Indian journal of clinical practice january 2015 by IJCP

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ISSN 0971-0876

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Volume 25, Number 8

January 2015, Pages 701â&#x20AC;&#x201C;800

Peer Reviewed Journal

American Family Physician

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ENT

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

Dr KK Aggarwal Group Editor-in-Chief Dr Veena Aggarwal MD, Group Executive Editor

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

Anand Gopal Bhatnagar Editorial Anchor Advisory Bodies Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

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

Volume 25, Number 8, January 2015 FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF

706 Harvard Top 10 Cardiovascular Advances of 2014

KK Aggarwal

AMERICAN FAMILY PHYSICIAN

708 Diagnostic Approach to Patients with Tinnitus

Kenneth S. Yew

717 Practice Guidelines 718 Photo Quiz CARDIOLOGY

720 Comparative Evaluation of ACE Inhibitors for their Beneficial Effects in Patients with Ischemic Left Ventricular Systolic Dysfunction and Undergoing Coronary Artery Bypass Surgery

PS Gandhi, RK Goyal, AR Jain, BS Mallya, MC Chag, VM Gupta, DS Shah, BR Trivedi, NA Shastri, CB Mehta, KA Jain, NS Bhavasar, UJ Shah

COMMUNITY MEDICINE

735 Quality Parameters for Ideal Clinic

Param Hans Mishra

DENTISTRY

739 Nanotechnology and Nanoparticles: Small is Large

Jacob Kurien, Jayasekharan VP, E Anuradha Sunil, Eapen Cherian

ENT

743 Comparing the Incidence of Hearing Impairment in Normal to High-risk Newborns

MV Subba Rao, BJ Prasad, Maheshwar Reddy

HEMATOLOGY

747 Rifampicin- and Pyrazinamide-induced Thrombocytopenia: A Rare Presentation

Praveen B Gautam, Suresh Kumar

INTERNAL MEDICINE

750 Pineal Gland: The Third Eye

V Padma, NN Anand, C Ramakrishnan

757 Multisystem Involvement in Melioidosis: A Case Report

Priyadarshini Gunaseelan, Swamikannu M, Vaidehi R, Sarveswari KN

OBSTETRICS AND GYNECOLOGY

760 A Rare Case of Natural Pregnancy at Advanced Maternal Age

Gayatri Mathuriya, Deepika Bansal

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

762 Bicornuate Uterus: A Case Report

G Rajathi, V Vathsala, WMS Johnson

766 Adding Estrogen Along with Progesterone as Luteal Phase Support, Enhances Outcomes in ART Cycles: A Randomized Control Study

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

Aritra Pradhan, Surabhi Tomar Sharma, Ridhi Kathuria

PEDIATRICS

770 Management of Dry Cough in Pediatric Population: Role of Pholcodine

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.

Sridhar Ganapathy

PHARMACOLOGY

775 Oxidative Stress in Hypercholesterolemic Patients and Antioxidant Status of Fluvastatin

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.

Md. Abu Nasar, Tarannum F Subhani

EXPERT VIEW

782 Golden Hours in Medical Practice

KK Aggarwal

AROUND THE GLOBE

783 News and Views MEDILAW

789 Advertising and Medical Ethics

KK Aggarwal

INSPIRATIONAL STORY

793 My Precocious and Precious Son LIGHTER READING

795 Lighter Side of Medicine

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FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF Dr KK Aggarwal

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

Harvard Top 10 Cardiovascular Advances of 2014 ÂÂ

Novel drugs cut cholesterol levels by half: A new class of drugs, given by injection just once or twice a month, can slash harmful low-density lipoprotein (LDL) cholesterol levels by about 50%. Studies are under way to see if any of these agents, called PCSK9 inhibitors, prevent heart attacks or improve heart disease survival.

ÂÂ

Drug offers new hope for heart failure: In people with chronic heart failure, a new drug known as LCZ696 lowered the risk of being hospitalized with heart failure or dying from heart disease by 20%. The benefits were so striking that researchers ended a large study of the drug early.

ÂÂ

Replacing aortic valves without surgery: Transcatheter aortic valve replacement (TAVR) offers a nonsurgical way to fix a stiff, narrowed aortic valve. Compared with people who had open-heart surgery, those who had TAVR had a higher 1-year survival rate. TAVR delivers the new valve to the heart through a catheter threaded into an artery in the groin. Currently, it is approved for people considered too sick or high-risk for surgery.

ÂÂ

Renal denervation loses luster: A promising experimental treatment for stubbornly high blood pressure failed an important test. Renal denervation, which uses radiofrequency waves to zap nerve endings in arteries leading to the kidneys, seemed to alter how the kidneys regulate blood pressure. But, the technique proved no more effective than a sham procedure for lowering blood pressure.

ÂÂ

Wireless sensors for severe heart failure: A new device helps doctors keep tabs on people with serious heart failure by measuring pressure in the pulmonary artery, which transports blood from the heart to the lungs. The battery-free sensor of the CardioMEMS HF System wirelessly sends data to the physician, who can then adjust the person's treatment as needed—and ideally prevent hospitalizations.

ÂÂ

Weight-loss surgery for people with diabetes: Weight-loss (bariatric) surgery helped obese people with diabetes eliminate most of their diabetes medications and get by with fewer drugs to control their blood pressure and cholesterol. Surgery was far more effective than weight-loss counseling plus frequent blood sugar testing, and drugs to treat diabetes. Being obese and having diabetes greatly increases the risk of cardiovascular disease.

ÂÂ

Treating sleep apnea may lower blood pressure: Treating obstructive sleep apnea—a common problem that causes people to briefly stop breathing many times throughout the night—may help

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FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF lower blood pressure in people who have heart disease or are prone to it. CPAP, or continuous positive airway pressure, delivers a constant stream of air through a face mask, which prevents the back of the throat from collapsing and blocking airflow. ÂÂ

New anti-clotting drug approved to lower risk of heart attack: A new FDA-approved medicine that decreases blood clot formation lowers the risk of heart attack in people who have already had a heart attack or peripheral artery disease. Vorapaxar (Zontivity), the first in a new class of drugs called PAR-1 antagonists, prevents platelets from clumping together and forming clots.

ÂÂ

Better outcomes after a stroke with shorter 'door-to-needle' times: A new American Heart Association initiative dubbed Target: Stroke encouraged 11 hospital-based strategies to speed treatment for stroke. Thanks to the faster treatment, fewer people died in the hospital, and more people returned home instead of going to a rehabilitation facility.

ÂÂ

Updated advice for preventing a second stroke: New guidelines to lower the likelihood of a repeat stroke among stroke survivors include better screening for diabetes and obesity; advice to follow a Mediterranean-style diet; the use of new oral anti-clotting drugs as alternatives to warfarin; screening for sleep apnea in some people; and longer monitoring for atrial fibrillation among people who have a stroke of unknown cause. ■■■■

Indian Journal of Clinical Practice, Vol. 25, No. 8, January 2015

707

AMERICAN FAMILY PHYSICIAN

Diagnostic Approach to Patients with Tinnitus KENNETH S. YEW

ABSTRACT Tinnitus, a common symptom encountered in family medicine, is defined as the perception of noise in the absence of an acoustic stimulus outside of the body. Because tinnitus is a symptom and not a disease, its underlying cause must be determined to best help patients. Although tinnitus is often idiopathic, sensorineural hearing loss is the most common identified cause. It can also be caused by other otologic, vascular, neoplastic, neurologic, pharmacologic, dental, and psychological factors. More serious causes, such as Meniere disease or vestibular schwannoma, can be excluded during the evaluation. History and physical examination of the head, eyes, ears, nose, throat, neck, and neurologic system guide subsequent evaluation. Almost all patients with tinnitus should undergo audiometry with tympanometry, and some patients require neuroimaging or assessment of vestibular function with electronystagmography. Supportive counseling should begin during the initial evaluation to help patients cope with tinnitus. Counseling may also improve the chances of successful subsequent treatment.

