference in CRP levels measured by enzyme-linked immunosorbent assay (ELISA) between healthy children and adults.10 It should be noted that the sample size of <15 years patients in our study was very small. Further we measured hs-CRP and not just CRP. There was no significant (p > 0.05) difference between hs-CRP levels in both sexes in our study. Similar findings were noted in the study by Zhou et al in 2015.9 However, in a study by Shikuma et al in 2011,7 there was significant difference in hs-CRP levels between male and female patients following initiation of efavirenz-based ART. Gender differences in hs-CRP have been reported in the general population. Women with National Cholesterol Education Program (NCEP)defined metabolic syndrome have higher hs-CRP levels

INTERNAL MEDICINE compared to men with the metabolic syndrome.11 One of the important finding in our study was that there was no significant difference (p > 0.05) in hs-CRP levels between patients on ART and ART-naïve patients.

This is in contradiction to findings from earlier studies probably because of small sample size (15%) of preART patients in our study. In a study by Noursadeghi et al published in 2005 approximately 30% of patients with HIV receiving long-term ART were shown to have CRP levels >3.0 mg/L,12 the highest CRP levels being observed in those who were currently treated with ART.13 Furthermore, elevated hs-CRP levels have been observed in ART-treated compared with ART-naïve HIVpositive patients in another study by Guimarães et al published in 2008.14 Changes in CRP levels following protease inhibitor (PI) therapy were studied in the AIDS Clinical Trials Group (ACTG) 5056s. This study assessed changes in CRP levels following indinavirbased highly active antiretroviral therapy (HAART) and noted that CRP levels remained stable or decreased slightly over an average of 42 months.15 A similar slight decline overall was seen in the HIV Study with Epzicom And Truvada (HEAT) study over 96 weeks following initiation of lopinavir and ritonavir given with either ABC/3TC or tenofovir/emtricitabine.16 The overall trend of decreasing CRP levels over time in both studies was observed only in men. On the contrary to both these studies, continuation of ACTG 5056 by Shikuma et al in 2011 utilizing NNRTI-based HAART over 96 weeks found a slight statistically insignificant increase in hs-CRP in men but a significant increase in hs-CRP in women.7 Another interesting finding from our study was that there was no statistically significant (p > 0.05) difference in hs-CRP levels between patients on different ART regimen. Majority of our patients were taking NACO Regimen 1 consisting of zidovudine, lamivudine and nevirapine. Nine patients were taking Regimen 2a consisting of tenofovir, lamivudine and efavirenz.

Only 2 patients were taking Regimen 2 consisting of zidovudine, lamivudine and efavirenz. Most of the studies have studied the change in hs-CRP levels with the introduction of different ART regimen like the ACTG 5059 or HEAT study. But these studies did not directly compare the hs-CRP levels in patients on different ART regimen. In 2014, Hattab et al published their study that compared the change in inflammatory markers including hs-CRP from the baseline 2 years following the start of two different ART regimens. In this study, they found that hs-CRP levels fell slightly although not significantly from the pre-ART period, but there was

no differential effect of the studied antiretroviral drugs regimen on hs-CRP levels.17 Further Boger et al in 2009 did not find a difference in hs-CRP in subjects on PI versus non-PI-based ART.18 These were in accordance with our study results.

In our study, significant difference in hs-CRP levels in different BMI groups was noted even after patients with BMI in the obesity range (>27.5 kg/m2) were excluded from the study. Post-hoc analysis of ANOVA results by Tukey's HSD test found out that there was significant (p = 0.031) difference in hs-CRP levels between the normal (BMI - 18.5 to 23 kg/m2) and overweight (BMI - 23 to 27.5 kg/m2) group. High BMI is a known risk factor for increased hs-CRP in general population.

This was also confirmed in HIV patients by Boger et al in 2009.18 There was significant difference (p = 0.012) in hs-CRP levels between patients with normal hemoglobin and mild anemia in our study. This is in stark contrast to the findings in a study by Wisaksana et al in 2011 in HIV patients from Indonesia, which showed no correlation of hs-CRP with serum ferritin levels or degree of anemia.19 We found that there was no statistically significant difference (p > 0.05) in hs-CRP levels in patients with varying duration of illness with or without ART. For our analysis, we divided our study population into three groups based on the duration of illness from the time of initial diagnosis: <3 years, 3-5 years and >5 years. We found no difference in hs-CRP levels between these three groups with no regards to whether or not they were on any ART regimen. Also, we found that there was no significant (p > 0.05) difference in hs-CRP levels with respect to WHO stages of HIV infection. It is to be noted that we had not included patients with Stage 4 HIV in our study. Only patients in Stage 1, 2 or 3 were included.

We could not find any study done earlier that could support or refute these two findings.

Using Spearman’s correlation test, we found a statistically significant negative correlation between hs-CRP and CD4 counts of our study population with both parameters taken as continuous variable.

The correlation coefficient was -0.555 with p value <0.001. This correlation was also tested in different subpopulation within our study divided based on the parameters as mentioned earlier. The negative correlation between hs-CRP and CD4 count was noted in all of the above mentioned subpopulation and it was statistically significant (p < 0.05) in all except in subgroup with underweight (p = 0.155, cc = -0.460) patients.

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INTERNAL MEDICINE In an article published by Guimarães et al in 2008 assessing the hs-CRP levels in 171 HIV-infected patients treated (n = 129) or not with antiretroviral drugs (n = 42) and their correlation with factors related to cardiovascular risk and HIV infection, no correlation was found between hs-CRP levels and CD4 cell counts and HIV-viral load.14 Despite extensive research we could not find a similar study with similar objectives, probably because we already have a reliable marker for disease monitoring in HIV patients in the form of CD4 count estimation.

Studies are usually done to find out other effective markers that can supersede already existing one and are not done to test the efficacy of a less reliable marker such as hs-CRP, which probably could never be more reliable than a disease-specific marker such as CD4 count. Efforts are already on to phase in HIV RNA levels in place CD4 count estimation as HIV RNA assays are more efficacious than CD4 count for disease monitoring.

However, developing nations of South-East Asia and Africa are still struggling to economically account for growing demands of HIV care including routine 6-monthly CD4 estimation for disease monitoring.

In such resource, poor setting hs-CRP measurements could come in handy as a cheaper relatively reliable marker for monitoring disease activity. Hence, our study could be regarded as a pioneer study in this regard. Until now, majority of studies concerned with measuring hs-CRP in HIV patients have studied only its potential role as an independent risk factor for cardiovascular disease in HIV patients. Few studies done in Africa have studied hs-CRP as a marker of disease progression in HIV patients20 and for predicting HIV-related outcomes.21 CONCLUSION AND DRAWBACKS To conclude, with this study we set out to explore the possibility of serum hs-CRP levels as a tool for monitoring of disease activity in HIV-infected patients.

We decided to correlate hs-CRP levels with an already existing reliable marker of HIV disease progression i.e., CD4 count, to look for any linear relationship between the two markers. The major inspiration for this study was two studies from Africa. One by Drain et al, 200721 who found CRP to be a cheaper tool that could predict HIV-related outcomes among women and children in a resource poor setting of Tanzania. The other study was published in 2010 by Redd et al20 who found the rise in CRP levels during HIV-1 disease progression

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despite the absence of microbial translocation in Rakai, Uganda.

The popular perception that CRP levels will be increased invariably in HIV patients irrespective of disease activity due to presence of other opportunistic infection cannot be entirely true. Not all HIV patients will harbor opportunistic infection at all times in their disease course. With advanced HAART, now more and more patients are going in for long-term remission. We believe that hs-CRP has the potential to be a cheaper alternate disease activity marker in place of CD4 count in this population of patients with long-term remission.

We found a significant negative correlation between the hs-CRP levels and CD4 count i.e., with decreasing CD4 count, hs-CRP showed increasing trend. This is in contrast to previous studies that showed no correlation between the two. This result could be regarded as a small stepping stone towards our study goal. However, our study was done in a single center and it was a cross-sectional study. Multicenter, follow-up studies are required in future to fully explore the possibility of hs-CRP as a replacement marker in place of CD4 count for monitoring of HIV patients.

Our study was a cross-sectional study, and the study design was appropriate for the study’s objective which was determining hs-CRP levels in HIV-infected patients and assessing correlation if any that exists between measured hs-CRP levels and CD4 count of the patient. But our design may not be ideal for our study goal which is to assess the potential of hs-CRP levels as a replacement marker in place of CD4 count for monitoring disease progression in HIV patients, which requires long-term follow-up and serial simultaneous measurement of both hs-CRP and CD4 count to determine whether the observed correlation between the two is repeatable and reproducible. This was not done in our study due to economic and time restraints.

Acknowledgment We are thankful to Medical Officer and all the staffs of ART Centre, JN Medical College, AMU, Aligarh for their immense help throughout this study.

REFERENCES 1. Fauci AS, Lane HC. Human immunodeficiency virus disease: AIDS and related disorders. In: Harrison’s Principles of Internal Medicine. 19th Edition, Volume 2; pp. 1215-85.

2. Interim WHO clinical staging of HIV/AIDS and HIV/ AIDS case definitions for surveillance - African region.

INTERNAL MEDICINE World Health Organization; 2005. Available at: http:// www.who.int/hiv/pub/guidelines/clinicalstaging.pdf 3. WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIVrelated disease in adults and children. World Health Organization; 2007. Available at: http://www.who.int/ hiv/pub/guidelines/HIVstaging150307.pdf 4. WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet. 2004;363(9403):157-63.

5. WHO. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System. Geneva, World Health Organization; 2011 (WHO/NMH/NHD/MNM/11.1).

Available at: http://www.who.int/vmnis/indicators/ haemoglobin.pdf. Accessed on 17th Jan, 2017.

6. Antiretroviral therapy guidelines for HIV-infected adults and adolescents. May 2013. Available at: http:// www.hivpolicywatch.org/duremaps/data/guidelines/ IndiaAdultARTguidelines2013.pdf. Accessed on 17th Jan 2017.

7. Shikuma CM, Ribaudo HJ, Zheng Y, Gulick RM, Meyer WA, Tashima KT, et al; AIDS Clinical Trials Group A5095 Study Team. Change in high-sensitivity C-reactive protein levels following initiation of efavirenz-based antiretroviral regimens in HIV-infected individuals. AIDS Res Hum Retroviruses. 2011;27(5):461-8.

8. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, et al; Centers for Disease Control and Prevention; American Heart Association.

Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107(3):499-511.

9. Zhou DT, Kodogo V, Dzafitita M, Øktedalen O, Muswe R, Stray-Pedersen B. Lipids and hsCRP as markers of coronary heart disease risk in HIV infected adults. Int J Sci Technol Res. 2015;4(8):252-7.

10. Ribeiro MA. Levels of C-reactive protein in serum samples from healthy children and adults in São Paulo, Brazil. Braz J Med Biol Res. 1997;30(9):1055-9.

11. Saltevo J, Vanhala M, Kautiainen H, Kumpusalo E, Laakso M. Gender differences in C-reactive protein, interleukin-1 receptor antagonist and adiponectin levels in the metabolic syndrome: a population-based study. Diabet Med. 2008;25(6):747-50.

13. Masiá M, Bernal E, Padilla S, Graells ML, Jarrín I, Almenar MV, et al. The role of C-reactive protein as a marker for cardiovascular risk associated with antiretroviral therapy in HIV-infected patients. Atherosclerosis. 2007;195(1): 167-71.

14. Guimarães MM, Greco DB, Figueiredo SM, Fóscolo RB, Oliveira AR Jr, Machado LJ. High-sensitivity C-reactive protein levels in HIV-infected patients treated or not with antiretroviral drugs and their correlation with factors related to cardiovascular risk and HIV infection.

Atherosclerosis. 2008;201(2):434-9.

15. Henry K, Kitch D, Dube M, Zackin R, Parker RA, Sprecher D, et al; Adult AIDS Clinical Trials Group.

C-Reactive protein levels over time and cardiovascular risk in HIV-infected individuals suppressed on an indinavir-based regimen: AIDS Clinical Trials Group 5056s. AIDS. 2004;18(18):2434-7.

16. McComsey GA, Smith KY, Patel P, Bellos NC, Sloan L, Lackey P, et al. Similar reductions in markers of inflammation and endothelial activation after initiation of abacavir/lamivudine (ABC/3TC) or tenofovir/ emtricitabine (TDF/FTC) in the HEAT study. 16th Conference on Retroviruses and Opportunistic Infections, Montreal, Canada; Feb. 8-11, 2009.

17. Hattab S, Guihot A, Guiguet M, Fourati S, Carcelain G, Caby F, et al. Comparative impact of antiretroviral drugs on markers of inflammation and immune activation during the first two years of effective therapy for HIV-1 infection: an observational study. BMC Infect Dis. 2014;14:122.

18. Boger MS, Shintani A, Redhage LA, Mitchell V, Haas DW, Morrow JD, et al. Highly sensitive C-reactive protein, body mass index, and serum lipids in HIV-infected persons receiving antiretroviral therapy: a longitudinal study. J Acquir Immune Defic Syndr. 2009;52(4): 480-7.

19. Wisaksana R, Sumantri R, Indrati AR, Zwitser A, Jusuf H, de Mast Q, et al. Anemia and iron homeostasis in a cohort of HIV-infected patients in Indonesia. BMC Infect Dis. 2011;11:213.

20. Redd AD, Eaton KP, Kong X, Laeyendecker O, Lutalo T, Wawer MJ, et al; Rakai Health Sciences Program.

C-reactive protein levels increase during HIV-1 disease progression in Rakai, Uganda, despite the absence of microbial translocation. J Acquir Immune Defic Syndr.

2010;54(5):556-9.

21.

12. Noursadeghi M, Miller RF. Clinical value of C-reactive protein measurements in HIV-positive patients. Int J STD AIDS. 2005;16(6):438-41.

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Drain PK, Kupka R, Msamanga GI, Urassa W, Mugusi F, Fawzi WW. C-reactive protein independently predicts HIV-related outcomes among women and children in a resource-poor setting. AIDS. 2007;21(15):2067-75.