Keywords: Tinnitus, sensorineural hearing loss, audiometry, tympanometry, neuroimaging, electronystagmography

innitus is a common symptom encountered in family medicine. It is defined as sound perception in the absence of sound input external to the patient. Subjective tinnitus is the most common type, and is audible only to the patient, without internal or external sound input. Objective tinnitus is rare, accounting for less than 1% of cases.1 It involves the perception of an internal sound, such as a bruit, as tinnitus. The causes of objective tinnitus are chiefly vascular or muscle dysfunction.2 Tinnitus lasting at least five minutes was reported by 30% of persons 49 years and older in an Australian population-based cohort.3 In a U.S. population-based study, slightly more than 8% of persons 48 years and older were affected by tinnitus that was moderately severe or that impacted sleep.4 Although it can be transient, older persons are more likely to have persistent tinnitus.5 A simple and efficient approach to the evaluation and diagnosis of tinnitus can safely detect the minority of persons with more serious etiologies, such as Meniere disease or vestibular schwannoma.

KENNETH S. YEW, MD, MPH, is a family physician at Family Medicine of Albemarle in Charlottesville, Va., and clinical assistant professor of family medicine at the Uniformed Services University of the Health Sciences in Bethesda, Md. At the time the article was written, Dr. Yew was a staff physician at the Loudoun Community Health Center in Leesburg, Va. Source: Adapted from Am Fam Physician. 2014;89(2):106-113.

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ETIOLOGY Because tinnitus is a symptom and not a disease, there is no objective test to confirm its existence or grade its severity.6 For this reason, much of the workup for tinnitus is without evidence. The etiology of tinnitus is often multifactorial, but in many cases, it is a response of the central nervous system to insufficient or abnormal input from the ear, comparable to phantom limb syndrome.7 In this syndrome, persons perceive their limb even after it has been amputated. In a similar manner, tinnitus persists even after surgical transection of the auditory nerve.7 Tinnitus occurs in most persons with normal hearing who are exposed to silence.8 It can be affected by input outside of the auditory system. For example, in patients with somatosensory tinnitus, movements of the head, neck, or limbs or palpation of myofascial trigger points can modulate or reproduce tinnitus.9 The belief that tinnitus is entirely psychosomatic is outmoded. Appreciation of a personâ&#x20AC;&#x2122;s subjective response to tinnitus can help establish a therapeutic alliance that will support further education and therapy. Table 1 lists the common etiologies of tinnitus.1,2,10-15 The condition most often associated with tinnitus is sensorineural hearing loss caused by presbycusis or occupational noise exposure.3,16 Conductive hearing loss from cerumen impaction, middle ear effusion, or otosclerosis is also associated with tinnitus.4 Although certain metabolic conditions were previously thought to

AMERICAN FAMILY PHYSICIAN Table 1. Selected Causes of Tinnitus Subjective Otologic: hearing loss, cholesteatoma, Meniere disease, vestibular schwannoma Toxicologic: medication or substance use Somatic: temporomandibular joint dysfunction, head or neck injury Traumatic: cerumen removal10 Neurologic: multiple sclerosis, spontaneous intracranial hypotension,11 type I Chiari malformation,12 idiopathic intracranial hypertension,13 vestibular migraine14 Infectious: viral, bacterial, fungal Metabolic (weak evidence): hyperlipidemia, diabetes mellitus, vitamin B12 deficiency Objective Patulous eustachian tube Vascular: arterial bruit, venous hum, arteriovenous malformation, vascular tumors, carotid atherosclerosis, dissection, or tortuosity; Paget disease Neurologic: palatal myoclonus, idiopathic stapedial or tensor tympani muscle spasm Note: Causes listed in approximate order from most to least common. Information from references 1, 2, and 10 through 15.

cause tinnitus, there is little evidence to support this.15 A Medline search found no studies linking tinnitus with thyroid disease. The search found a single case report and a weakly suggestive observational study linking tinnitus with vitamin B12 deficiency,17,18 as well as several case series and small observational studies inconsistently suggesting a link between tinnitus and hyperlipidemia or diabetes mellitus.19-24 More than 130 medications have been reported to cause tinnitus or hearing loss.25 To decrease the risk of iatrogenic tinnitus, patients should avoid using more than one potentially ototoxic agent concurrently, and should limit the dose and duration, especially if other risk factors for tinnitus are present. Table 2 lists common medications consistently associated with tinnitus.25,26 Some studies suggest that a somatosensory component may be present in some patients with tinnitus, although this is not fully understood. Tinnitus may be associated with temporomandibular joint dysfunction27 and whiplash,3 and may be modulated by body movements.28 Several neurologic conditions can produce tinnitus. For example, spontaneous intracranial hypotension is an uncommon but increasingly recognized cause of daily or thunderclap headache; it results from a

spontaneous cerebrospinal fluid leak often following a forceful Valsalva maneuver.11 Spontaneous intracranial hypotension is characterized by a positional headache similar to a postâ&#x20AC;&#x201C;dural puncture headache, and patients may have associated tinnitus. Idiopathic intracranial hypertension is another neurologic cause of tinnitus that occurs primarily in women who are overweight.13 Vestibular migraine is characterized by vertiginous symptoms coincident at least twice with migraine symptoms in persons with a history of recurrent vestibular symptoms and migraine.14 Meniere disease is characterized by intermittent episodes of vertigo, fluctuating hearing loss, tinnitus, and ear pressure secondary to malabsorption of endolymphatic fluid in the inner ear.29 Patients may present with any one of these symptoms or a combination of symptoms, making early diagnosis a challenge.30 Meniere disease has an annual incidence of 4.3 per 100,000 persons, a prevalence of 17 to 46 per 100,000 persons, and a peak age of onset of 40 to 60 years.29 Diagnosis depends on the presence of typical symptoms, with or without audiometrically documented hearing loss.31 When hearing loss is documented in patients with Meniere disease, it is usually noted in lower pitches.30 Vestibular schwannoma, formerly known as acoustic neuroma, is a benign tumor of the acoustic nerve presenting most commonly as progressive unilateral or asymmetric hearing loss, with or without tinnitus, vertigo, or both.32-34 It is rare for tinnitus to be the only symptom.35 Only 1% to 2% of patients presenting with the classic symptoms of unilateral hearing loss with or without unilateral tinnitus have a schwannoma.36 The incidence is about one per 100,000 persons in the United States,37 although it has been increasing over the past several decades, in part because of better detection.38 Although some investigators have speculated that cellular telephone use has contributed to this apparent increase,39 studies do not show a consistent association. Tinnitus is associated with increased prevalence of depression and anxiety; however, the precise timing and sequence of the relationship is unclear.40,41 There is no evidence that affective disorders cause tinnitus, but anxiety or depression may alter a patientâ&#x20AC;&#x2122;s toleration of tinnitus or be exacerbated by tinnitus.40,41 Individual personality factors, such as being more socially withdrawn, less tolerant of stress, and more likely to feel victimized by lifeâ&#x20AC;&#x2122;s circumstances, were associated with longer duration of and greater annoyance from tinnitus in a New Zealand cohort.42