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Indigenous Axillary Crutch Associated Diparesis RAJESH CHETIWAL*, UC OJHA†, P LAKHWANI‡, OP LAKHWANI#

ABSTRACT Introduction: Indigenously made wooden crutches are commonly used by handicapped persons for ambulation due to availability and cost benefit ability. Axillary crutches associated palsy has been described in literature but presenting as severe diparesis is rarely reported. Diparesis as isolated neurological presentation is not frequently seen and associated with rare pathologies. Case report: We describe such a patient, a known-case of Buerger’s disease with below knee amputation using indigenous wooden axillary crutches presented as diparesis. Case is presented to report such an occurrence and the possible predisposing factors and discuss its management. Discussion: Improper length, unpadded axillary support and lack of hand support predispose the compression of brachial plexus which is further aggravated by prolong standing. Awareness of proper crutch making among by indigenous makers, proper selection and use of crutches by the patient may solve the problem and provide convenience to patients.

Keywords: Brachial plexus palsy, axillary crutch, crutch palsy

D

iparesis is a clinical condition used to describe weakness of the both the upper extremities.

Isolated neurological presentation as diparesis is not frequently seen in clinical practice; however, various differential diagnosis1 including incomplete spinal cord injuries, central cord syndrome, peripheral neuropathies including leprosy, mononeuropathy multiplex,2 human immunodeficiency virus (HIV)related, bilateral brachial plexus palsy, bilateral nerve entrapments, atypical variants of amyotrophic lateral sclerosis3 are among etiologies of this rare clinical presentation.

Brachial plexus paralysis due to use of axillary crutches is rarely seen in clinical practice.4 If present bilaterally, it can result in diparesis without any other systemic feature. Current case report presents such an occurrence with use of indigenously made wooden crutches.

*Associate Professor †Director, Occupational Health and Environmental Research Head, Dept. of Pulmonary Medicine ‡Associate Consultant #Associate Professor Dept. of Orthopedics ESI-PGIMSR, Basaidarapur, New Delhi Address for correspondence Dr OP Lakhwani Associate Professor ESI-PGIMSR, Basaidarapur Ring Road, New Delhi E-mail: orth365@gmail.com

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CASE REPORT A 50-year-old male presented with complaints of weakness and decreased sensations in bilateral upper limbs, which were gradually progressive over last 4-6 months. Patient was a chronic tobacco user and a known-case of Buerger’s disease. He underwent right side below knee amputation 8 months back for intractable ischemic pain and gangrenous changes in right lower limb. Since then, he was using indigenously made wooden axillary crutches for ambulation.

Following the amputation severe pain persisted which used to get partially relieved on standing thus, compelling patient to stand over the axillary crutches for long periods. He even complained of disturbance in sleep on account of the severe pain and on occasions fell asleep while standing on the crutches. No other systemic complaints were present.

Clinical examination revealed bilateral muscular atrophy of humeral, forearm, thenar and hypothenar region. Muscle tone was normal. He was having weakness of hand grip, wrist flexion and extension, elbow extension and flexion (Medical Research Council [MRC Grade 3]). Shoulder had minimal motor deficit MRC Grade 4. He had sensory deficit in radial, median and ulnar nerve distribution. The biceps and supinator reflexes were not ilicitable bilaterally. Peripheral vascular pulses in both upper limbs were well felt. The weakness was lower motor neuron type and involved sensory and motor neurons.

Clinical examination of neck, back, X-ray of chest and

NEUROLOGY cervical spine were normal. Patient was found to be using snugly fitting indigenously made of unpadded wooden crutches of inappropriate length and design (Figs. 1 i and ii) without hand support. Both the elbows remained in extension upon weight-bearing over crutches.

Routine blood investigations and skiagram of cervical spine were within normal limits. HIV serology to rule out related neuritis was negative. An electromyography (EMG) and nerve conduction study showed increased insertional activity and spontaneous activity and reduced motor unit recruitment in bilateral interosseous, biceps and extensor carpi radialis muscles.

History and clinical examination corroborated with electrophysiological studies were suggestive of brachial diparesis secondary to compression by inappropriate use of axillary crutches.

Indigenous axillary crutches used by the patient were discontinued immediately and simultaneously physical therapy was initiated. Oral methylcobalamin 750 µg twice-daily for 4 weeks and methylprednisolone 16 mg daily in tapering dose were given for a period of 2 weeks. Medication for peripheral vascular disease was also given. Patient was prescribed crutches of appropriate length measured from 2 inches below the anterior axillary fold to a point 6 inches in front of and

lateral to the toes on the ground allowing elbow flexion of around 300, while bearing weight over crutches.

Patient was followed up regularly monthly and had complete recovery of neurological sensory and motor function bilaterally over a period of 8 months.

DISCUSSION Brachial plexus neuropathy following axillary crutches is a known entity but such severe involvement presenting as diparesis is very rare. Patient with the upper limb weakness may be considered for more common etiologies like cervical spondylitis, myopathies and other central nervous system disorder presenting with neurologic deficit, but isolated upper limbs sensory motor weakness are not their feature.

Peripheral neuropathies may present with bilateral symptoms; however, predisposing factors,5,6 clinical feature, electrophysiological study7 and deficit pattern differentiate them. Neurological complication in crutch palsy occurs due to compression of brachial plexus in axilla. In the present case, neurological compression was predisposed by high length (height) of the crutches, lack of axillary cushion pad and absence of the proper hand support causing leaning over the crutches with resultant impingement in axilla and compression of brachial plexus. Prolonged standing over the crutches due to ischemic pain also contributed.

Crutch palsy is a rare occurrence in rural set-up due to use of improperly designed indigenous wooden axillary crutches. It most commonly involves posterior cord but in the present case all three nerves were involved, which is a rare presentation. Diagnosis can be made by detailed history, clinical examination and confirmed by neurophysiological studies. Discontinuation of crutches, oral steroids, methylcobalamin and rehabilitative therapy is usually the prescribed regime for treatment.

Resolution time as long as 9 months has also been reported.6 It is most imperative to guide the patient regarding use and selection of crutches conforming to standard specifications.

Figures 1 i and ii. Showing the indigenous wooden crutches (i): a - lack of axillary cushion, b - absence of hand grip; (ii) Patient with improper indigenous crutch with c - axillary impingement, d - extended elbows diminishing propulsive force.

Selection and measurement of crutches8,9 and proper gait training is important for proper crutch walking without fatigue and to prevent further injury. Walking with crutches use requires body balance and upper limbs strength for holding crutches and weight-bearing.

Proper measurement of crutches (Fig. 2) can be done either in lying down or standing position of patient wearing the foot wear. Three inches from the anterior fold of his axilla to the sole of his shoe is measured and then 2” (5 cm) is added or 5” lateral and anterior to foot wear on ground is measured. Hand grip support

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NEUROLOGY

Cushioned axillary pad Frame strengthen by wrapping rope or clothes Hand rest support

Wrapped by rope or cloth to strengthen

Wooden log or Split into two part bamboo partially

Figure 2. Basic design for proper indigenously crutch making.

adjusted to provide the elbows flexion of about 30° to help in propulsion.

In rural areas, indigenously made crutches are often, used this being a cost beneficial method for rehabilitation. It is a good aid provided it conforms to standards (Fig. 3).

Diparesis due to axillary crutches related to brachial plexus compression is a rare neurological presentation.

This case study adds to the rare clinical spectrum of crutch-induced brachial palsy and patient should be cautioned about proper design and selection and use.

REFERENCES 1. Sturzenegger M, Rutz M. Bilateral radial nerve paralysis.

Diagnostic and differential diagnostic aspects. Schweiz Med Wochenschr. 1990;120(37):1325-34.

2. Lyons J, Venna N, Cho TA. Atypical nervous system manifestations of HIV. Semin Neurol. 2011;31(3):254-65.

Axillary cushioned support

2 Fingers or 3" below anterior axillary fold

Elbow 30° flexion Hand rest Crutch length

3. San-juan OD, Castro-Macías JI, Cárdenas-Hernández G. Brachial diplegia as a variant of amyotrophic lateral sclerosis (Vulpian-Bernhart syndrome): the first case reported in Mexico and a review of the literature. Rev Neurol. 2008;46(1):30-1.

4. Poddar SB, Gitelis S, Heydemann PT, Piasecki P. Bilateral predominant radial nerve crutch palsy. A case report. Clin Orthop Relat Res. 1993;(297):245-6.

5. Rudin LN, Levine L. Bilateral compression of the radial nerve; crutch paralysis. Phys Ther Rev. 1951;31(6):229-31.

6. Raikin S, Froimson MI. Bilateral brachial plexus compressive neuropathy (crutch palsy). J Orthop Trauma.

1997;11(2):136-8.

7. Subramony SH. Electrophysiological findings in crutch palsy. Electromyogr Clin Neurophysiol. 1989;29(5):281-5.

8. Beckwith JM. Analysis of methods of teaching axillary crutch measurement. Phys Ther. 1965;45(11):1060-5.

9. Cornman JC, Freedman VA, Agree EM. Measurement of assistive device use: implications for estimates of 5" anterior and lateral to toes on ground device use and disability in late life. Gerontologist.

Figure 3. Measurement of the standard axillary crutches.

2005;45(3):347-58.

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ORTHOPEDICS

Tubercular Osteomyelitis of Talus in a Child: A Case Report and Review of Literature RITESH RUNU*, MANTU JAIN†, VIDYA SAGAR‡, ARNAB SINHA‡, SAURAV KUMAR‡, SANTOSH KUMAR#

ABSTRACT Introduction: Talar tuberculosis is very rare presentation of osteoarticular tuberculosis. Affection of foot is less than 10% in osteoarticular tuberculosis. Presentation of this disease in peripheral bones is highly unusual posing diagnostic dilemma and missed diagnosis. Delayed diagnosis may lead to complications. Case report: A 19-month-old young male child presented with painful swelling over left foot and inability to bear weight. Hemogram was inconclusive. Radiograph showed lytic lesion in talus with cortical breach in the superior cortex. Aspiration biopsy was inconclusive and open curettage was done under anesthesia.

Culture reports were negative but histopathological examination proved tuberculosis. Patient was given antitubercular therapy for 9 months and improved. Conclusion: Tuberculosis can affect any part of skeleton and high level of suspicion is essential.

Culture negative lesion should be investigated and histopathological examination is essential for any lytic or infective lesion.

Keywords: Tuberculosis, talus, osteomyelitis, osteolytic

T

ubercular talar osteomyelitis is an uncommon entity in children. Although tuberculosis of foot is well reported but talar tuberculosis is rare.1,2 Involvement of talus due to subacute hematogenous osteomyelitis in children has been reported by several authors.3-8 But, tubercular involvement of talus in children less than 2 years is rare.1,2,9-17 Moreover, the mimicking radiological feature with aneurysmal bone cyst, giant cell tumor and other infections poses diagnostic dilemma.18-20 Here, we report a rare case of tubercular talar osteomyelitis in a 19-month-old young male child who presented with pain and inability to bear weight on left lower limb.

CASE REPORT A 19-month-old baby presented to our OPD with pain and intermittent low-grade fever for 5 months.

*Associate Professor Dept. of Orthopedics, IGIMS, Patna, Bihar †Assistant Professor Dept. of Orthopedics, AIIMS, Bhubaneswar, Odisha ‡Senior Resident #Additional Professor Dept. of Orthopedics, IGIMS, Patna, Bihar Address for correspondence Dr Mantu Jain 106 Mahadev Orchid, Cosmopolis Road, Dumduma, Bhubaneswar - 751 019, Odisha E-mail: montu_jn@yahoo.com

Repeated consultation was done for fever with poor response. Limp was not noticed earlier, since child started walking at 14 months and repeated falls were taken as normal. The child had no history of cough, night sweating, loss of weight and appetite. Birth history and perinatal history were insignificant.

Immunization schedule was followed as per guidelines including BCG vaccination at birth.

On examination, the general condition was fine. Vitals were stable and child was afebrile. On examination of left foot, it was swollen, tender and warm below the medial malleolus (Fig. 1). There was a boggy swelling over the talonavicular area medially. Ankle range of motion was normal. Foot pronation and supination was restricted. Distal neurovascular assessment was unremarkable. On investigation, hemoglobin (Hb) 9.90 g/dL, total leukocyte count (TLC) -14,680/mm3, differential leukocyte count (DLC) showed neutrophils 30%, lymphocytes = 56%, blood urea -7.3 mg/dL, serum creatinine - 0.6%, erythrocyte sedimentation rate (ESR) 55 mm and C-reactive protein (CRP) titer was raised.

Test for viral markers were unreactive. X-ray showed osteolytic lesion in talus with breach in dorsal cortex (Fig. 2). On needle aspiration from talus, we found sanguineous fluid. It was sent for culture sensitivity, which was found sterile. On histopathological examination, only blood cell was found. The patient was kept on below knee pop slab, antibiotics and analgesics with no improvement.

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ORTHOPEDICS after consultation with pediatric department. The patient was discharged on below knee POP cast in equinus. Total 9 months of antitubercular therapy was given with 3 months each for intensive, continuation and maintenance phase. At 1-year follow-up, the patient is doing well with complete healing of the lesion.

DISCUSSION

Figure 1. Clinical picture of the patient showing swelling and signs of inflammation.

Figure 2. X-ray anteroposterior and lateral view showing a lytic lesion involving the talus.

After a week, the patient was operated with differential diagnosis of chronic osteomyelitis of talus and aneurysmal bone cyst. Through anteromedial incision along tibialis anterior the talus was approached.

Talonavicular joint was exposed to confirm the talus.

The talus was drilled over the neck proximal to talonavicular joint and it was thoroughly curetted.

Material obtained was sent for Gram staining and ZiehlNeelsen (ZN) staining, aerobic culture and sensitivity and histopathological examination. Once the normal endosteum was found then the wound was thoroughly lavaged and closure done. Postoperatively, the patient was kept on intravenous antibiotics and below knee plaster-of-Paris (POP) cast in equinus. ZN staining was positive for acid-fast bacilli. The culture and sensitivity report was no growth, after 10 days; histopathological report confirmed tuberculosis. At 12th day, the stitches were removed and antitubercular therapy were started

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Tuberculous involvement of skeleton is 1-3% of extrapulmonary tuberculosis.1 Involvement of foot among osteoarticular tuberculosis is less than 10%.1 Among all bones of foot, osteomyelitis of talus is rare.1-8 Our search in electronic and print media revealed cases mostly about subacute hematogenous osteomyelitis of talus and foot bones.3-8 Dhillon1 and Mittal2 have reported exclusively on tuberculosis of foot bones. Only one case of talar osteomyelitis out of 24 cases was reported by Dhillon et al1 and none out of 44 cases in a series by Mittal et al.2 Isolated case reports on talus have been reported in recent years and are given chronologically in Table 1.9-17 Our patient is the youngest case to be reported.