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AMERICAN FAMILY PHYSICIAN Table 2. Medications Associated with Tinnitus Drug class

Specific agents

Comments

Anti-inflammatory agents

Aspirin

Especially doses > 2.7 g per day

Nonsteroidal anti-inflammatory drugs

All agents implicated

Sulfasalazine

—

Antimalarial agents

Quinine and chloroquine

—

Antimicrobial agents

Aminoglycosides

Tinnitus usually is an initial sign of ototoxicity, often with rapid progression to hearing loss; hearing loss or tinnitus that persists two to three weeks after discontinuing the drug is likely permanent

Macrolides

Erythromycin: rare at dosages < 2 g per day

Tetracyclines: doxycycline, minocycline

Higher risk in women; symptom onset one to three days after initiation of therapy

Vancomycin

Rare if not used with other ototoxic agents

Other anti-infectives: imipenem/cilastatin, linezolid, sulfonamides, fluoroquinolones, voriconazole, amphotericin B, ganciclovir, ribavirin

—

Antineoplastic agents

Vinca alkaloids, etoposide, protein kinase inhibitors, platinum derivatives

—

Loop diuretics

All agents implicated

Highest risk with high doses and/or rapid infusions

Miscellaneous agents

— Antiarrhythmics, anticonvulsants, antihypertensives, antiulcer drugs, hormones, psychotropic drugs, atorvastatin, bupropion, risedronate, varenicline

Regional anesthetics

Lidocaine, bupivacaine

Topical agents

Topical otic preparations containing ototoxic — drugs

—

Information from references 25 and 26.

CLINICAL DIAGNOSIS

History and Physical Examination History and physical examination are the primary diagnostic tools for tinnitus. Table 3 lists historical items that are helpful in the evaluation of a patient with tinnitus.2-4,6,11,13,16,25,27,30-32,43-49 Key elements of the physical examination include the head, eyes, ears, nose, throat, neck, and neurologic system. Table 4 provides physical examination findings that are helpful in the evaluation of a patient with tinnitus.2,3,10,11,32,35,45,50,51

Ancillary Studies, Imaging, and Diagnostic Tests Figure 1 is a suggested evaluation algorithm based on tinnitus chronicity, accompanying features, and examination findings. Almost all patients presenting with persistent tinnitus should undergo pure tone audiometry with assessment of air and bone conduction, speech discrimination testing, and tympanometry.34,49

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Table 5 provides sensitivity and specificity data for several ancillary and imaging studies in the evaluation of patients with tinnitus.29,33,36,52,53 The optimal definition for asymmetric hearing loss has not been studied by randomized controlled trials linked to longterm patient outcomes. A recent cross-sectional study of all published definitions of asymmetric hearing loss found an average difference of 10 dB or greater over 1 to 8 kHz had the best sensitivity for vestibular schwannoma. An average difference of 15 dB or greater over 0.5 to 3 kHz maximized specificity.36 Previously, the auditory brainstem response (ABR) test has been used to screen for vestibular schwannoma in patients with asymmetric sensorineural hearing loss, unilateral tinnitus or hearing difficulties, symptoms of vestibular dysfunction, or abnormal neurologic examination.35 The ABR test uses a series of clicks to stimulate the ear and then monitors for afferent nerve propagation of the resulting signal.33 However, a systematic review of magnetic resonance imaging (MRI)

AMERICAN FAMILY PHYSICIAN Table 3. Patient History Findings for Evaluating Tinnitus General category

Finding

Comments

Associated events

Hearing change, previous chronic noise exposure, acoustic trauma, otitis media, head or neck trauma, dental treatment

Hearing loss and noise exposure are the most consistent risk factors associated with tinnitus3,16 Head injury,43 whiplash,3 dizziness,3 and otosclerosis4 are risk factors for incident tinnitus Dental treatment may produce somatosensory tinnitus via temporomandibular joint disorders or neck stress

Use of a medication known to cause tinnitus

More than 130 agents are reported to cause tinnitus or hearing loss (Table 2)25

Headaches

Spontaneous intracranial hypotension can cause tinnitus with orthostatic headache,11 whereas obesity, headache, and tinnitus suggest idiopathic intracranial hypertension2,13; both are indications for neuroimaging, lumbar puncture, or myelography2,11

Hearing loss

Most common risk factor for tinnitus, occurring in at least one-third of patients3

Noise annoyance, intolerance, or pain

Hyperacusis is present in up to 40% of patients with tinnitus44

Temporomandibular joint or neck pain

May be associated with tinnitus27; therapy for pain may improve tinnitus

Vertigo

Suggests Meniere disease especially if unilateral, episodic, and associated with hearing loss,30,31 although vestibular schwannoma can also produce vertigo45

Description of tinnitus

Fluctuation, pitch, quality, loudness

Ringing, buzzing, or cicada-like sound is most common;46 low frequency most typical of Meniere disease;30 persons with unilateral pulsatile tinnitus are 80 times more likely to have a vascular loop adjacent to cranial nerve VIII than those without that symptom47

Family history of tinnitus, hearing loss, or neurofibromatosis

â&#x20AC;&#x201D;

Meniere disease and otosclerosis are heritable, but overall, tinnitus has a very small genetic component48

Impact of tinnitus

Percent of time the patient is aware of or annoyed by tinnitus (e.g., interference with daily activities, sleep, work, or leisure; auditory perceptual difficulties; effects on general health6)

Helps assess severity and subjective impact of tinnitus

Location

Unilateral or bilateral

Two-thirds of patients have bilateral tinnitus;46 unilateral is more likely somatosensory, vestibular schwannoma, or Meniere disease

Onset

Gradual or abrupt

Abrupt onset is more likely with somatosensory etiology and less likely to be vestibular schwannoma32

Timing

Intermittent or continuous

â&#x20AC;&#x201D;

Associated symptoms

Information from references 2 through 4, 6, 11, 13, 16, 25, 27, 30 through 32, and 43 through 49.

for the evaluation of suspected vestibular schwannoma concluded that MRI superseded ABR testing.33 Most U.S. otolaryngologists order a contrast-enhanced MRI of the brain and internal auditory canals in the setting of asymmetric hearing loss to rule out vestibular schwannoma. Conversely, a systematic review from the

United Kingdom concluded that nonâ&#x20AC;&#x201C;contrast-enhanced T2- and T2*-weighted MRI was the most cost-effective initial examination second to abnormal audiometry because its sensitivity was expected to be comparable with locally available contrast-enhanced MRI studies.33 Similar reviews have not been performed in the United

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AMERICAN FAMILY PHYSICIAN Table 4. Physical Examination Findings for Evaluating Tinnitus General category

Finding

Comments

Ear

Cerumen impaction

Removing cerumen aids examination, and may have a therapeutic benefit in tinnitus50 Cerumen removal is infrequently associated with development of tinnitus10

Effusion, cholesteatoma, or retrotympanic lesion

Physical cause for hearing loss is the most common risk factor for tinnitus3

Eye

Papilledema or visual field changes

Increased intracranial pressure may suggest mass or idiopathic intracranial hypertension

Musculoskeletal

Change in perception of tinnitus during teeth grinding, side-to-side or resisted head twisting

Diminished or enhanced tinnitus perception with these maneuvers suggests a somatosensory component

Neck tenderness or limited range of motion

Tenderness in these areas may suggest a somatosensory component and need for dental or otolaryngology referral

Temporomandibular joint tenderness, pain, or crepitus with motion Tenderness of mastication muscles Neurologic

Vascular

Abnormal cranial nerve testing Abnormal equilibrium, finger-to-nose test, or dysdiadochokinesia

Increased likelihood for vestibular schwannoma;32,35,45 can be associated with intracranial hypertension2 or hypotension11

Bruits or murmurs over the ear canal, periauricular area, orbits, neck, and chest

May suggest etiology in patients with pulsatile tinnitus51

Change in tinnitus with light pressure to the ipsilateral internal jugular vein

In patients with pulsatile tinnitus, resolution of the tinnitus with this maneuver suggests venous pulsatile tinnitus2

Information from references 2, 3, 10, 11, 32, 35, 45, 50, and 51.

States. In patients unable to undergo MRI, ABR testing or computed tomography is an acceptable alternative.33 For patients with suspected Meniere disease, vestibular testing with electronystagmography, in addition to audiometry and neuroimaging, can help exclude other vestibular disorders. Electronystagmography is a battery of four tests designed to record eye movements in response to visual or vestibular stimuli, thus assessing the peripheral vestibular system. The most common electronystagmography finding in patients with Meniere disease is unilateral vestibular hypofunction.29 No single test confirms a diagnosis of Meniere disease. Rather, the diagnosis is based on a history of fluctuating episodes of tinnitus, hearing loss, aural pressure, vertigo, or a combination of these symptoms. In patients with pulsatile tinnitus, the choice of imaging test depends on whether arterial or venous tinnitus is suspected. In addition to audiometry, patients with suspected arterial pulsatile tinnitus, retrotympanic lesions, or arterial bruits in the head should be assessed by head and neck computed tomography

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angiography.51 An arterial bruit confined to the neck can be assessed using carotid Doppler ultrasonography, neck computed tomography angiography, or magnetic resonance angiography.51 Suspected venous pulsatile tinnitus requires MRI, magnetic resonance venography, and, in patients with suspected idiopathic intracranial hypertension, a lumbar puncture and measurement of cerebrospinal fluid pressure.51 In a case series of 145 patients with pulsatile tinnitus, the most common diagnoses were idiopathic intracranial hypertension, atherosclerotic carotid artery disease, and glomus tumors; these diagnoses accounted for two-thirds of all patients in the study.54 Laboratory tests seldom reveal a treatable cause of tinnitus, and little existing evidence supports their use. Laboratory testing should be guided by clinical suspicion rather than the presence of tinnitus because the diagnostic yield is likely to be low. For patients with asymmetric sensorineural hearing loss and tinnitus, syphilis and Lyme serologies are cost-effective ways to identify treatable causes.55

AMERICAN FAMILY PHYSICIAN

Evaluation of Tinnitus Patient presents with tinnitus

Duration

Less than three weeks

Assess for recent exposure to excess noise, head and neck trauma, otitis media, or ototoxic medication use

Three weeks or more

Intermittent hearing loss or vertigo?

Yes

Evaluate for Meniere disease with audiometry, electronystagmography, and MRI; consider referral to otolaryngologist

Yes

Suspected arterial origin: perform head and neck computed tomography, magnetic resonance angiography, or carotid doppler ultrasonography

Examine for cerumen impaction; head, neck, or TMJ pain; or focal neurologic finding

Pulsatile? No

Suspected venous origin: perform magnetic resonance venography; if results are normal or if idiopathic intracranial hypertension is suspected, measure cerebrospinal fluid pressure

Treat suspected underlying causes and observe; perform audiometry and MRI for focal neurologic findings; if symptoms persist, proceed to evaluation for tinnitus lasting more than three weeks

Nonvascular origin: evaluate for palatal, stapedial, and tensor tympani muscle myoclonus or otosclerosis Abnormal physical examination findings?

Yes

Retrotympanic mass, cholesteatoma, or focal neurologic findings: perform audiometry and MRI Cerumen impaction: treat and follow up TMJ dysfunction or change in tinnitus with head or neck movement: consider referral for specific therapy

Yes

Unilateral? No

Evaluate for vestibular schwannoma with audiometry and MRI

Order audiometry

Audiometry result?

Normal: refer to otolaryngologist or audiologist per patient preference and subjective severity of tinnitus

Unilateral or asymmetric sensorineural hearing loss: perform MRI to evaluate for vestibular schwannoma

Other abnormal audiometry results: consider referral to otolaryngologist and audiologist for further evaluation or hearing aids

Figure 1. Algorithm for the evaluation of tinnitus. MRI = Magnetic resonance imaging; TMJ = Temporomandibular joint.

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AMERICAN FAMILY PHYSICIAN Table 5. Ancillary and Specialized Tests for Evaluating Tinnitus Test

Description

Sensitivity (95% confidence interval)

Specificity (95% confidence interval)

Auditory brainstem response

Measures propagation of sound stimuli along acoustic nerve

For vestibular schwannoma: 85% (82% to 87%)33

For vestibular schwannoma: 77% (73% to 81%)33

Contrast-enhanced MRI

—

For vestibular schwannoma: 100%33

For vestibular schwannoma: near 100%52

MRI

—

For vestibular schwannoma:

T2-weighted MRI: 98% (94% to 99%)33

T2-weighted MRI: 90% to 100%33

T2*-weighted MRI: 96% (86% to 99%)33

T2*-weighted MRI: 86% to 99%33

For vestibular schwannoma: 92%36

For vestibular schwannoma: 45%36

Pure tone audiometry

Usually measures air and bone conduction between 250 and 8,000 Hz In Meniere disease, hearing loss is typically “upsloping,” affecting low frequencies (below 2,000 Hz)29

Speech discrimination

Scored recognition of phonetically balanced words

For vestibular schwannoma: 45%53

—

Vestibular testing

Electronystagmography

For Meniere disease: 50%29

—

MRI = Magnetic resonance imaging. Information from references 29, 33, 36, 52, and 53.

INFORMATION FOR PATIENTS A population-based study of older patients found that tinnitus persisted in more than 80% of individuals during a follow-up of five years and increased in severity in nearly 50%.5 However, most of the relatively small number of persons with “very annoying” tinnitus at baseline expressed less annoyance at five years, suggesting improved coping over time.5 Because many patients with chronic tinnitus do not have a specific etiology beyond presbycusis,44 supportive counseling can help patients understand the generally benign nature of tinnitus and learn to cope with it. Counseling can also support subsequent therapeutic efforts. In those with intractable and lifealtering tinnitus, several otolaryngology and audiology programs offer clinics for learning coping techniques. REFERENCES 1. Folmer RL, Martin WH, Shi Y. Tinnitus: questions to reveal the cause, answers to provide relief. J Fam Pract. 2004;53(7):532-540. 2. Sismanis A. Pulsatile tinnitus. Otolaryngol Clin North Am. 2003;36(2):389-402, viii.