The diagnosis is usually difficult since presentation is vague and nonspecific.4,7 Flexion at hip and knee with limb in external rotation may be present.4 Swelling and redness in the foot may be delayed feature.4 Location of swelling is variable. Verbreek4 reported swelling on the lateral aspect while Ganaisan5 reported swelling over the ankle area. We noticed swelling on the medial aspect of mid-foot. Constitutional symptoms are usually nil.1,2,6,7 In our case, low-grade fever and inability to bear weight for 5 months was the only complaint.

Table 1. Isolated Cases of TB Talus as Reported in Chronological Order Author

Year of reporting

Age of patient (years)

Anand et al9

2002

8

Teklali et al10

2003

20 months

Ebrahimzadeh et al11

2006

7

Mardanpour et al12

2010

52

Arora et al13

2014

45

2014

14

2015

42

2015

14

2016

5

Dahuja et

al14

Mohammad et al15 Sekhon et Khan et

al16

al17

ORTHOPEDICS Delayed diagnosis is usually due to lack of constitutional symptoms, poor localizing signs, low level of suspicion and simulating radiological features.1-8,18,19 Symptoms to admission was 5 months average (Dhillon1), 1 month (Ganaisan5), 2-12 weeks (Ezra6), 5 days to 4 weeks (Grattan-Smith7) and 1-5 months (Skevis8). In our case it was 5 months.

Following the rule, we found granuloma in our case.

Culture negative and lack of conclusive diagnosis can be curtailed by early biopsy. Delay in diagnosis may lead to complete destruction of bone and joints. Hence, early diagnosis is the priority.

Hemogram shows signs of infection with raised ESR,1,4-8 but CRP is rarely raised.4,6 In our case, the ESR and CRP was raised along with lymphocytosis.

Age is no bar for osteoarticular tuberculosis. Any osteolytic lesion in talus or foot bones should be investigated and high level of suspicion is essential to rule out tuberculosis. All the abscesses should be biopsied to prevent missed diagnosis. Early diagnosis and complete treatment of tuberculosis should be the aim.

Conventional radiography is the primary tool for diagnosis. Phemister's triad of periarticular osteoporosis, marginal erosions and narrowing of joint space is usually seen in osteoarticular tuberculosis. But, this feature is not evident in foot bones always.2 Mittal et al2 observed five patterns of foot bone lesions in tuberculosis: cystic, rheumatoid, subperiosteal, kissing and spina ventosa. In our case, it was cystic type of lesion, which has central osteolytic lesion with no sequestrum and no periosteal reaction.

The lesion in foot usually mimics other conditions as well.18-20 Aneurysmal bone cyst, giant cell tumors and infections of foot bones mimics cystic type of tuberculosis. Shirazi et al20 noted aneurysmal bone cyst was as common as giant cell tumor of small bones of hand and feet. Infections and inflammatory simple cysts were equally prevalent in less than 10 years old children.20 We found blood on aspiration from talus in our case. Hence, our differential diagnosis was aneurysmal bone cyst and chronic osteomyelitis.

Computed tomography (CT) scan, magnetic resonance scan and bone scan of foot is usually required to localize the lesion and to see the soft tissue condition.1,2,4-7,18 Magnetic resonance imaging (MRI) shows changes consistent with chronic osteomyelitis.5 Bone scan with gallium-67 (Ga-67) and technetium-99 (Tc-99) shows increased tracer uptake in the tarsal bones.6,7 On getting negative report on aspiration cytology and culture sensitivity we directly opted for curettage exploration of the lesion as suggested by Dhillon et al.1 The same has been done by other authors.1,7,18,20 The culture report is usually negative since osteoarticular tuberculosis is a paucibacillary condition.1,2,7 Open curettage and biopsy is usually required for diagnosis.1,2,7,8,18-20 Minimal pus and granulation tissue is found with evidence of necrotic bone and polymorphonuclear infiltrate.7 As a rule, we send sample for culture in every case of suspected tumor and we do histopathological examination of every abscess.

CONCLUSION

REFERENCES 1. Dhillon MS, Aggarwal S, Prabhakar S, Bachhal V. Tuberculosis of the foot: An osteolytic variety. Indian J Orthop. 2012;46(2):206-11.

2. Mittal R, Gupta V, Rastogi S. Tuberculosis of the foot.

J Bone Joint Surg Br. 1999;81(6):997-1000.

3. Pabla R, Tibrewal S, Ramachandran M, Barry M. Primary subacute osteomyelitis of the talus in children: a case series and review. Acta Orthop Belg. 2011;77(3):294-8.

4. Verbeek PA, de Roest JG, van Raaij TM. Osteomyelitis of the talus in a limping child. Ned Tijdschr Geneeskd.

2012;155(35):A5103.

5. Ganaisan P, Singh A, Kumar C, Manikam R. A limping child: on a first look it is hip or knee in origin! No! Itâ&#x20AC;&#x2122;s a Talus osteomyelitis. Int J Orthop Surg. 2013;20(1).

6. Ezra E, Wientroub S. Primary subacute haematogenous osteomyelitis of the tarsal bones in children. J Bone Joint Surg Br. 1997;79(6):983-6.

7. Grattan-Smith JD, Wagner ML, Barnes DA. Osteomyelitis of the talus: an unusual cause of limping in childhood. AJR Am J Roentgenol. 1991;156(4):785-9.

8. Skevis XA. Primary subacute osteomyelitis of the talus.

J Bone Joint Surg Br. 1984;66(1):101-3.

9. Anand A, Sood LK. Isolated tuberculosis of talus without ankle and subtalar joint involvement. Med J Malaysia.

2002;57(3):371-3.

10. Teklali Y, El Alami ZF, El Madhi T, Gourinda H, Miri A. Tuberculosis of the talus in the child. Eur J Orthop Surg Traumatol. 2003;13(1):52-4.

11. Ebrahimzadeh MH, Sadri E. Isolated tuberculosis of the talus bone. Arch Iran Med. 2006;9(2):159-60.

12. Mardanpour KK, Rahbar M. Isolated tuberculosis of the talus bone. Casp J Intern Med. 2010;1(2):75-7.

13. Arora K, Choudhry P. Tuberculosis of talus bone in middle aged man - A case report. Int J Orthop Trauma Nursing.

2014;18(1):35-8.

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ORTHOPEDICS 14. Dahuja A, Dahuja G, Kaur R, Bansal K. Isolated tuberculosis of talus: a case report. Malays Orthop J. 2014;8(1):61-2.

18. Sharma S, Gupta P, Sharma S, Singh M, Singh D. Primary aneurysmal bone cyst of talus. J Res Med Sci. 2012;17(12):1192-4.

15. Mohammad F, Singh S, Lal AK, Kumar S. Tuberculosis of talus: a case report. Indian J Orthop Surg. 2015;2(2):46-7.

19. Luna AR, Fahandez-Saddi H, Garcia AV, Reina Cde J, Martin JV. Aneurysmal bone cyst in children involving infrequent locations. Report on two cases. Chir Organi Mov. 2004;89(4):347-52.

16. Sekhon G, Gill SS, Singh M, Gautam R. Tuberculosis of the talus bone. Int J Develop Res. 2015;11:5993-5.

20.

17. Khan FA, Khoshhal K, Saadeddin M. Tuberculosis of talus and cuboid - a report of 2 children. Acta Orthop Scand. 1999;70(6):637-9.

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Shirazi N, Gupta V, Kapoor I, Harsh M, Chauhan N, Ahmad S. Osteolytic lesions of hand and feet: a sevenyear experience from a tertiary referral centre of North India. Malays J Pathol. 2014;36(2):115-24.

Menopausal Hormone Therapy Brings Improvement in the Bone Health of Women Menopausal hormone therapy can significantly improve the bone mass and structure and thus can prevent and treat osteoporosis specifically in women younger than 60 years old, suggests a study published online in the Journal of Clinical Endocrinology & Metabolism. Researchers observed that the bone health benefits of the menopausal hormone therapy lasted for at least 2 years even after the cessation of the therapy.

Discovery of a Novel Blood Test to Detect Early Stages of Arthritis A new blood test that assesses changes in oxidized, nitrated and sugar-modified amino acids in the bloodstream of an individual can significantly classify and predict the early stages of arthritis, suggests a study published online in the journal Arthritis Research & Therapy. According to the authors the new test classifies and detects the early stages of arthritis with “relatively high sensitivity and specificity.” Hence by early detection of the diseased condition by means of this test, health professionals can start the treatment early and prevent painful and debilitating disease.

Targeting Serotonin System for Developing Therapies for Alzheimer’s Associated Bone Disorders A study published online in the Journal of Alzheimer's Disease, observed a reduced bone mineral density at an early stage in the tau-based mouse models of Alzheimer's disease. Further, it was suggested that modifications in tau protein is a result of serotonin-producing cells of the brainstem of such mice models. Thus, by carefully exploring the serotonin system, new therapeutic targets can be developed for the treatment of Alzheimer’s associated bone disorders.

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PEDIATRICS

Zinc Supplementation During the Growing Years SHWETA PATHAK GUPTA

ABSTRACT Zinc is an essential mineral perceived by the people today as being of “exceptional biological and public health importance”, mainly during prenatal and postnatal development. Zinc deficiency affects about 2 billion people in the developing world and is associated with many diseases. In growing children, it causes growth retardation, delayed sexual maturation, infection susceptibility and mainly diarrhea. Consumption of excessive zinc can cause ataxia, lethargy and copper deficiency.

Keywords: Zinc, zinc metabolism, gastroenteritis, zinc deficiency

ZINC AS AN ESSENTIAL ELEMENT

Importance of zinc in growing children is as follows:

Zinc is an essential trace element for humans. Zinc is found in nearly 100 specific enzymes. It is "typically the second most abundant transition metal in organisms" after iron and it is the only metal which appears in all enzyme classes. In proteins, zinc ions are often coordinated to the amino acid side chains of aspartic acid, glutamic acid, cysteine and histidine.

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Vital for growth and cell division

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Vital for fertility

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Vital for the immune system

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Vital for taste, smell and appetite

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Vital for skin, hair and nails

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Vital for vision.

There is 2-4 g of zinc distributed throughout the human body. Most zinc is in the brain, muscle, bones, kidney and liver, with the highest concentrations in the prostate and parts of the eye. Semen is particularly rich in zinc, which is a key factor in prostate gland function and reproductive organ growth.

WHO NEEDS ZINC?

IMPORTANCE OF ZINC FOR GROWING CHILDREN Zinc is an essential component of the diet and is required for the synthesis of enzymes involved in nucleic acid and protein metabolism, including DNA polymerase, RNA polymerase, alcohol dehydrogenase, carbonic anhydrase and alkaline phosphatase. It is well-known that zinc deficiency may result in diseases such as skin dermatitis and lead to taste disorders.

However, the association of zinc deficiency with the pathogenesis of liver disease is less well-understood.

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

The essentiality of zinc in humans was established in 1963. During the past 50 years, tremendous advances in both clinical and basic sciences of zinc metabolism in humans have been observed.

Children and even adults need zinc in sufficient quantities. Children need zinc to grow, adults need zinc for maintenance of optimum health. Growing infants, children and adolescents, pregnant women and lactating mothers, athletes, vegetarians and the elderly often require more zinc.

Barnes and Moynahan (1973) reported a 2-year-old girl with severe acrodermatitis enteropathica who was being treated with diiodohydroxyquinoline and a lactase-deficient synthetic diet but was not showing any satisfactory response to this therapy. The serum zinc concentration was significantly decreased.

They, therefore, administered oral zinc sulfate to correct this deficiency. Surprisingly, the skin lesions and gastrointestinal symptoms cleared after zinc supplementation.

A severe deficiency of zinc has also been observed in patients with Wilson’s disease who received penicillamine therapy as decoppering agent.

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PEDIATRICS This treatment may induce excessive zinc loss and cause severe deficiency of zinc.

proportion of episodes lasting more than 7 days were also substantially reduced.

Implications of zinc deficiency in children is discussed in the following section.

The mechanism of action of zinc in the management of diarrhea is not completely understood. It is likely to be involved in improving the absorption of fluids from the intestine, helping with clearance of organisms, and supporting regeneration and mucosal integrity, and is likely to have an immunity-related mechanism.

ZINC AND GROWTH Growth is the first limiting effect of zinc deficiency in experimental animals. Zinc deficiency decreases circulating insulin-like growth factor 1 (IGF-1) concentration independent of total energy intake.

In humans, zinc deficiency decreases circulating IGF-1 concentration. IGF-1 receptor possesses tyrosine kinase activity. On activation of the receptor by IGF, a cascade of phosphorylation occurs within the cell leading to regulation of cell cycle and cell division. Tyrosine phosphorylation of the receptor is essential for its activation, and I hypothesize that because zinc has been shown to inhibit various protein tyrosine phosphatases, phosphorylation of the tyrosine kinase receptor by zinc is perhaps the most important critical step of zinc action on human growth.

Thus, it appears that zinc has multiple roles in growth.

It is required for IGF-1 generation and phosphorylation of IGF-1 receptor, which are involved in cell division and growth.

ZINC AND GASTROENTERITIS Gastroenteritis, presenting mostly as diarrhea, is associated with severe zinc deficiency and is frequently seen in developing countries. A pooled analysis of all published and unpublished randomized controlled trials of zinc supplementation in children up to 5 years old with acute or persistent diarrhea found that zinc-supplemented children had a 15% lower probability of continuing diarrhea on a given day.

A Canadian group working in Karachi, Pakistan, reported that mean (SD) longitudinal prevalence of diarrhea among 75 young children aged 6-12 months at high risk of diarrhea-related mortality who received micronutrients with zinc for 2 months was 15% (10%) child-days compared with 26% (20%) child-days in the placebo group.

Among almost 300 children from India with diarrhea resulting in dehydration and hospitalization, stool output was reduced in more than 30% (95% CI 1-52%) of children receiving zinc treatment compared with children receiving placebo. Duration of illness and

Other roles of zinc can also be discussed, for instance in immunity.

SIDE EFFECTS OF ZINC SUPPLEMENTATION Till date, there have been no reports of severe adverse reactions from any form of zinc supplementation used in the treatment of diarrhea. A zinc dose of 40 mg has been approved as being safe to use by the US Food and Drug Administration (FDA), and a zinc dosage of more than this can pose certain risks. Too much zinc will probably interfere with the metabolism and absorption of other essential minerals in the body, especially iron, magnesium and copper, reduce the body's immune function and reduce the high-density lipoprotein cholesterol level. Oral zinc sulfate supplements can also cause side effects such as stomach upset, heartburn and nausea.

CONCLUSION Zinc is an essential element for growth and cell division, fertility, for the immune system, for taste, smell and appetite, for skin, hair and nails, for vision, especially in growing children. Diarrhea is associated with severe zinc deficiency and is frequently seen in developing countries such as India, Bangladesh, Pakistan, etc. The government should start specific programs to educate people about the importance of zinc in growing years of children.

SUGGESTED READING 1. Goldman RD. Zinc supplementation for acute gastroenteritis. Can Fam Physician. 2013;59(4):363-4.

2. Matsumura H, Nirei K, Nakamura H, Arakawa Y, Higuchi T, Hayashi J, at al. Zinc supplementation therapy improves the outcome of patients with chronic hepatitis C. J Clin Biochem Nutr. 2012;51(3):178-84.

3. Prasad AS. Discovery of human zinc deficiency: its impact on human health and disease. Adv Nutr. 2013;4(2):176-90.

4. Roy SK, Hossain MJ, Khatun W, Chakraborty B, Chowdhury S, Begum A, et al. Zinc supplementation in children with cholera in Bangladesh: randomised controlled trial. BMJ. 2008;336(7638):266-8.

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EXPERT’S VIEW

Which Hypertensive Patients are Most Likely to Benefit from β-blockers?

SK JAIN

A

lpha1-adrenergic blockers are drugs that work by blocking the α1-receptors located postsynaptically on the vascular smooth muscle cells. Thus, they prevent the uptake of circulating or neurally-released catecholamines. This causes vasodilatation and reduction in blood pressure (BP).1,2 The patients who are most likely to be benefited from a-adrenoceptor blockade are: ELDERLY MALE WITH BENIGN PROSTATIC ENLARGEMENT Lower urinary tract symptoms (LUTS) and hypertension are both common problems in elderly men. Overstimulation of the sympathetic nervous system mediated by all α1-adrenergic receptor subtypes is involved in the etiology of both hypertension and the dynamic manifestations of LUTS.3 Through sympatholytic effects on prostatic smooth muscle; α1-blockers reduce LUTS, increase urine flow and decrease residual bladder volume in symptomatic benign prostatic hyperplasia (BPH). The various α1-blockers have equal efficacy against the dynamic manifestations of LUTS. The primary differences between them lie in their potential to produce cardiovascular adverse events (predominantly hypotension and associated BPrelated effects) and their impact on various aspects of sexual function.4 Selective α1-blockers were originally developed for the treatment of hypertension.5 At clinically prescribed doses, prazosin, doxazosin and terazosin appear to have comparable levels of clinical efficacy.6 Terazosin and doxazosin have an improved adverse effect profile compared with prazosin. However, selectivity for the α1a and/or α1d subtypes over the α1b subtype appears to be important for clinical

Senior Pulmonologist Moolchand Medcity, New Delhi

‘uroselectivity’. Agents with greater selectivity for the α1b subtype have therapeutic advantage of BP regulation particularly in the elderly.7 SMOKERS Smoking is included in factors influencing prognosis in hypertensive patients.8 Tobacco use compounds the cardiovascular risk attributable to hypertension.9 Smokers can be considered α-stimulated and so selective α1-inhibitors might be potent antihypertensive drugs in these patients. Doxazosin was superior to atenolol in this respect.10 RENAL FAILURE Prazosin and terazosin can be used in patients with renal failure in the same dose as in nonuremic patients.11 The plasma concentration of prazosin is not affected by hemodialysis. The drug can be easily titrated with few side effects.

CHRONIC OBSTRUCTIVE AIRWAY DISEASE These drugs can be safely used in hypertensive patients with concomitant bronchospasm. They do not affect atopic or reactive airway disease. Prazosin may exhibit mild bronchodilator activity in some subjects.12 PREGNANCY Pregnant hypertensive patients can be safely given these drugs to lower BP. Some authors advocate these drugs as first-line therapy in hypertension of pregnancy.13 REFERENCES 1. Kaplan NM. Treatment of hypertension: Drug therapy.

In: Neal WW (Ed.). Textbook of Clinical Hypertension.

6th Edition, 1994. pp.191-280.

2. Pandit RB. Hypertension and CHD risk: whither alpha-1 blockers? Indian Heart J. 1996;48(3):265-71.

3. Andersson KE. Alpha-adrenoceptors and benign prostatic hyperplasia: basic principles for treatment with alphaadrenoceptor antagonists. World J Urol. 2002;19(6):390-6.

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EXPERT’S VIEW 4. Chobanian AV, Barkis GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-72.

5. Kaplan SA, Kaplan NM. Alpha-blockade: monotherapy for hypertension and benign prostatic hyperplasia.

Urology. 1996;48(4):541-50.

6. Akduman B, Crawford ED. Terazosin, doxazosin and prazosin: current clinical experience. Urology. 2001; 58(6 Suppl 1):49-54.

7. Schwinn DA, Michelotti GA. Alpha 1-adrenergic receptors in the lower urinary tract and vascular bed: potential role for the alpha1d subtype in filling symptoms and effects of ageing on vascular expression. BJU Int. 2000;85 Suppl 2: 6-11.

Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension.

J Hypertens. 2003;21(6):1011-53.

9. Whitworth JA; World Health Organization, International Society of Hypertension Writing Group. 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens. 2003;21(11):1983-92.

10. Karvonen M, Orma E, Keys A, Fidanza F, Brozek J. Cigarette smoking, serum-cholesterol, blood-pressure and body fatness; observations in Finland. Lancet.

1959;1(7071):492-4.

11. Curtis JR, Bateman FJ. Use of prazosin in management of hypertension in patients with chronic renal failure and in renal transplant recipients. BMJ. 1975;4(5994):432-4.

12. Marlin GE, Thompson PJ, Reddel HK, Chow CM, Cheng S. Bronchodilator activity of prazosin in patients with allergic rhinitis and asthma. Br J Clin Pharmacol.

1983;13(3):445-8.

13. Davey DA, Dommisse J. The management of hypertension 8. European Society of Hypertension-European Society of Cardiology Guidelines Committee. 2003 European in pregnancy. S Afr Med J. 1980;58(14):551-6.

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MEDILAW

Issuing a Medical Certificate: Guidelines for Medical Practitioners A 30-year-old man submitted a medical certificate including fitness certificate to his office on resuming work. When the HR Manager examined the certificates, he found a discrepancy between the date that the employee had been certified as being sick, and the date of issue. The certificate had been issued for a period of 20 days and also did not have the signature of the employee. The company filed a complaint with the medical council seeking verification of the authenticity of the medical certificate issued by the doctor.

Proceed

This is a complaint from the HR Dept of a company regarding a retrospective certificate issued by this doctor for a minor illness dated in the present. The signature or thumb impression of the patient on the certificate issued is missing.

The certificate issued is not in line with the guidelines for issuance of medical certificate. Hence, this is an act of professional misconduct.

A warning is issued.

Lesson: A medical certificate under normal circumstances should specify the anticipated period of absence from duty necessitated because of the ailment of the patient. Due consideration should be given to the circumstances before issuing a certificate certifying a period of illness in back date particularly in relation to a patient with a minor short illness, which is not evident on the date of examination and should add supplementary remarks, where appropriate, to explain the circumstances that warranted the issuance of certificate retrospective in nature.

The medical certificate should carry the signature or thumb impression of the patients. (DMC/647/2010)

to Mr Y on the same date stating that the patient was fit to resume work from 21.12.2009.

CASE SUMMARY ÂÂ

A complaint was submitted to the Delhi Medical Council by Mr X, CEO of a company A who asked the Council to examine and verify a medical certificate submitted by one of his employees, Mr Y. The certificate was issued by Dr Z.

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The Council examined the complaint, the written statement of Dr Z, which confirmed that the medical certificate in question was issued by him to Mr Y for the period mentioned therein, the medical certificate issued and other relevant documents.

The Council also heard the doctor in person.

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The medical certificate was found to be issued on 17.12.2009 for a period of 52 days with effect from 31.10.2009 to 21.12.2009 for illness specified as enteric fever with peripheral neuritis with injury of the left big toe. The fitness certificate was also issued

Observations of the Delhi Medical Council ÂÂ

The Council observed that the certificate issued was not in line with the Regulation 1.3.3 of the MCI Code of Ethics Regulations, 2002; which states that:“He/She shall not omit to record the signature and/ or thumb mark, address and at least one identification mark of the patient on the medical certificates or report.

The medical certificate shall be prepared in the format prescribed under the aforesaid regulation.”

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The certificate was issued on 17.12.2009 with effect from 31.10.2009 to 21.12.2009. Hence, it was retrospective in nature. A medical certificate should generally certify a period of absence from duty prospectively, from the date on which the patient is examined by the doctor i.e., it may

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879

MEDILAW

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state the anticipated period of absence from duty necessitated because of the ailment of the patient.

(v) Indicate the date the Certificate was written and signed

The certificate was issued for a period of 52 days, which is a very long duration for the illness specified in the certificate ‘‘Enteric fever with peripheral neuritis with injury (Lt) big toe’’ that too without proper investigations.

(vi) Name, signature, qualifications and registered number of the consulting registered medical practitioner

The Council issued guidelines that doctors should abide by when issuing medical certificates. (a) “Medical certificates are legal documents. Medical practitioners who deliberately issue a false, misleading or inaccurate certificate could face disciplinary action under the Indian Medical Council (Professional Conduct, Etiquette and Ethics), Regulations, 2002. Medical practitioners may also expose themselves to civil or criminal legal action. Medical practitioners can assist their patients by displaying a notice to this effect in their waiting rooms.

It is, therefore, a misnomer to state that medical certificate is “not valid for legal or Court purposes”, and should be avoided. Registered medical practitioners are legally responsible for their statements and signing a false certificate may result in a registered medical practitioner facing a charge of negligence or fraud.

(b) The certificate should be legible, written on the doctor’s letterhead and should not contain abbreviations or medical jargon. The certificate should be based on facts known to the doctor. The certificate may include information provided by the patient but any medical statements must be based upon the doctor’s own observations or must indicate the factual basis of those statements.

The Certificate should only be issued in respect of an illness or injury observed by the doctor or reported by the patient and deemed to be true by the doctor.

The certificate should:

When issuing a sickness certificate, doctors should consider whether or not an injured or partially incapacitated patient could return to work with altered duties.

(c) The medical certificate under normal circumstances, as a rule, should be prospective in nature i.e., it may specify the anticipated period of absence from duty necessitated because of the ailment of the patient. However, there may be medical conditions which enable the medical practitioner to certify that a period of illness occurred prior to the date of examination. Medical practitioners need to give careful consideration to the circumstances before issuing a certificate certifying a period of illness prior to the date of examination, particularly in relation to patients with a minor short illness which is not demonstrable on the day of examination and should add supplementary remarks, where appropriate, to explain the circumstances which warranted the issuances of certificate retrospective in nature. (d) It is further observed that under no circumstances, a medical certificate should certify period of absence from duty, for a duration of more than 15 days. In case, the medical condition of the patient is of such a nature that it may require further absence from duty, then in such case a fresh medical certificate may be issued. (e) Record of issuing medical certificate - Documentation should include:

(i) Indicate the date on which the examination took place

–

Patient to put signature/thumb impression on the medical certificate

(ii) Indicate the degree of incapacity of the patient as appropriate

–

Identification marks to be mentioned on medical certificate

(iii) Indicate the date on which the doctor considers the patient is likely to be able to return to work

–

That a medical certificate has been issued

(iv) Be addressed to the party requiring the certificate as evidence of illness e.g., employer, insurer, magistrate

880

(vii) The nature and probable duration of the illness should also be specified. This certificate must be accompanied by a brief resume of the case giving the nature of the illness, its symptoms, causes and duration.

Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

– The date/time range covered by the medical certificate –

The level of incapacity (i.e., unfit for work, light duties, etc. within scope of practice)

MEDILAW An official serially numbered certificate should be utilized.

The original medical certificate is given to the patient to provide the documentary evidence for the employer.

The duplicate copy will remain in the Medical Certificate book for records. The records of medical certificate are to be retained with the doctor for a period of 3 years from the date of issue.”

Judgment After examination of the facts, the Council considered it an act of professional misconduct and issued a warning to Dr Z.

Reference 1. DMC/DC/F.14/Comp.647/2010/

RELEVANT MCI REGULATIONS FOR ISSUANCE OF MEDICAL CERTIFICATES 1.3.3 A Registered medical practitioner shall maintain a Register of Medical Certificates giving full details of certificates issued. When issuing a medical certificate he/she shall always enter the identification marks of the patient and keep a copy of the certificate. He/She shall not omit to record the signature and/or thumb mark, address and at least one identification mark of the patient on the medical certificates or report. The medical certificate shall be prepared as in Appendix 2.

1.4.1 Every physician shall display the registration number accorded to him by the State Medical Council/Medical Council of India in his clinic and in all his prescriptions, certificates, money receipts given to his patients.

1.4.2 Physicians shall display as suffix to their names only recognized medical degrees or such certificates/diplomas and memberships/honors, which confer professional knowledge or recognizes any exemplary qualification/ achievements.

7.3 If he/she does not display the registration number accorded to him/her by the State Medical Council or the Medical Council of India in his clinic, prescriptions and certificates, etc. issued by him or violates the provisions of regulation 1.4.2.

7.7 Signing Professional Certificates, Reports and Other Documents: Registered medical practitioners are in certain cases bound by law to give, or may from time to time be called upon or requested to give certificates, notification, reports and other documents of similar character signed by them in their professional capacity for subsequent use in the courts or for administrative purposes etc. Such documents, among others, include the ones given at Appendix–4. Any registered practitioner who is shown to have signed or given under his name and authority any such certificate, notification, report or document of a similar character which is untrue, misleading or improper, is liable to have his name deleted from the Register.

Source: MCI Code of Ethics Regulations, 2002.