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3. Gopinath B, McMahon CM, Rochtchina E, Karpa MJ, Mitchell P. Risk factors and impacts of incident tinnitus in older adults. Ann Epidemiol. 2010;20(2):129-135. 4. Nondahl DM, Cruickshanks KJ, Wiley TL, Klein R, Klein BE, Tweed TS. Prevalence and 5-year incidence of tinnitus among older adults: the epidemiology of hearing loss study. J Am Acad Audiol. 2002;13(6):323-331. 5. Gopinath B, McMahon CM, Rochtchina E, Karpa MJ, Mitchell P. Incidence, persistence, and progression of tinnitus symptoms in older adults: the Blue Mountains Hearing Study. Ear Hear. 2010;31(3):407-412. 6. McCombe A, Baguley D, Coles R, McKenna L, McKinney C, Windle-Taylor P. Guidelines for the grading of tinnitus severity: the results of a working group commissioned by the British Association of Otolaryngologists, Head and Neck Surgeons, 1999. Clin Otolaryngol Allied Sci. 2001;26(5):388-393. 7. Møller AR. Tinnitus: presence and future. Prog Brain Res. 2007;166:3-16. 8. Tucker DA, Phillips SL, Ruth RA, Clayton WA, Royster E, Todd AD. The effect of silence on tinnitus perception. Otolaryngol Head Neck Surg. 2005;132(1):20-24. 9. Rocha CA, Sanchez TG. Myofascial trigger points: another way of modulating tinnitus. Prog Brain Res. 2007;166: 209-214.

AMERICAN FAMILY PHYSICIAN 10. Folmer RL, Shi BY. Chronic tinnitus resulting from cerumen removal procedures. Int Tinnitus J. 2004;10(1):42-46. 11. Schievink WI. Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension. JAMA. 2006;295(19): 2286-2296. 12. Albers FW, Ingels KJ. Otoneurological manifestations in Chiari-I malformation. J Laryngol Otol. 1993;107(5): 441-443. 13. Jindal M, Hiam L, Raman A, Rejali D. Idiopathic intracranial hypertension in otolaryngology. Eur Arch Otorhinolaryngol. 2009;266(6):803-806.

25. Seligmann H, Podoshin L, Ben-David J, Fradis M, Goldsher M. Drug-induced tinnitus and other hearing disorders. Drug Saf. 1996;14(3):198-212. 26. Cianfrone G, Pentangelo D, Cianfrone E, et al. Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus: a reasoned and updated guide. Eur Rev Med Pharmacol Sci. 2011;15(6):601-636. 27. Bernhardt O, Gesch D, Schwahn C, et al. Signs of temporomandibular disorders in tinnitus patients and in a population-based group of volunteers: results of the Study of Health in Pomerania. J Oral Rehabil. 2004;31(4):311-319.

14. Neff BA, Staab JP, Eggers SD, et al. Auditory and vestibular symptoms and chronic subjective dizziness in patients with Meniere’s disease, vestibular migraine, and Meniere’s disease with concomitant vestibular migraine. Otol Neurotol. 2012;33(7):1235-1244.

28. Pinchoff RJ, Burkard RF, Salvi RJ, Coad ML, Lockwood AH. Modulation of tinnitus by voluntary jaw movements. Am J Otol. 1998;19(6):785-789.

15. Crummer RW, Hassan GA. Diagnostic approach to tinnitus. Am Fam Physician. 2004;69(1):120-126.

30. Havia M, Kentala E, Pyykkö I. Hearing loss and tinnitus in Meniere’s disease. Auris Nasus Larynx. 2002;29(2): 115-119.

16. Sindhusake D, Golding M, Newall P, Rubin G, Jakobsen K, Mitchell P. Risk factors for tinnitus in a population of older adults: the blue mountains hearing study. Ear Hear. 2003;24(6):501-507. 17. Shemesh Z, Attias J, Ornan M, Shapira N, Shahar A. Vitamin B12 deficiency in patients with chronic-tinnitus and noise-induced hearing loss. Am J Otolaryngol. 1993;14(2):94-99. 18. Cochran JH Jr, Kosmicki PW. Tinnitus as a presenting symptom in pernicious anemia. Ann Otol Rhinol Laryngol. 1979;88(2 pt 1):297. 19. Gosselin EJ, Yanick P Jr. Audiologic and metabolic findings in 90 patients with fluctuant hearing loss. J Am Audiol Soc. 1976;2(1):15-18. 20. Kazmierczak H, Doroszewska G. Metabolic disorders in vertigo, tinnitus, and hearing loss. Int Tinnitus J. 2001;7(1):54-58. 21. Klagenberg KF, Zeigelboim BS, Jurkiewicz AL, MartinsBassetto J. Vestibulocochlear manifestations in patients with type I diabetes mellitus. Braz J Otorhinolaryngol. 2007;73(3):353-358. 22. Pessin AB, Martins RH, Pimenta Wde P, Simões AC, Marsiglia A, Amaral AV. Auditory evaluation in patients with type 1 diabetes. Ann Otol Rhinol Laryngol. 2008;117(5):366-370. 23. Pulec JL, Pulec MB, Mendoza I. Progressive sensorineural hearing loss, subjective tinnitus and vertigo caused by elevated blood lipids [published correction appears in Ear Nose Throat J. 1998;77(2):145]. Ear Nose Throat J. 1997;76(10):716-720, 725-726, 728 passim. 24. Sutbas A, Yetiser S, Satar B, Akcam T, Karahatay S, Saglam K. Low-cholesterol diet and antilipid therapy in managing tinnitus and hearing loss in patients with noiseinduced hearing loss and hyperlipidemia. Int Tinnitus J. 2007;13(2):143-149.

29. Sajjadi H, Paparella MM. Meniere’s disease. Lancet. 2008;372(9636):406-414.

31. Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Menière’s disease. American Academy of Otolaryngology-Head and Neck Foundation, Inc. Otolaryngol Head Neck Surg. 1995;113(3):181-185. 32. Baguley DM, Humphriss RL, Axon PR, Moffat DA. The clinical characteristics of tinnitus in patients with vestibular schwannoma. Skull Base. 2006;16(2):49-58. 33. Fortnum H, O’Neill C, Taylor R, et al. The role of magnetic resonance imaging in the identification of suspected acoustic neuroma: a systematic review of clinical and cost effectiveness and natural history. Health Technol Assess. 2009;13(18):iii-iv, ix-xi, 1-154. 34. Saliba I, Martineau G, Chagnon M. Asymmetric hearing loss: rule 3,000 for screening vestibular schwannoma. Otol Neurotol. 2009;30(4):515-521. 35. Lustig LR, Rifkin S, Jackler RK, Pitts LH. Acoustic neuromas presenting with normal or symmetrical hearing: factors associated with diagnosis and outcome. Am J Otol. 1998;19(2):212-218. 36. Cheng TC, Wareing MJ. Three-year ear, nose, and throat cros-sectional analysis of audiometric protocols for magnetic resonance imaging screening of acoustic tumors. Otolaryngol Head Neck Surg. 2012;146(3):438-447. 37. Propp JM, McCarthy BJ, Davis FG, Preston-Martin S. Descriptive epidemiology of vestibular schwannomas. Neuro Oncol. 2006;8(1):1-11. 38. Tos M, Stangerup SE, Cayé-Thomasen P, Tos T, Thomsen J. What is the real incidence of vestibular schwannoma? Arch Otolaryngol Head Neck Surg. 2004;130(2):216-220. 39. Hardell L, Carlberg M, Söderqvist F, Mild KH. Pooled analysis of case-control studies on acoustic neuroma diagnosed 1997-2003 and 2007-2009 and use of mobile and cordless phones. Int J Oncol. 2013;43(4):1036-1044.

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AMERICAN FAMILY PHYSICIAN 40. Guitton MJ. Tinnitus and anxiety: more than meets the ear. Curr Psychiatry Rev. 2006;2(3):333-338.

Nord-Trøndelag health study. Arch Otolaryngol Head Neck Surg. 2010;136(2):178-182.