Appendix 2

Form of Certificate Recommended for Leave or Extension or Communication of Leave and for Fitness Signature of patient or thumb impression ___________________________________________ To be filled in by the applicant in the presence of the Government Medical Attendant, or Medical Practitioner.

Identification marks: a. __________________________

b. __________________________

I, Dr. _________________________ after careful examination of the case certify hereby that __________ whose signature is given above is suffering from _________________ and I consider that a period of absence from duty of __________________ with effect from ________________ is absolutely necessary for the restoration of his health.

I, Dr. _______________________ after careful examination of the case certify hereby that ___________on restoration of health is now fit to join service.

Place: ________________ Date: ______________

Signature of Medical Attendant Registration No.: ______________________

(Medical Council of India/State Medical Council of ……….......................…. State) Note: The nature and probable duration of the illness should also be specified. This certificate must be accompanied by a brief resume of the case giving the nature of the illness, its symptoms, causes and duration.

Source: MCI Code of Ethics Regulations, 2002.

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CONFERENCE PROCEEDINGS

69th Annual National Conference of Indian Psychiatric Society (ANCIPS 2017) REBT: BASIC CONCEPTS AND CLINICAL PERSPECTIVES Dr Vivek Kirpekar, Nagpur ÂÂ

Rational emotive behavioral therapy (REBT) can be a good psychotherapeutic tool in the hands of a practicing psychiatrist.

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The theory of REBT talks about beliefs that interfere with rational thinking to cause emotional and behavioral problems.

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Disputation of irrational thoughts is probably the most important step in therapy.

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We all are fallible human beings.

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‘I must’, ‘you must’ and the ‘world must’ are three irrational core beliefs.

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Anxiety disorders, depression are conditions where REBT can be used.

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REBT is based on philosophies of Eastern world along with Western concepts.

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Neuroscience-based nomenclature: This framework classifies psychotherapeutic medications into 6 dimensions and has already classified 108 of the approximately 150 psychotherapeutic medications.

Dimension 1: Pharmacological domain; Dimension 2: Mode of action; Dimension 3: Approved indications; Dimension 4: Efficacy and side effects; Dimension 5: Practical notes; Dimension 6: Neurobiology-preclinical and clinical.

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Classification of Psychotherapeutic Medications, Circa 2017: D2 antagonists and partial agonists, monoamine reuptake inhibitors, agonists and MAOIs, GABA-enhancing agents (PAMs-BDZs), voltage-gated calcium and sodium ion channel blockers, catecholamine reuptake inhibitors and releasers, AChE inhibitors, others (lithium, H1 antagonists).

common

NEUROSCIENCE-BASED CLASSIFICATION OF PSYCHOTHERAPEUTIC MEDICATIONS: MATCHING DIAGNOSIS OF TREATMENT Dr Ravi Tandon, USA Nomenclature or a framework for the use of any form of medication is of great importance. It certainly can help in a number of ways. It could help in organizing the available information on medications and importantly can assist in providing a structure to incorporate recent advancements.

Dr Ravi, through his presentation, shared his knowledge on important classification systems for psychotherapeutic medications.

WHO Psychotherapeutic Medications ClassificationATC System ÂÂ

NO5 Psycholeptics (calming effect): Antipsychotic, anxiolytic and hypnotics/sedatives.

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NO6: Antidepressants, stimulants and nootropics, psycholeptics and psychoanaleptics in combination and anti-dementia drugs.

882

This taxonomical classification is complex and yet uninformative making it more confusing and contributes to stigma. Contrary, clinicians in current practice used a much simpler classification that group the drug system as antipsychotics, antidepressants, mood stabilizers, stimulants, benzodiazepines and others. Nevertheless, this practice also has its own detriments such as inconsistent clinical practice. To keep up with scientific advances and clinical reality, new classification systems have been developed such as Neuroscience-based nomenclature (NbN) and Circa 2017.

Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

Though experts are designing new classification systems for psychotherapeutic medications this area still requires a lot of attention for the proper management of psychiatric disorders.

ANCIPS 2017 CATERS TO THE NEEDS OF ALL Dr SD Singh, Cochin ANCIPS 2017 is a wide and deep feast of knowledge, which caters to the needs of all groups. Practicing Psychiatrists will get tips and guidelines to enhance the quality of practice, whereas academicians will get information about new arenas to be explored. Young Psychiatrists will be developing acquaintances, from where they can build up professional relations, which

CONFERENCE PROCEEDINGS will stimulate them to work further on the area of their interest. For senior persons, it is a chance to meet old friends and perhaps avail a holiday from the busy professional turbulence.

VILAZODONE HAS FASTER AND MORE EXTENSIVE RESPONSE RATES WITH BETTER TOLERABILITY IN DEPRESSION Dr Prasanna Khatawkar, Pune What is the mechanism underlying the fast onset of action of vilazodone in patients of depression?

The presynaptic 5-HT1A autoreceptors are associated with decreased serotonin secretion, whereas the postsynaptic 5-HT1A receptors increase serotonin secretion. The delayed efficacy observed with antidepressants like SSRIs is due to the desensitization or down-regulation of 5-HT1A autoreceptors over longer periods of time. However, with vilazodone, due to its partial agonist activity at 5-HT1A autoreceptors, the desensitization or down-regulation of 5-HT1A autoreceptors is hypothesized to occur over a shorter period.

What are the advantage of 5-HT1A partial agonist action of vilazodone?

The 5-HT1A partial agonist action of vilazodone has the potential to shorten the onset of antidepressant activity, decrease side effects attributed to serotonin reuptake inhibition (e.g., sexual dysfunction) and provide enhanced benefits for symptoms of anxiety.

Is there any long-term data available on the safety and efficacy of vilazodone?

Data is available on the long-term effects of vilazodone from a 52-week study by Robinson et al (2011). The study primarily assessed the safety and tolerability of vilazodone in patients with major depressive disorder (MDD) and concluded that vilazodone 40 mg/day for 1 year was safe and well-tolerated by adults with MDD. What is the effect of vilazodone on weight?

Weight gain by vilazodone recipients in placebocontrolled trials has been found to be low. In the longterm study by Robinson et al (2011), the mean weight gain at 52 weeks was as low as 1.7 kg.

What is the place of vilazodone in the therapy of depression?

The unique mechanism of action of vilazodone suggests that it might provide faster and more extensive response rates with better tolerability, particularly with respect

to sexual dysfunction, than some other commonly used antidepressants. It has the potential to satisfy the current unmet needs such as antidepressants with faster onset of action, improved tolerability, lower rates of weight gain, sexual dysfunction and other common side effects.

Has vilazodone been evaluated in the treatment of anxiety disorders?

Two randomized clinical trials have recently documented the efficacy and safety of vilazodone in patients with generalized anxiety disorder (GAD).

The first study conducted by Gommoll et al (2015), investigated the efficacy, safety and tolerability of vilazodone for GAD in 395 patients for 10 weeks.

Vilazodone showed significant superior efficacy over placebo in mean changes on Hamilton rating scale for anxiety (HAM-A) from baseline to the end of doubleblind treatment (Week 8).

The second study comprised of 667 patients with GAD, n = 223 for vilazodone 20 mg/day, n = 223 for vilazodone 40 mg/day, n = 221 for placebo. The results showed that vilazodone 40 mg/day group had significant superior efficacy over placebo group in mean changes on HAM-A from baseline to the end of double-blind treatment (Week 8).

BRAIN AND GUT AXIS: PSYCHIATRIC UNDERPINNINGS Dr Sujit Sarkhel, Kolkata Dr Sujit in his presentation briefed the audience about the importance of microbiota of small intestine in influencing the development of a number of psychiatric disorders in humans through the microbiota-gutbrain axis. ÂÂ

Small intestine harbors almost 200-600 million nerve cells. Additionally, a strong network of nerve fibers (approx. 1,000-2,000 nerve fibers) connects the brain with the small intestine.

ÂÂ

Brain and gut connection in human body occurs via three pathways: Neural, immune and endocrine pathways.

ÂÂ

Around 40,000 species of microorganisms reside in the small intestine that are strongly involved in modulating the BGA to constitute the microbiotagut-brain axis.

ÂÂ

Findings from animal studies have indicated that gut microbiota is actively involved in the development of ENS and stress responses.

Additionally, recent evidence suggests that

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CONFERENCE PROCEEDINGS these microorganisms may be involved in the pathogenesis of functional bowel disorders as well as psychiatric disorders such as autism, depression, anxiety and schizophrenia. ÂÂ

It would be of no surprise if prebiotics, probiotics and antibiotics would become future treatments for psychiatric disorders considering their potential in influencing microbiota of intestine.

ÂÂ

There is a need for additional human trials to clearly establish the role of gut microbes in modulating the brain, emotion and related disorders.

IMPROVING ADHERENCE IN MANAGEMENT OF SCHIZOPHRENIA Prof Dr RN Sahu, Indore The most challenging aspect of treating patients with schizophrenia is nonadherence to prescribed drug treatments, which has been reported to be as high as 40-50%. It is a frequent cause of impairment, hospitalization, higher risk of suicide, longer time to remission, poorer prognosis, loss of job, dangerous behavior, arrest, violence, drug and alcohol consumption, psychiatric emergences, poor mental performance and low satisfaction with life. Improving adherence can have significant positive impact on patients. So, it is important to focus on factors that increase risk of nonadherence.

Nonadherence risk factors identified up to date include: Previous nonadherence, poor insight, negative attitude or negative response to treatment, current or past drug-dependency, poor relationship with the therapist, shorter length of illness, hospital discharge without an adequate follow-up plan or environment, distress associated with specific side effects or general fear of side effects, inadequate efficacy with persistent symptoms and believing that medication is no longer needed.

Factors positively related to adherence include a good therapeutic relationship with the physician and perceiving the benefits of medication. Medicationspecific characteristics can also affect treatment compliance. Poor response to antipsychotics is a common reason for stopping medication. The usual lag time required to titrate some medications up to a therapeutic dose and the delay of days to weeks to onset of therapeutic effect may contribute to nonadherence as patients may lose patience waiting for a response and stop the medication. Intolerable side effects also contribute to poor adherence to treatment.

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Before planning any intervention to improve adherence, an attempt should be made to understand the patient’s perspective on their illness and the treatment. This will be help in planning the treatment and interventions.

Patients need to be provided targeted education about mental illness and the medications used to treat them, with particular focus on the importance of medication adherence and problems that may arise if medications are discontinued.

Providing instructions or teaching skills that may make medication adherence easier and less demanding may also help. A good communication between patients and providers and involving family members in patient care is important.

Behaviorally-focused interventions such as reinforcing specific medication-taking patterns may improve patient adherence. Medication-related strategies include IM injections of depot medications for those patients who are unable or unwilling to comply with oral medications or have repeatedly failed to adhere to daily medication regimens and simplifying medication regimens as much as possible. Once-daily drugs can be very useful in simplifying the medication regimen.

It is vital that clinicians be aware of the pharmacological properties of the drugs, so dosing strategies can be optimized and also to recognize situations in which potential drug-drug interactions may occur.

Unnecessary polypharmacy should be avoided and the number of different drugs should be limited to the minimum required to control symptoms. This will help in monitoring the clinical response and adverse effects in patients and also reduce the risk of drugdrug interactions.

MANAGEMENT OF BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA Dr SC Tiwari, Lucknow Behavioral and psychological symptoms of dementia or neuropsychiatric symptoms of dementia as defined by the consensus statement of IPA is “Symptoms of disturbed perception, thought content, mood or behavior that frequently occur in patients with dementia”.

It is psychiatric disorder that is commonly observed in geriatric care and is associated with both behavioral as well as psychological symptoms. Through this talk, Dr Tiwari shared his personal clinical experience and management protocol being followed at

CONFERENCE PROCEEDINGS Dept. of Geriatric Mental Health, King Georges’ Medical University for the treatment of patients with BPSD. ÂÂ

ÂÂ

Diagnosis of BPSD is often challenging as it often overlaps with other psychological disorders such as delirium and hence the golden rule is to always rule out delirium before initiating any management strategy.

Management strategies such as comprehensive assessment that includes evaluation of biopsychological-environmental factors. Different standardized scales such as BEHAVE-AD, NPL, ADAS-noncog may be useful. Additionally, establishing care plans can also be of great help.

ÂÂ

Whenever diagnosis is in doubt, always use a minimized pharmacological approach and watch.

ÂÂ

Management of BPSD also involves pharmacological and nonpharmacological strategies.

ÂÂ

Deep ulcers and sinuses over the accessible sites may be present. Puffy-hand syndrome and muscle contractures are common.

ÂÂ

ANA, ANCA and anti-dsDNA screening should be done.

ÂÂ

Infections such as HIV, HBV and HCV should be screened for.

ÂÂ

Patients may or may not have adjunct psychiatric morbidity.

ÂÂ

Patients have to be managed by a good consultation liaison network.

A CASE OF CONGENITAL MUSCULAR DYSTROPHY Dr Ranjan Bhattacharyya, Dr Supriya Kumar Mondal, Dr Siddhartha Shankar Saha; West Bengal ÂÂ

Congenital muscular dystrophy (CMD) refers to a group of muscular dystrophies that become apparent in early infancy or at birth.

ÂÂ

Muscular dystrophies are mostly genetic and a degenerative disease primarily affects voluntary muscles.

ÂÂ

Alpha-dystroglycanopathies, both phenotypically and genetically, are a heterogeneous group of disorders and a subgroup of these patients has characteristic brain imaging findings.

ÂÂ

The case vignette shows a 4-year-old girl, who presented in the OPD with history of throwing tantrums, delayed developmental milestones, irritability and anger outbursts. She had h/o admission in pediatric neurology indoor with complex partial seizures controlled by tab oxcarbazepine. She was born full-term of nonconsanguineous marriage by LUCS. There was progressive muscular weakness since early infancy with difficulty in sucking and breathing. MRI of brain revealed polymicrogyria, white matter changes and subcortical cerebellar cysts.

ÂÂ

The pattern recognition of MRI features may serve as a clue to the diagnosis of alpha-dystroglycanopathy, although definite diagnosis could be obtained only by muscle biopsy and genetic testing.

ÂÂ

In Japan, Fukuyama disease is fairly common, second to Duchenne muscular dystrophy but a milder form like this case is rare.

ÂÂ

High index of suspicion and early diagnosis is required to initiate prompt therapy, which is mainly supportive with rigorous physiotherapy, antiepileptic drugs, parental and genetic counseling.

Nonpharmacological approach is always the

first-line of treatment and includes: Cognitive/ emotional-orientated interventions, sensory stimulatory interventions, behavioral management techniques (ABC approach, identify antecedents, describe behaviors and note consequences) and psychological interventions.

Pharmacological approach includes medications

like:

zz Anti-dementia

drugs, such as ChEIs (effective in apathy, depression and aberrant motor behavior) and memantine (effective in agitation and irritability)

zz Antidepressants,

(effective in irritability)

such as citalopram depression, apathy and

zz Antipsychotic drugs effective in aggression,

psychosis and agitation but ineffective for other dementia symptoms.

ÂÂ

Pharmacological agents should be used cautiously for the management of BPSD as they are associated with serious side effects and their prolonged use can adversely affect cognition.

DIAGNOSTIC CLINICAL FEATURES OF PENTAZOCINE-INDUCED ULCERS: A CASE SERIES Dr Mona Srivastava, Varanasi ÂÂ

IV pentazocine is commonly used.

ÂÂ

Complications of pentazocine abuse may be cutaneous and muscular.

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CONFERENCE PROCEEDINGS

72nd Annual Conference of the Association of Physicians of India (APICON 2017) SHORT-TERM COSTS VS. LONG-TERM VALUE India has over 69 million patients with diabetes and is expected see a 65% increase by 2030.1 A compelling fact, however, is that proportion of annual income spent on healthcare by the urban poor has increased from 24.5% to 34.0% within a 7-year period, and diabetes expenditure saw a 2-fold increase during this period.2 The Cost of Diabetes in India (CODI) study, a large community-based survey of diabetes costs, reported that ambulatory care constitutes 65% of cost (Antidiabetic drug cost is 17%), whereas hospitalization cost is 35%.3 What many of us do not realize is that 60% of associated healthcare costs are due to complications related to diabetes.4 With respect to management of diabetes, sulfonylureas (SUs) have been extensively prescribed in patients with T2DM, since the time they have been introduced.

However, their use has gradually declined from 61% in 1997 to 22% in 2012. One of the reasons being the increased events of hypoglycemia as SUs stimulate insulin secretion virtually independent of plasma glucose level. SUs, when prescribed in combination with metformin, are up to six times as likely as other oral agents to cause hypoglycemia. A study reported that 28% of cases with SU-induced hypoglycemia required hospitalization, which eventually results in increased cost. Furthermore, there is an increased risk of total mortality, diabetes-related death, CVD, CVDrelated death with the use of SUs in combination as well as SUs alone.6 An effective alternative to SUs can be DPP-4 inhibitors, already available and marketed in India, which include sitagliptin, vildagliptin, saxagliptin and linagliptin.

A new low-cost addition to this group is Teneligliptin, a molecule which is neither approved in the USA nor in Europe. It was registered in the US FDA for Phase 1 clinical development in 2007 and Phase 2 clinical developments in European Medicines Agency in 2009, but, there has been no significant progress since.7 Although the published trials on Teneligliptin reported no serious cardiac events attributed to teneligliptin, a thorough cardiovascular dedicated outcome trial is highly desirable.7 While other gliptins including

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sitagliptin, vildagliptin and linagliptin have proven CV safety based on the vast evidence from CV trials or meta-analyses.14 Gliptins such as vildagliptin, sitagliptin, which are marginally high in immediate drug cost, but prove to be cost-effective on long-term evaluation.9 This is mainly because these gliptins have demonstrated benefits beyond their glucose-lowering effects. Sitagliptin is associated with 10% risk reduction of MI and 15% risk reduction of other cause mortality compared to SUs, thus decreasing expense associated with hospitalization due to these comorbidities.1 Addition of vildagliptin to metformin leads to increased drug acquisition cost, but reduces the cost related to adverse events, managing comorbidities and patient monitoring, thus proving to be a cost-effective treatment strategy in the long-term.11 Vildagliptin has also shown to reduce microvascular complications compared to SUs.1 A new class of diabetes medications, SGLT2 inhibitors have also been shown to be efficacious second-line treatments for T2DM with limited risk of hypoglycemia and significant positive CV benefits on CV risk and neutral effects on weight and BP. This class of drugs has been found to be cost-effective as second-line therapy in comparison to other agents.13 As is evident, the cost analysis of diabetes medications shows that over a period, the actual cost associated with antidiabetic medicines is less and the expenditure increases in the management of associated comorbidities.

Hence, while choosing an antidiabetic medication, the long-term health and economic burden for a patient should form an important part of a healthcare provider’s decision making to provide the patients a quality life they deserve and desire.

References 1. Adapted from IDF Atlas 2015. Available at: http://www. idf.org/membership/sea/india. Accessed on 1st Dec, 2016.

2. Ramachandran A, et al. Diabetes Care. 2007;30(2):252-6.

3. Overview of Diabetes Burden. Available [online] at URL: http://www.nhp.gov.in/overview-of-diabetes-burden_ mtl. Accessed on 16th January, 2017.

4. Kapur A. Indian J Med Res. 2007;125:473-82.

CONFERENCE PROCEEDINGS 5. Iglay K, et al. Curr Med Res Opin. 2016;32(7):1243-52.

ÂÂ

Monitor BG 1 hourly, and also keep an eye on K+.

6. Genuth S. Diabetes Care. 2015;38(1):170-5.

ÂÂ

Use PROTOCOL that suits your CCU and stick to it.

ÂÂ

Differ from sliding scale regimen; it’s no more used.

7. Singh AK. Indian J Endocr Metab. 2017;21:11-7.

8. Ghosh S, et al. Diabetes Metab Syndr Obes. 2016;9:347-53.

9. Waugh N, et al. Health Technol Assess. 2010;14(36).

DIURETICS IN PRIMARY HYPERTENSION: RELOADED

10. Chen J, et al. Value Health. 2014;17(7):A349.

11. Viriato D, et al. J Med Econ. 2014;17(7):499-507.

Prof Sundeep Mishra, New Delhi

12. Kolaczynski WM, et al. Diabetes Therapy. 2016;7(3):483-96. ÂÂ

Diuretics are the gold standard of antihypertensive therapy especially in uncomplicated primary HT.

ÂÂ

Despite robust data, the use of diuretics is on the decline.

Dr Dilip Mhaisekar, VC, Maharashtra University of Health Sciences, Nasik

ÂÂ

Diuretics have shown a definite reduction in stroke rates and CV events.

What according to you have been the top 3 advances in medicine in the last year?

ÂÂ

Low-dose diuretic treatment is well-tolerated and may be an excellent initial choice for hypertensive patients, even elderly.

ÂÂ

Low-dose thiazides are inferior in reducing CV events. High-dose is effective but increases side effects.

ÂÂ

Messerli meta-analysis reveals that if a clinical indication calls for a thiazide-type diuretic, indapamide or chlorthalidone remain the drugs of choice.

ÂÂ

Chlorthalidone is 1.5-2 times as potent as hydrochlorothiazide and has shown CV events reduction, but 1 in 8 patients required potassium supplements with chlorthalidone. It also causes persistent 23% increase in SNA, which correlates with insulin resistance.

ÂÂ

Indapamide, a thiazide-like diuretic whether used alone or in combination has not only shown a consistent BP-lowering response but also improvement in CV outcomes.

ÂÂ

One head-to-head comparison (meta-analysis) with chlorthalidone found that indapamide may be superior in efficacy (stroke, CV death and even all-cause mortality) but even better safety.

ÂÂ

One of the reasons for the salutatory effects of indapamide could be its predominantly vascular effect.

13. Gurgle HE, et al. Vasc Health Risk Manag. 2016;12:239-49.

14. Mannucci E, Monami M. Adv Ther. 2017;34(1):1-40.

A TÊTE-À-TÊTE WITH DR DILIP MHAISEKAR

A new concept for treating tuberculosis has come as well as advanced technology for treatment of diabetes.

Sleep medicine is the need of the hour and an upcoming branch.

What would be your message for the young upcoming doctors?

The presence of allopathic doctors is almost nonexistent in villages. It is important to motivate them for rural service. Today, we have a lot of medical colleges compared to previous years. There is currently shortage of about 40% of faculty; we are also facing an acute shortage of specialists and super specialists. In this regard, we have started fellowship courses in various specialties to get more specialty doctors in society.

HYPERGLYCEMIA IN CRITICAL CARE: MANAGEMENT Dr Mangesh Tiwaskar, Mumbai ÂÂ

Globally, diabetes is a major healthcare challenge, the situation is especially bad in India.

ÂÂ

Challenge becomes stiffer in hospitalized patients.

ÂÂ

Hyperglycemia and Intertwined Dragons.

ÂÂ

HbA1c estimation at admission can help in many ways.

ÂÂ

Keep the BG goal of 140-180 mg/dL in critically ill patients.

ÂÂ

BG <100 mg/dL and >180 mg/dL is NOT acceptable in ICU settings.

ÂÂ

Complete blood count is a treasure house of information.

ÂÂ

IV insulin infusion is the best choice to manage hyperglycemia in the CCU.

ÂÂ

Parameters like RDW are often overlooked.

ÂÂ

Reticulocyte count + PS is very informative.

hospitalization

are

like

ABC OF CBC Dr Pankhi Dutta, Mumbai

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CONFERENCE PROCEEDINGS ÂÂ

Newer parameters like Ret-He might do away with a host of biochemical tests (cost and TAT of CBC).

ÂÂ

We could many a times effectively conclude its angiographic correlation.

ÂÂ

Platelet counts, impedance methods of counting, has known limitations.

ÂÂ

We can also conclude the immediate risk even with minor ECG change.

ÂÂ

Improved methods like PLT-F are available.

ÂÂ

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Immature platelet fraction (IPF) is a new parameter of clinical utility in management of dengue.

ECG therefore continues to remain one primary help; however, advanced you may be in imaging applications.

NEW IN DIABETES: ADVANCED AND APPROVED DELIVERY DEVICES FOR INSULIN

APPROACH TO A PATIENT WITH PROLONGED PYREXIA/PUO SUSPECTED TO HAVE TUBERCULOSIS

Dr Jothydev Kesavadev, Trivandrum ÂÂ

No more needles or pains for insulin injections!

ÂÂ

Insulin being physiological in action, brings better outcomes in any type of diabetes.

ÂÂ

Advance i-Port has a subcutaneous cannula through which both the basal and bolus insulin can be delivered.

ÂÂ

i-Port reduces chances of lipohypertrophy, enhances drug adherence and improves QoL.

ÂÂ

Advance i-Port makes injection painless and 75 injections are possible in 72 hours.

ÂÂ

640 G is the first-generation artificial pancreas.

ÂÂ

It automatically switches off insulin delivery 30 min before an impending hypoglycemia with a preprogrammed hypoglycemia threshold.

ÂÂ

First device to incorporate an integrated algorithm for automatic resumption of insulin delivery when glucose level normalizes.

ÂÂ

A blessing to those with type 1 diabetes and to those with brittle type 2 diabetes.

ÂÂ

Newer innovations are too expensive for the common man, but significantly cost-effective in terms of prolonging productive life span.

Prof Dr MA Jalil Chowdhury, Dhaka, Bangladesh ÂÂ

Infectious cause is still the major cause of pyrexia of unknown origin (PUO) worldwide. Amongst the infectious causes, TB is the commonest one in many parts of the world, particularly in the Indian subcontinent.

ÂÂ

TB should be considered in any of the patients who have prolonged pyrexia where no cause is found after initial extensive work-up.

ÂÂ

The most important work up of a PUO case is to re-examine the patient by a physician who has not seen the case in the past.

ÂÂ

It is not easy to confirm the diagnosis of extrapulmonary TB because of difficulty in getting the sample for histopathology or microbiology or reluctance of the physicians in sending the sample if obtained for mycobacterial culture.

ÂÂ

A patient with PUO suspected to have TB should not die without antituberculous chemotherapy.

PREMIXED INSULINS Dr Sanjay Kalra, Karnal ÂÂ

Premixed insulin is the most commonly used insulin preparation in India. The first Indian premixed guidelines were developed in 2009, and updated in 2013.

ÂÂ

There is a need to revisit the Indian premixed insulin guidelines, in view of emerging evidence and introduction of newer co-formulations. In his talk, Dr Kalra evaluated the available premixed formulations, examined existing evidence related to premixed formulations, and the present consensus statement of recommendations on the topic developed by the Expert group.

ÂÂ

Recommendations based on consensus on initiation and intensification of premixed insulin in T2DM management were presented for the

PRACTICAL APPROACH TO A PATIENT WITH ECG CHANGES Dr Shirish (MS) Hiremath, Pune ÂÂ

There have been huge advances in the understanding of chest pain, yet ECG continues to be first step in assessment.

ÂÂ

Over years with advanced imaging, our understanding of ECG has improved tremendously.

Also, we have learnt to handle limitations of ECG derivation more carefully.

ÂÂ

The importance of ECG in chest pain assessment stands tall.

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Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

CONFERENCE PROCEEDINGS following situations: Initiation of premixed insulin at diagnosis; initiation of OD premix insulin/coformulation; initiation of BID premixed insulin/ co-formulation; intensification with BID and TID premixed insulin/co-formulation. Three recommendations pertained to the use of premixed insulin in other forms of diabetes, or in specific situations: Use of premixed insulin in gestational diabetes mellitus; use of premixed insulin in T1DM; premixed insulin use during Ramadan. ÂÂ

ÂÂ

In the setting of high carbohydrate consumption in India, or in patients with predominant postprandial hyperglycemia, premixed insulin/co-formulation can offer an effective and convenient glycemic control.

The new consensus guidelines on premixed insulins will help healthcare practitioners initiate and intensify premixed insulin effectively, and achieve optimal glucose control.

CLINICAL APPROACH TO TREMORS Prof Dr AV Srinivasan, Chennai It is important to make a distinction between rest, postural, action or with intention or task-specific tremors. Tremor characteristics and classification is based on nature, location, frequency, amplitude, rhythmicity, relation to rest and movement, pathology, etiology and age of onset. Approach to a patient with tremors begins with a good history and physical exam, keen sense of observation and a systematic differential diagnosis.