41. Holmes S, Padgham ND. Review paper: more than ringing in the ears: a review of tinnitus and its psychosocial impact. J Clin Nurs. 2009;18(21): 2927-2937.

49. Langguth B, Goodey R, Azevedo A, et al. Consensus for tinnitus patient assessment and treatment outcome measurement: Tinnitus Research Initiative meeting, Regensburg, July 2006. Prog Brain Res. 2007;166:525-536.

42. Welch D, Dawes PJ. Personality and perception of tinnitus. Ear Hear. 2008;29(5):684-692. 43. Nondahl DM, Cruickshanks KJ, Wiley TL, et al. The ten-year incidence of tinnitus among older adults. Int J Audiol. 2010;49(8):580-585. 44. Lloyd SK, Baguley DM. A patient with tinnitus. Clin Otolaryngol. 2008;33(1):25-28.

50. Goodey R. Tinnitus treatment: state of the art. Prog Brain Res. 2007;166:237-246. 51. Sismanis A, Girevendoulis A. Pulsatile tinnitus associated with internal carotid artery morphologic abnormalities. Otol Neurotol. 2008;29(7):1032-1036.

45. Kentala E, Pyykkö I. Clinical picture of vestibular schwannoma. Auris Nasus Larynx. 2001;28(1):15-22.

52. House JW, Bassim MK, Schwartz M. False-positive magnetic resonance imaging in the diagnosis of vestibular schwannoma. Otol Neurotol. 2008;29(8):1176-1178.

46. Sindhusake D, Mitchell P, Newall P, Golding M, Rochtchina E, Rubin G. Prevalence and characteristics of tinnitus in older adults: the Blue Mountains Hearing Study. Int J Audiol. 2003;42(5):289-294.

53. Ferguson MA, Smith PA, Lutman ME, Mason SM, Coles RR, Gibbin KP. Efficiency of tests used to screen for cerebello-pontine angle tumours: a prospective study. Br J Audiol. 1996;30(3):159-176.

47. Chadha NK, Weiner GM. Vascular loops causing otological symptoms: a systematic review and meta-analysis. Clin Otolaryngol. 2008;33(1):5-11.

54. Sismanis A. Pulsatile tinnitus. A 15-year experience. Am J Otol. 1998;19(4):472-477.

48. Kvestad E, Czajkowski N, Engdahl B, Hoffman HJ, Tambs K. Low heritability of tinnitus: results from the second

55. Wilson YL, Gandolfi MM, Ahn IE, Yu G, Huang TC, Kim AH. Cost analysis of asymmetric sensorineural hearing loss investigations. Laryngoscope. 2010;120(9):1832-1836.

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AMERICAN FAMILY PHYSICIAN

Practice Guidelines AUA RELEASES GUIDELINE ON EARLY DETECTION OF PROSTATE CANCER In April 2013, the American Urological Association (AUA) released a guideline on early detection of prostate cancer, namely to reduce prostate cancer mortality. RECOMMENDATIONS

Younger Than 40 Years The prevalence of prostate cancer in men younger than 40 years is very low, and even if cancer is found in men this age, the disease is of low volume and low Gleason grade. No prospective randomized trials assessing the benefits of prostate-specific antigen (PSA) testing included men younger than 40 years; therefore, there is no information to determine benefit in this population. Harms, however, include adverse effects of biopsies and possibly treatment. For these reasons, the AUA recommends against PSA screening in men in this age group.

40 to 54 Years of Age There is no high-quality evidence to support routine screening in men 40 to 54 years of age, assuming these men are not at increased risk of prostate cancer (e.g., family history, black). Therefore, the AUA does not recommend routine screening in this population. It should be noted that this recommendation is not meant to suggest that there is no benefit from screening, but rather that the harms associated with screening are substantial enough that they likely outweigh the benefits.

55 to 69 Years of Age To make a decision about PSA screening, physicians should weigh the benefits of preventing mortality in one man for every 1,000 screened over 10 years against the

possible harms of screening and treatment. Therefore, the AUA strongly recommends shared decision making in men 55 to 69 years of age who are considering PSA screening, with the decision being based on the patientâ&#x20AC;&#x2122;s values and preferences. The patientâ&#x20AC;&#x2122;s life expectancy should be included in the discussion of benefits and harms. Baseline mortality risk from other conditions, risk of prostate cancer, and the level to which screening may impact life expectancy and risk of morbidity from prostate cancer or treatment should also be discussed. The AUA indicates that the benefits of screening likely outweigh harms in this population, justifying the recommendation for shared decision making. In men who have participated in shared decision making and have chosen to undergo screening, a screening interval of at least two years may be preferred over screening every year. Although randomized controlled trials have used two- and four-year screening intervals, a specific interval has not been determined. Estimates from modeling studies indicate that, compared with annual screening, biennial screening preserves most of the benefits of screening, while reducing the number of tests, the risk of false-positive results, and overdiagnosis.

70 Years and Older The AUA does not recommend routine PSA screening in men 70 years and older, or in men with a life expectancy less than 10 to 15 years. This recommendation is based on the lack of evidence of benefit in this population, and on the clear evidence of harms. Although men 70 years and older can have a life expectancy of more than 10 to 15 years, and some men in this age group are in excellent health and may benefit from screening, data to indicate overall benefit in this population are limited. Shared decision making and consideration of individual values, preferences, and quality of life goals are vital.

Source: Adapted from Am Fam Physician. 2014;89(2):137.

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Photo Quiz ANEMIA AND MUCOCUTANEOUS TELANGIECTASIAS A 29-year-old woman presented with an eight-month history of progressive fatigue and recurrent epistaxis. She reported that her father and her grandmother also had a history of nosebleeds. The physical examination revealed telangiectasias on her lower lip, tongue, and fingers (Figures 1 and 2). Laboratory tests showed severe hypochromic microcytic anemia, with a hemoglobin level of 4.1 g per dL (41 g per L; normal range: 12 to 14 g per dL [120 to 140 g per L]).

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

Figure 1.

A. Blue rubber bleb nevus syndrome. B. CREST syndrome. C. Hereditary hemorrhagic telangiectasia. D. Peutz-Jeghers syndrome.

Figure 2.

SEE THE FOLLOWING PAGE FOR DISCUSSION.

Source: Adapted from Am Fam Physician. 2014;89(2):89-90.

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AMERICAN FAMILY PHYSICIAN DISCUSSION The correct answer is C: hereditary hemorrhagic telangiectasia. This autosomal dominant vascular disorder, which is also referred to as Osler-WeberRendu disease, has a variety of clinical manifestations, including epistaxis, gastrointestinal bleeding, iron deficiency anemia, and mucocutaneous telangiectasias. Epidemiologic studies suggest the prevalence is one in 5,000 to 8,000 persons in most populations.1 Spontaneous, recurrent epistaxis from telangiectasia of the nasal mucosa is the most common clinical manifestation of hereditary hemorrhagic telangiectasia. Although some patients experience minimal or only occasional episodes, many have daily bleeds that can lead to iron deficiency anemia.2 Mucocutaneous telangiectasias occur in about 75% of patients with the condition, typically presenting after childhood and increasing in size and number with age. They are most common on the lips, tongue, buccal mucosa, and fingertips. Pulmonary, hepatic, and cerebral arteriovenous malformations are possible and may lead to embolic stroke, brain abscess, and hemorrhagic stroke. A hereditary hemorrhagic telangiectasia diagnosis is clinical and based on the Curacao criteria: spontaneous, recurrent epistaxis; multiple mucocutaneous telangiectasias; visceral involvement (e.g., gastrointestinal, pulmonary, cerebral, or hepatic arteriovenous malformations); and a first-degree relative with the disease.3,4 The diagnosis can be made Summary Table