WHAT IS THE BEST ADD-ON DRUG FOR METFORMIN IN THE MANAGEMENT OF T2DM? PIOGLITAZONE

ÂÂ

PRACTICAL APPROACH TO GIDDINESS Dr Sudha Vidyasagar, Manipal ÂÂ

Giddiness is a common symptom of various diseases.

ÂÂ

It is important to distinguish vertigo from giddiness.

ÂÂ

Vertigo due to peripheral and central causes can be identified. For giddiness, cardiac causes such as orthostatic hypotension and arrhythmias must be ruled out.

ÂÂ

A good history and examination for cardiac and CNS lesions will give diagnosis.

ÂÂ

Simple bedside tests such as Dix-Hallpike test are useful; ECG and CNS imaging when needed.

ÂÂ

Psychiatry causes such as anxiety, and drugs causing hypotension must also be ruled out.

ÂÂ

Treatment is according to etiology.

COMA: A PRACTICAL APPROACH Prof Dr V Nagarajan, Madurai ÂÂ

The spectrum of coma ranges from stuprose to deep coma.

ÂÂ

History from relatives, or who brought the case is mandatory. In neurological exam, look for meningeal signs, tone and posturing, fundus, cranial nerves, ↑ICP and brain stem reflexes.

ÂÂ

In functional coma, meningeal signs and focal deficits are absent, brain stem reflexes are present, unequivocal but reactive pupil, plantar flexor (cf structural coma).

ÂÂ

Mandatory investigations include counts, blood glucose, urea, electrolytes, acid base; ammonia, liver function, lactate, cholinesterase level, LP (CI if ↑ICP), cultures, EEG, imaging (to rule out mass lesion, cerebral lesions, massive infarcts and coning).

Dr Anil Kumar Virmani, Jamshedpur ÂÂ

Pioglitazone is the only antihyperglycemic agent to reduce insulin resistance at all levels.

ÂÂ

It has relatively potent HbA1c-lowering properties, low risk of hypoglycemia, durable glycemic control and confers CV benefits.

ÂÂ

It takes care of multiple defects in diabetes, including central adiposity, which is crucial in the Indian context.

ÂÂ

A possible link with bladder cancer has largely been refuted.

Side effects of weight gain, bone fractures in postmenopausal women and elderly, and elevated risk of heart failure, can be mitigated by using a lower dose of <30 mg, lifestyle modification, judicious selection of patients and being pharmacovigilant.

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

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

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

Who is Eligible?

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

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

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

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

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

To promote heart care research in India.

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

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

The patient must be needy and underprivileged, to be assessed

by Fund Committee.

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

The review of applications may take 4-6 weeks.

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

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

To promote and train hands-only CPR.

Activities of the Fund Financial Assistance

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

Financial assistance is given to eligible non emergent heart patients.

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

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

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

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

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

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

Drug Subsidy

Identity proof with proof of residence

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

BPL Card (If Card holder)

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

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

Income proof (preferably given by SDM)

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

Free Diagnostic Facility

Free Education and Employment Facility

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

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

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

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

About Heart Care Foundation of India

Help Us to Save Lives

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

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

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

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

Donate Now...

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

Committee Members

Chief Patron

President

Raghu Kataria

Dr KK Aggarwal

Entrepreneur

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

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

Advisors Mukul Rohtagi Ashok Chakradhar

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

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

Rishab Soni

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

http://heartcarefoundationfund.heartcarefoundation.org

AROUND THE GLOBE

News and Views ACC Expert Consensus Document on Anticoagulation in AF Patients The American College of Cardiology (ACC) has published Expert Consensus Decision Pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation (AF). The recommendations published in the Journal of the American College of Cardiology address various issues such as whether to interrupt, when to interrupt, whether to bridge, how to bridge and how to restart anticoagulation.

ADA New Position Statement on Diabetic Neuropathy The new American Diabetes Association (ADA) position statement published in the January 2017 issue of Diabetes Care has reviewed prevention and management of distal symmetric polyneuropathy (DSPN), diabetic autonomic neuropathies including cardiovascular autonomic neuropathy (CAN), as well as less common forms of neuropathy. The statement does not recommend opioids as a first- or second-line therapy to treat diabetic neuropathic pain. Electrophysiological testing or referral to a neurologist is rarely needed for screening, except in cases of atypical clinical features, unclear diagnosis or if a different etiology is suspected.

Lumacaftor + Ivacaftor Effective for Long-term Treatment of Cystic Fibrosis According to results of the phase 3, 96-week PROGRESS study, the combination of lumacaftor and ivacaftor is effective for the long-term treatment of patients with cystic fibrosis homozygous for the F508delCFTR mutation. The combination was associated with a 42% slower rate of decline in percent predicted FEV1 (ppFEV1) compared to matched registry controls.

The study is published in The Lancet Respiratory Medicine, online December 20, 2016.

Zoledronic Acid Administered at Longer Intervals is Effective in Patients with Bone Metastases Among patients with bone metastases due to breast cancer, prostate cancer or multiple myeloma, the use of zoledronic acid every 12 weeks compared with the standard dosing interval of every 4 weeks did not result in an increased risk of skeletal events over 2 years, suggesting longer interval as an acceptable

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treatment option. Zoledronic acid is a third-generation aminobisphosphonate. These findings are published January 3, 2017 in JAMA.

Reoperation Rates Higher Following DCIS for Breast-conserving Surgery In a population-based registry study published online December 21, 2016 in JAMA Surgery, the overall reoperation rate (re-excisions and mastectomies) in patients who underwent wire-guided breast-conserving surgery was 17.6%. The risk of a reoperation owing to positive margins was 3 times higher in patients with ductal carcinoma in situ (37.3%) vs. those with invasive breast cancer (13.4%) suggesting the need for a more accurate localization method.

Updated Review on Medical Management of Severe Alcoholic Hepatitis An expert review on diagnostic approach and medical management of severe alcoholic hepatitis is published in the January 2017 issue of the journal Clinical Gastroenterology and Hepatology. Patients with alcoholic hepatitis who have jaundice should be hospitalized to encourage abstinence, restore adequate nutrition and exclude serious infections. Iodinated contrast dye should be administered with caution given the risk of acute kidney injury. Nephrotoxic drugs, including diuretics, should be avoided or used sparingly in patients with AH, since AKI is an early manifestation of multiorgan failure. The review includes 12 such Best Practice recommendations.

High Leptin/Adiponectin Indicates Higher Cardiovascular Risk After Gestational Diabetes A high leptin/adiponectin (L/A) ratio in pregnancy, especially in women with gestational diabetes is associated with an unfavorable cardiovascular disease risk profile during follow-up, says a study published January 10, 2017 in Cardiovascular Diabetology.

An increase in the L/A ratio of 1 unit was associated with a higher cardiovascular risk in gestational diabetes compared to normal pregnancy.

A Training Program on Writing Accurate Death Certificates The BMC and Tata Memorial Hospital have joined hands with the Centers for Disease Control and

AROUND THE GLOBE Prevention (CDC) to train doctors on how to issue accurate death certificates, as reported in the Times of India on January 11, 2017 by Malathy Iyer. A 2-year training program regarding this began at Tata Memorial Hospital, Mumbai. A study done by the BMC health department had found lack of uniformity in filling the death certificate, hence, the need for such a training program… (TOI, January 11, 2017).

Draft Notification for Prevention of Cruelty to Animals (Dog Breeding and Marketing) Rules, 2016 The Ministry of Environment, Forest and Climate Change has invited comments on the draft notification of Prevention of Cruelty to Animals (Dog Breeding and Marketing Rules), 2016. The Ministry will be notifying the proposed draft Rules in the Gazette of India for public information. Any interested person can make any suggestion on the said draft rules in writing for consideration of the Central Government to the Deputy Secretary, Animal Welfare Division, Ministry of Environment, Forest and Climate Change, Indira Paryavaran Bhawan, New Delhi, within 30 days of such publication of the Rules… (Ministry of Environment and Forests, 10th January, 2017)

Strict Adherence to Physical Activity Recommendations not Required, Says Study A pooled analysis of population-based surveys of more than 60,000 adults has shown that weekend warriors i.e., those who exercise during weekends, just 1-2 days per week, also lower their risk of all-cause mortality as much as those who exercise regularly, three or more times in a week. Mortality due to cardiovascular disease and cancer also reduced in these individuals.

These findings are published January 7, 2017 in JAMA Internal Medicine.

EEG Findings in Critically Ill may Indicate Increased Risk for Seizures In a new study published online in JAMA Neurology on December 19, 2016, EEG findings like lateralized periodic discharges, lateralized rhythmic delta activity and generalized periodic discharges were associated with seizures, but generalized rhythmic delta activity was not. High frequency and Plus modifier were associated with an additional risk in all patterns except generalized rhythmic delta activity; and increased pattern prevalence was associated with risk for seizures in lateralized periodic discharges and generalized periodic discharges.

Extended-release Morphine Sulfate Approved for Chronic Pain The US Food and Drug Administration (FDA) has approved Arymo ER (morphine sulfate extendedrelease tablets), a new extended-release opioid with abuse-deterrent properties, to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. However, the FDA says that abuse by the intravenous, intranasal and oral routes is still possible.

Study Links Migraine to Increased Risk of Perioperative Stroke Migraine should be looked for when assessing perioperative risk in patients who undergo surgery, says a study reported online January 10, 2017 in the BMJ. In the prospective hospital registry study, history of migraine was associated with an increased risk of perioperative ischemic stroke within 30 days of surgery.

These patients also had a higher hospital readmission rate at 30 days.

Use of Acellular Dermal Matrix for Abdominal Wall Reconstruction Improves Outcomes The use of acellular dermal matrix (ADM) for abdominal wall reconstruction was associated with 11.5% and 14.6% hernia recurrence rates at 3- and 5-year followup, respectfully in a study, which suggests that avoiding bridged repairs and human cadaveric ADM may improve long-term abdominal wall reconstruction outcomes using ADM. The study was published online December 16, 2016 in the Journal of the American College of Surgeons.

Patients with Psoriatic Arthritis at High risk of Coronary Plaque Sixty percent of patients with psoriatic arthritis without known cardiovascular diseases who underwent coronary CT angiography were found to have detectable plaques as compared to 35% of controls, according to a study in the Annals of the Rheumatic Diseases reported January 4, 2017. And, noncalcified and mixed type plaques were detected in patients with psoriatic arthritis vs. controls, 51.1% vs. 25.8%, respectively.

Global Burden of High Blood Pressure has Markedly Increased According to a new analysis of data published in the January 10, 2017 issue of the Journal of the American Medical Association, the problem of high blood pressure is worldwide and it has serious consequences. The data

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AROUND THE GLOBE collected from the Global Burden of Disease, Injuries, and Risk Factor Study 2015 (GBD 2015 included more than 8 million people from 154 countries. Between 1990 and 2015, the rate of systolic blood pressure (SBP) of at least 110-115 mmHg increased from 73,119 to 81,373 per 1,00,000 persons, and SBP of 140 mmHg or higher increased from 17,307 to 20,526 per 1,00,000 persons.

SBP of at least 110-115 mmHg was associated with more than 10 million deaths and more than 212 million DALYs in 2015, a 1.4-fold increase since 1990. India is among the five countries that accounted for more than half of global DALYs associated with SBP of at least 110-115 mmHg: The other countries were China, Russia, Indonesia and the United States.

Tobacco Control can Save Billions of Dollars and Millions of Lives Policies to control tobacco use, including tobacco tax and price increases, can generate significant government revenues for health and development work, according to a new landmark global report from WHO and the National Cancer Institute of the United States of America. Such measures can also greatly reduce tobacco use and protect people’s health from the world’s leading killers, such as cancers and heart disease. But left unchecked, the tobacco industry and the deadly impact of its products cost the world’s economies more than US$ 1 trillion annually in healthcare expenditures and lost productivity, according to findings published in The economics of tobacco and tobacco control… (WHO, 10th January, 2017).

Top US Cancer Centers Support HPV Vaccination as Cancer Prevention A joint statement from 69 National Cancer Institute (NCI)-designated cancer centers in the US, issued on January 11, has supported vaccination against human papillomavirus (HPV). The statement says that though many of the HPV-associated cancers are preventable with the safe and effective vaccine, HPV vaccination rates across the US remain low. It concludes by saying that “HPV vaccination is CANCER PREVENTION.”

Serum Albumin is a Prognostic Biomarker in Guillain-Barré Syndrome A new study has demonstrated that low albumin levels after intravenous immunoglobulin (IVIG) treatment in patients with Guillain-Barré syndrome (GBS) were strongly related to a severe clinical course and poor outcome. Hypoalbuminemia after treatment with IVIG is related to a more severe clinical course and a poorer outcome. These findings were published online December 27, 2016 in JAMA Neurology.

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Study Shows Association Between Early Lactate Levels and Mortality in Sepsis in Children As per an article published online January 9, 2016 in JAMA Pediatrics, children with clinically suspected sepsis were more likely to die within 30 days if their initial serum lactate was >36 mg/dL. Lactate levels had a sensitivity of 20% and specificity of 92% for mortality.

Red Meat Increases Risk of Diverticulitis High consumption of red meat, particularly unprocessed red meat, is associated with an increased risk for diverticulitis, according to a study published online January 9, 2017 in the journal Gut. Higher consumption of poultry or fish was not associated with risk of diverticulitis.

NOACs may Increase Risk of Intraocular Bleeding Some new oral anticoagulants (NOACs) are associated with an increased risk of intraocular hemorrhage, according to a new analysis of data published online December 23, 2016 in the journal Eye. Rivaroxaban had the highest signal of association with both retinal and vitreous hemorrhage. Dabigatran was also significantly associated with retinal and vitreous hemorrhage.

‘Early Moments Matter’, a UNICEF Campaign for Children’s Brain Development UNICEF has launched #EarlyMomentsMatter, a new campaign supported by the LEGO Foundation to drive increased awareness about the importance of the first 1,000 days of a child’s life and the impact of early experiences on the developing brain. During this critical window of opportunity, brain cells can make up to 1,000 new connections every second—a once-ina-lifetime speed.

These connections contribute to children’s brain function and learning, and lay the foundation for their future health and happiness. A lack of nurturing care— which includes adequate nutrition, stimulation, love and protection from stress and violence—can impede the development of these critical connections. The campaign kicks off with #EatPlayLove—a digital and print initiative aimed at parents and caregivers that shares the neuroscience on how babies’ brains develop…

(UNICEF, January 10, 2017)

AAP Launches Simulation to Train Pediatricians on Use of Performance Enhancing Substances The use of appearance and performance-enhancing substances among youth has increased tremendously over the past decade. Physicians should be aware of the

AROUND THE GLOBE use of performance-enhancing substances by pediatric patients; be prepared to identify risk factors, signs and symptoms; ask screening questions and offer anticipatory guidance related to their use. The American Academy of Pediatrics (AAP) launched ‘Artificial Perfection: Talking to Teens about Performance Enhancement’, a free, role-play simulation designed to prepare pediatricians and other child health professionals to lead real-life conversation with teens about appearance and performance-enhancing substances. Take the simulation at: aap.kognito.com... (American Academy of Pediatrics, January 11, 2017)

AHA Statement on Management of Pregnancy in Patients with Complex Congenital Heart Disease A new scientific statement for healthcare professionals from the American Heart Association (AHA) published in the journal Circulation, January 12, 2017 says that women with high-risk congenital heart disease can have successful pregnancies but should seek counseling before conception to understand how their conditions could affect pregnancy and their child’s health. Pregnant women with high-risk congenital heart disease need to deliver their children in a medical center with expertise in pregnancy management.

Landmark Study Defines Normal Ranges for Testosterone Levels A large study of more than 9,000 nonobese European and American men aged 19-39 years has established harmonized reference ranges, 264-916 ng/dL, for total testosterone in men that, when applied to assays that have been appropriately calibrated, will effectively enable clinicians to make a correct diagnosis of hypogonadism and limit unnecessary treatments, according to a new study published January 10, 2017 in the Journal of Clinical Endocrinology & Metabolism.

Study Links Risk of Respiratory Failure with Antipsychotic Drugs Findings from an observational study published online January 4, 2017 in JAMA Psychiatry indicate a dosedependent increased risk of acute respiratory failure from use of antipsychotic drugs in patients with chronic obstructive pulmonary disease (COPD).

The risk increased from 1.52-fold risk for a low daily dose to 3.74-fold risk for a high dose. The study further suggests that clinicians should exercise caution when prescribing antipsychotics to patients with COPD and avoid high doses if possible.

First AAN Guideline on Use of Functional MRI in Presurgical Evaluation of Patients with Epilepsy The American Academy of Neurology (AAN) has released the first evidence-based guideline on the use of functional MRI (fMRI) in the presurgical evaluation of patients with epilepsy. The guideline recommends fMRI as an option for lateralizing language functions in place of the more invasive intracarotid amobarbital procedure in patients with medial temporal lobe epilepsy, temporal epilepsy in general or extratemporal epilepsy. It may be also considered to predict postsurgical language deficits after anterior temporal lobe resection. These guidelines are published in the journal Neurology, January 11, 2017.

Past History of Aminoglycoside Use is a Risk Factor for AKI with Current Aminoglycoside Treatment According to a study published in the January 2017 issue of the journal Pediatric Nephrology, when dosing and monitoring hospitalized children being treated with aminoglycoside prior aminoglycoside, treatment is a risk factor for acute kidney injury (AKI). Younger age, admission to hematology-oncology department and tobramycin use were also found to be independently associated with AKI. A past history of aminoglycoside treatment should be elicited when prescribing them.

Exercise plus Weight Loss Program Improves Asthma Control in Obese Patients Adding exercise to a short-term weight-loss program should be considered as a useful strategy for achieving clinical control of asthma in obese patients, says a new study published January 2017 issue of the American Journal of Respiratory and Critical Care Medicine. Compared with the weight-loss program plus sham (WL + S) group, the weight-loss program plus exercise (WL + E) group had improved clinical control scores and greater weight loss and aerobic capacity. The WL + E group also had improvements in lung function, anti-inflammatory biomarkers and vitamin D levels along with decrease in airway and systemic inflammation.

Recipient of a Kidney Transplant Donates Liver to Another A 42-year-old woman who had received a kidney transplant 2 years ago donated her liver, after being declared as brain dead, to a 66-year old patient with liver cirrhosis in Pune, as reported in ET Healthworld.

This is the first such case in India and only the second in the world. The woman’s liver was found fit to be harvested and transplanted despite her being on immunosuppressive drugs for the last two years…

(Umesh Isalkar, ET Healthworld, January 14, 2017)

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AROUND THE GLOBE survival or salvage cystectomy rates compared with pure urothelial carcinoma.

AACR Project GENIE Publicly Releases Large Cancer Genomic Data Set The American Association for Cancer Research (AACR) has released cancer genomic data aggregated through its initiative known as AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE). The data set includes nearly 19,000 de-identified genomic records collected from patients who were treated at eight international institutions, making it among the largest fully public cancer genomic data sets released to date.

The release includes data for 59 major cancer types, including data on nearly 3,000 patients with lung cancer, more than 2,000 patients with breast cancer, and more than 2,000 patients with colorectal cancer. The genomic data and a limited amount of linked clinical data for each patient can be accessed via the AACR website or downloaded directly from Sage Bionetworks… (AACR, January 5, 2017)

Prolonged Storage of Blood Prior to Transfusion Increases Hemolysis After 6 weeks of refrigerated storage, transfusion of autologous red cells to healthy human volunteers increased extravascular hemolysis, saturated serum transferrin and produced circulating nontransferrinbound iron, says a study published January 3, 2017 in the Journal of Clinical Investigation. These outcomes, associated with increased risks of harm, provide evidence that the maximal allowable red cell storage duration should be reduced to the minimum sustainable by the blood supply, with 35 days as an attainable goal.

Delayed Diagnosis of Dry Eye Disease Impairs Quality-of-life A negative perception of dry eye disease, delayed diagnosis and high frequency of treatment use have a negative impact on patients’ quality-of-life, according to a study reported online December 21, 2016 in the British Journal of Ophthalmology. Overall, 31% patients perceived dry eye disease as a ‘disease’ or even a ‘handicap’, and 66% as a ‘discomfort’.

Retrieval of Minimum 29 Lymph Nodes Improves Survival in Patients with Gastric Cancer Lymphadenectomy with minimum of 29 lymph nodes retrieved is associated with maximal survival advantage in advanced gastric cancer, according to findings from a large international dataset analysis published online December 22, 2016 in the Journal of the American College of Surgeons.

Antihypertensive Drugs Reduce the Risk of Glaucoma Evidence from a study published in the February 2017 issue of the journal Hypertension indicates that antihypertensive medication itself may have a preventive effect on the development of glaucoma. The study also found that hypertension is positively correlated with glaucoma.

Variant Histology of Urothelial Cancer does not Significantly Affect Clinical Outcomes

Management of Postmeal Glycemia Important to Preserve Kidney Function in Type 2 Diabetes

A study which compared the outcomes of histologic variants of urothelial cancer to pure urothelial cancer following treatment with trimodality bladder-sparing therapy concluded that variant histology does not significantly influence outcomes. In the study published online December 28, 2016 in European Urology, variant urothelial carcinoma responded to trimodality bladdersparing therapy; no significant differences were observed in complete response, overall survival, disease-specific

Postmeal triglyceridemia and variability of HbA1c and postmeal glycemia can predict the annual decline in estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes with different stages of nephropathy. The study published January 11, 2017 in the Journal of Diabetes & Metabolic Disorders suggests that consistency of glycemic control and management of postprandial glycemia and lipidemia are important to preserve kidney function in these patients.

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INSPIRATIONAL STORY

Begin with a Blank Page

I

f you could start your life all over what would be different? What would you change now if you were able to wave a magic wand and start from scratch?

Just imagine you have no ties, no burdens, no limits, no memories and no past.

What would your life look like? If the answer that comes to your mind is different than what you are doing, why is that? Is it because of someone else’s opinion? A spouse, a parent or may be your children?

The ultimate test of your life is to close your eyes and think of yourself on your deathbed. Lying there, preparing yourself to leave, look back at your life as you are currently living it.

How do you feel? Are you satisfied you lived completely? Or do you wish you had done differently?

Very few of our senior citizens look back on their life and say, “I sure wish I had spent more time at the office!” Nobody says, “I wish I had watched more TV!” This is what they say. “I wish I had been bolder.

I wish I had given more. I wish I had tried harder to see more, do more and feel more.” People wish that they had lived more. I, for one, have to admit to a certain amount of holding back on dreams and goals because of our 2 boys. As my life progresses I realize there is no reason to hold back.

We have not been exactly standing still either. We have done our best to live our dreams. We built a sailboat and sailed for 7 years traveling on the open ocean.

We lived in the snow in Aspen Colorado, and on the beach in South Carolina. An old brick mill was our home in Long Island, versus a boat dock in Palm Beach Florida. We are writers of books and music, actors in the theater, and we home–school the boys. We have built a horse farm, and businesses! Yet, there is so much more we want to do! It is a balancing act. We all must have sufficient finances to support a comfortable lifestyle, (although most of us tend to spend way too much on that!) Part of this balancing act is to understand what we are passionate about doing so that work becomes a joy instead of a job.

Is this not a major reason of lost dreams and goals?

Many people find work, call it a job and make a living

at it. But they begrudge every minute of it, going as far as using the job as a reason for playing the martyr. Find something else!

There are many, many teachers of the attraction philosophies of “making a life”. With as many opportunities today in every field imaginable, somewhere, something is calling to you.

Another part of the balancing act is to include those around you in frank and open discussions in what it is you want. I find some of my coaching clients have kept their wants and needs bottled up inside them forever!

They had already decided for the other person in their lives there was no interest in whatever it was they themselves wanted to do! How absurd! How can we possibly know what someone else wants!

Would it not be tragic to spend your life in a big city for 40 years, working at a job you despise because you thought your spouse liked it, even though you wanted to live in the country and be a farmer? Then one day you overhear your spouse tell her best friend all she ever wanted to do was live in the country? 40 years!

Sure this is a bit far fetched–but you would be amazed at what I hear!

Make an attempt today to start with a brand new page of your life. Create your life story how you want it.

If there are others in your life to be involved, have them do the same exercise. Then compare what your notes.

If this matches your current life, congratulations! You are one of the few. Now make it better.

However, if your written life stories sound like someone completely different, then you are living a life of conflict. Here is the good news. Your life is your life. No one can take that away from you. You are not indentured. You are not a slave. You are free to go, do, and be whomever you wish.

It might not be easy, but it sure might be worth it.

I coach people daily who are changing their lives. There are so many things to be grateful for, and so many things open to us. We owe it to all the ones before us who gave us this opportunity to take advantage of it.

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LIGHTER READING

DON’T BE NERVOUS This older man was on the operating table awaiting surgery and he insisted that his son, a renowned surgeon, perform the operation as he was about to receive the anesthesia he asked to speak to his son. “Yes dad, what is it?”

“Don’t be nervous, son. Do your best and just remember, if it doesn’t go well and if something happens to me, your mother is going to come and live with you and your wife.”

I’LL TRUST YOU THAT YOU PAID A man walks into a bar and has a couple of beers. Once he is done the bartender tells him he owes $9.00. “But I paid, don’t you remember?” says the customer.

“Okay,” says the bartender, “If you said you paid, you did.”

The man then goes outside and tells the first person he sees that the bartender can’t keep track of whether his customers have paid.

The second man then rushes in, orders a beer and later pulls the same stunt.

“My hairline is in recession, my stomach is a victim of inflation, and both of these together are putting me into a deep depression!”

I KEEP THINKING I’M GOD! Doctor, Doctor! I keep thinking I’m God! Doc: When did this start? Well first I created the sun, then the earth, then the…

JOGGING SHOES Deciding to take up jogging, the middle-aged man was astounded by the wide selection of jogging shoes available at the local sports shoe store.

While trying on a basic pair of jogging shoe, he noticed a minor feature and asked the clerk about it.

“What’s this little pocket thing here on the side for?”

“Oh, that’s to carry spare change so you can call your wife to come pick you up when you’ve jogged too far.”

The barkeep replies, “If you say you paid, I’ll take your word for it.”

Dr. Good and Dr. Bad

Soon the customer goes into the street, sees an old friend, and tells him how to get free drinks.

SITUATION: An obese patient with visceral fat wanted dietary

The man hurries into the bar and begins to drink high-balls when, suddenly, the bartender leans over sand says, “You know, a funny thing happened in here tonight. Two men were drinking beer, neither paid and both claimed that they did. The next guy who tries that is going to get punched right in the nose.”

advice.

You need a high fiber diet.

Go on a low calorie, high fiber diet.

© IJCP Academy

HUMOR

Lighter Side of Medicine

“Don’t bother me with your troubles,” the final patron responds. “Just give me my change and I’ll be on my way.”

A WALKING ECONOMY This guy is walking with his friend, who happens to be a psychologist. He says to this friend, “I’m a walking economy.” The friend asks, “How so?”

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Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

LESSON: A low calorie-high fiber diet with balanced nutritive elements

has a positive effect on fasting glucose, lipid profile, hypertension and visceral obesity, in obese people with impaired glucose tolerance with a consecutive lowering of cardiometabolic risk.

Information for Authors Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767).

Indian Journal of Clinical Practice strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so.

The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript.

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

Covering letter –

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–

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

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

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

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

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

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

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

Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the departments and institutions where the work was performed,

name of the corresponding authors, acknowledgment of financial support and abbreviations used.

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

A subtitle can be added if necessary.

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

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

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

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

– It should not contain abbreviations, footnotes or references.

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

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

– Ethical guidelines followed by the investigations should be described.

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

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

– Method of allocating the subjects into different groups.

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

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Confidence intervals for the measurements should be provided wherever appropriate.

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

Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

897

Discussion –

This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.

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

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

Examples of common forms of references are: Articles Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes.

Q. J. Expt. Physiol. 1955;40:89-111.

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

– All photomicrographs should indicate the magnification of the print.

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

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

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

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Do not use clips/staples on photographs and artwork.

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

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected summary, etc.)_______________________________ 2. Total number of pages ________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________

Books

5. Special requests _____________________________

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

Indian 1.____________Foreign 1.________________

Articles in Books

2.____________ 2.________________

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

3.____________ 3.________________

4.____________ 4.________________

Tables –

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

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

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898

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

Indian Journal of Clinical Practice, Vol. 27, No. 9, February 2017

6. Suggestions for reviewers (name and postal address)

7. All authors’ signatures________________________ 8.

Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________

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

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

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