if three or four criteria are present; the diagnosis is suspected if two are present, and is unlikely if one or none is present. Formal genetic testing can confirm the disease. Blue rubber bleb nevus syndrome, or Bean syndrome, is a rare disorder. Patients with this condition present with venous malformations of the skin and internal viscera appearing as multiple, blue to blue-gray macules, papules, and nodules.5 CREST (calcinosis cutis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) syndrome may lead to fibrotic skin changes, often involving the fingers, hands, and face. Macular telangiectasias, usually on the lips and palms, are matted or squared-off, as opposed to the raised lesions associated with hereditary hemorrhagic telangiectasia. Capillary abnormalities in the proximal nail fold, sclerodactyly, digital pitting scars, and loss of substance from the finger pad are also distinguishing characteristics.6 Peutz-Jeghers syndrome is a rare genetic disorder characterized by melanotic macules, gastrointestinal polyps, and increased cancer risk. Melanotic macules are typically flat, blue-gray to brown, 1- to 5-mm spots.7 REFERENCES 1. Westermann CJ, Rosina AF, De Vries V, de Coteau PA. The prevalence and manifestations of hereditary hemorrhagic telangiectasia in the Afro-Caribbean population of the Netherlands Antilles: a family screening. Am J Med Genet A. 2003;116A(4):324-328. 2. Shovlin CL. Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment. Blood Rev. 2010;24(6):203-219.

Condition

Characteristics

Blue rubber bleb nevus syndrome

Venous malformations of the skin and internal viscera appearing as multiple, blue to blue-gray macules, papules, and nodules

3. Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (RenduOsler-Weber syndrome). Am J Med Genet. 2000;91(1): 66-67.

CREST syndrome

Telangiectatic matted or squared-off macules on the lips and palms; capillary abnormalities in the proximal nail fold; sclerodactyly; digital pitting scars; loss of substance from the finger pad

4. Faughnan ME, Palda VA, Garcia-Tsao G, et al.; HHT Foundation Internationalâ&#x20AC;&#x201C;Guidelines Working Group. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet. 2011;48(2):73-87.

Hereditary hemorrhagic telangiectasia

Autosomal dominant vascular disorder; manifestations include epistaxis, gastrointestinal bleeding, iron deficiency anemia, and mucocutaneous telangiectasias

5. DĂ˛mini M, Aquino A, Fakhro A, et al. Blue rubber bleb nevus syndrome and gastrointestinal haemorrhage: which treatment? Eur J Pediatr Surg. 2002;12(2):129-133.

Peutz-Jeghers syndrome

Melanotic macules; gastrointestinal polyps; increased cancer risk

CREST = Calcinosis cutis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia.

6. Reddy BY, Hantash BM. Cutaneous connective tissue diseases: epidemiology, diagnosis, and treatment. Open Dermatol J. 2009;3(1):22-31. 7. Kopacova M, Tacheci I, Rejchrt S, Bures J. Peutz-Jeghers syndrome: diagnostic and therapeutic approach. World J Gastroenterol. 2009;15(43):5397-5408.

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CARDIOLOGY

Comparative Evaluation of ACE Inhibitors for their Beneficial Effects in Patients with Ischemic Left Ventricular Systolic Dysfunction and Undergoing Coronary Artery Bypass Surgery PS GANDHI*, RK GOYAL†, AR JAIN‡, BS MALLYA‡, MC CHAG‡, VM GUPTA‡, DS SHAH‡, BR TRIVEDI‡, NA SHASTRI‡, CB MEHTA‡, KA JAIN‡, NS BHAVASAR‡, UJ SHAH‡

ABSTRACT Three ACE inhibitors: Captopril, perindopril and ramipril were compared for their effectiveness in patients having LV systolic dysfunction (LVEF 30% as revealed by 2D echocardiography) and who underwent CABG. We enrolled 27 patients in captopril, 43 patients in perindopril and 70 patients in ramipril group. There was about 25-36% rise in LVEF after 3 and 6 months of ACE inhibitor administration in all three groups. Perindopril treatment produced a sustained improvement in LVEF. However, the difference in terms of percent improvement in LV contractility amongst three groups was not statistically significant. After 3 and 6 months of treatment with ACE inhibitor following coronary arterial grafting, the reduction in LV diameters did not differ significantly amongst three groups. There was a significant decrease (p < 0.05) in LV end-diastolic diameter from baseline levels in captopril and perindopril groups after 3 months which got increased after 6 months but remained below pretreatment levels in both the groups. In ramipril group, there was not much change in this parameter from baseline levels at 3 and 6 months of treatment. After 6 months of treatment, the percent reduction in LV end-systolic diameter was also sustained in perindopril-treated patients. The percent reduction was greater in the perindopril group (3 and 6 months: 7.39 ± 5.94 and 7.73 ± 3.43, respectively) as compared to that observed in captopril group (3 and 6 months: 5.67 ± 1.05 and 2.52 ± 3.11, respectively) and ramipril group (3 and 6 months: 7.30 ± 2.75 and 4.93 ± 3.22, respectively). Mitralvalve regurgitation was greatly reduced in the captopril group at 3 as well 6 months of ACE inhibitor administration. However, the percent reduction from baseline levels was not statistically significant amongst three groups. The percent improvement in functional status was significantly greater in the ramipril treatment group (36.46 ± 3.14) after 6 months of treatment as compared to that of captopril (6.67 ± 10.64) and perindopril (4.17 ± 2.73) group. In conclusion, our data show equal beneficial effects with all three ACE inhibitors in CABG patients with LV systolic dysfunction, with marginal superiority for perindopril.

Keywords: ACE inhibitor, left ventricular systolic, dysfunction, heart failure, coronary artery bypass surgery

bout 23 million people worldwide are afflicted with heart failure (HF) and 2 million new cases of HF are diagnosed each year worldwide.1 As per the heart and stroke statistics update of American Heart Association (AHA), nearly 5 millions

*Associate Professor Dept. of Pharmacology Shree Dhanvantary Pharmacy College, Kim, Surat, Gujarat †Institute of Lifesciences, Ahmedabad University, Ahmedabad, Gujarat ‡The Heart Care Clinic, Ahmedabad, Gujarat Address for correspondence Dr Purvi S Gandhi Associate Professor, Dept. of Pharmacology Shree Dhanvantary Pharmacy College, Near Railway Station, Surat - 394 110, Gujarat E-mail: psgandhi1975@gmail.com

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in the United States suffer from HF.2 A large survey namely MONItoring of trends and determinants in CArdiovascular disease (MONICA) survey found that the prevalence of left ventricular (LV) dysfunction in Britain was 2.27%.3 Indians and other South Asians are more likely to die from HF in comparison to Caucasians.4 The incidence of HF is on rise in past few decades.1 Since, myocardial infarction (MI) or severe ischemia, resulting from multiple-vessel coronary artery disease (CAD), is the main underlying cause in the LV systolic dysfunction; surgical revascularization of diseased coronary arteries by coronary artery bypass grafting (CABG) is one of the common interventions for the treatment of such patient population.5 However, post-surgical therapy with pharmacological measures

CARDIOLOGY is needed to sustain the beneficial effects of the former.6 Involvement of neurohormonal system especially sympathetic system and renin-angiotensin-aldosterone system (RAAS) in LV remodeling through direct as well as indirect mechanism is well-documented.7,8 Several angiotensin-converting enzyme (ACE) inhibitors and antagonists of angiotensinin II receptor subtype-1 (AT1) have shown a significant reduction in mortality and morbidity in patients having LV systolic dysfunction.9-14 Long-term treatment with ACE inhibitors produces absolute increases in LV ejection fraction (LVEF).15 Captopril has been found to reverse ventricular dilation caused by MI.16 Enalapril has also been reported to reverse progression of LV dilation in patients with asymptomatic systolic dysfunction.17 Thus, many clinical trials and researches are available showing beneficial effects of various ACE inhibitors and American College of Cardiology(ACC)/AHA practice guidelines recommend ACE inhibitors for treatment of LV systolic dysfunction, if not contraindicated.18 Majority of the reports on beneficial effects of ACE inhibitors in patients with LV dysfunction include placebo-controlled research and do not compare various ACE inhibitors in a single research for their beneficial effects on such patient population.10,19,20 In our earlier report, we found captopril and perindopril more efficient in improving LV contractility as compared to ramipril, lisinopril and losartan.21 Captopril and perindopril produced a significant increase in percent LVEF as compared to other ACE inhibitors and losartan. Perindopril also decreased insulin levels significantly. There was a significant correlation between decreases in blood glucose as well as insulin levels with improvements in LVEF.21 However, the evidence was based on assessment of biochemical parameters to correlate the improvements in LVEF produced by these drugs, while the clinical parameters include echocardiographic evaluation. Hence, we compared various ACE inhibitors in one research for their beneficial effects on patients having ischemic LV systolic dysfunction and undergoing CABG using echocardiographic parameters. MATERIAL AND METHODS The study presented here includes the research carried out at SAL Hospital and Sterling Hospital, Ahmedabad. The research was approved by the Ethics Committee of both the hospitals. Written informed consent was taken from all the patient’s, eligible for the investigation, Moreover, all patients were explained about the procedures, the risks and benefits of the interventions.

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Clinical Flow Chart Patient’s hospitalization for CABG Assessment for- Biographic, clinical and biochemical characteristics as well as yy 2D echocardiography and color Doppler parameters Enrollment of patient meeting selection criteria, in research, randomization, patient’s counseling and collection of patient’s informed consent Stabilization of patient for 1-2 day(s) depending upon the hemodynamic status Conduct of CABG by surgeons followed by observation: yy Under intensive care unit for 1-1.5 day(s) yy In ward for 3-5 days for any MACE or mortality Drug and dose setting during postsurgery in-hospital stay Discharge of patient from hospital on stabilization of hemodynamic status; patient’s counseling about: yy Medication and general measures to be taken by the patient yy Follow-up at the time of discharge Assessment of: yy Clinical characteristics yy 2D echocardiography and color Doppler parameters at 1, 3 and 6 months of surgery and drug administration yy Mortality and MACE recording up to 6 months Data compilation and analysis performed using Microsoft Windows XP and GPower (Version 2, by Franz Faul, Edgar Erdfelder, Germany; Source: Stat CD, Indian J Pharmacol, 2004).

Study Design It was a prospective, randomized, open-label research. The research did not include control group since ACE inhibitors have proven absolute beneficial effects on patients with LV systolic dysfunction. Further, as per the ACC/AHA guidelines for management of HF, all the patients with LV systolic dysfunction should be treated with ACE inhibitor, if there is no contraindication. Therefore, the control group was not included and comparison amongst three ACE inhibitors was carried out.

Patient Selection Inclusion Criteria Patients presented with ischemic LV systolic dysfunction (defined as LVEF 30% as revealed from two-dimensional [2D] echocardiography) and undergoing CABG were included.

CARDIOLOGY Exclusion Criteria Patients of age above 70 years, previous or recent history of second- or third-degree atrioventricular block, renal failure (serum creatinine >2.6 mg%), hepatic dysfunction (serum glutamate pyruvate transaminase [SGPT] >45 IU/L), cerebrovascular events, previous history of revascularization or valve replacement surgery were excluded from the study. Groups of Patients Patients meeting the selection criteria were randomized into three groups. Randomization was done using cards indicating ‘1’ designated to captopril, ‘2’ designated to perindopril and ‘3’ designated to ramipril therapy. Group I included patients receiving captopril after CABG. Group II included patients receiving perindopril treatment. In Group III, ramipril was the ACE inhibitor. Patients were evaluated at the time of enrollment a day or 2 before CABG and re-evaluated at 1, 3 and 6 months of CABG and ACE inhibitor administration. We enrolled 27 patients in Group I (captopril group), 43 patients in Group II (perindopril group) and 70 patients in ramipril group. TREATMENTS As per the strategy, the drug dose regimen was started with the minimum dose of the drug and allowed to attain the maximum dose. Serial dose titration was carried out depending upon the hemodynamic status of the patients. For captopril, the initial dose was 37.5 mg/day and reached up to maximum of 75 mg/day. Perindopril treatment was begun with the dose of 2 mg/day and reached maximum dose of 4 mg/day. Ramipril administration was started with 2.5 mg/day and the highest dose attained was 20 mg/day. In addition to ACE inhibitor, patients were also receiving other drugs directly affecting cardiac function such as diuretic(s), b-adrenoceptor blocker and digoxin. Other drugs used include amiodarone, isosorbide dinitrate, acetylsalicylic acid, statin, etc. depending upon the requirements. Patients were also advised of general measures about lifestyle modifications i.e., cessation of smoking or tobacco chewing or alcoholism, regular exercise of low-medium caliber, restricted total salt intake and fluid intake (2-3 liters/day) as well as fat intake. BIOGRAPHIC CHARACTERISTIC ASSESSMENT Patient’s biographic characteristics i.e., age and associated risk factors such as habit of smoking, tobacco

chewing or alcoholism and family history of ischemic heart disease (IHD) were noted by questioning at the time of enrollment. Body weight was measured with the help of pedal weighing balance. Patient’s height was measured in patient’s standing position using vertical height-measuring column device.

Clinical Assessment Clinical assessment included patient’s hemodynamic parameters i.e., pulse rate, systolic and diastolic blood pressure measured in patient’s seating position with elbow at the level of heart using sphygmomanometer. They were evaluated for the electrocardiogram (ECG) and CAD characteristics using coronary angiography (CAG) pattern carried out preoperatively. Functional capacity was determined as per New York Heart Association (NYHA) class for HF, assigning patients to 1 of 4 functional classes depending upon the degree of effort needed to elicit symptoms.22

2D echocardiography and Color Doppler Assessment 2D echocardiography and color Doppler assessment was performed using CarisPlus (Esaote, USA) machine by a cardiologist who was unaware of the treatment given. Recommendations of the American Society of Echocardiography were followed by the cardiologist for measuring various parameters. Images were obtained from the patient lying on the left side in a supine position with the body elevated at about 30°. LVEF was assessed using standard parasternal and apical views. Left ventricular end-diastolic diameter (LVEDd) and LV end-systolic diameter (LVEDs) were measured using four-chamber and two-chamber views with apical approach at the level of papillary muscle. Severity of mitral-valve regurgitation (MR) was found out using color Doppler assessment. LVEF, LVEDd, LVEDs and MR-grade were measured a day or 2 before and 1, 3 and 6 months following CABG and ACE inhibitor administration. Mortality and MACE was noted up to 6 months of drug treatment under consideration.

Biochemical Parameter Assessment Blood samples from patients were collected at the time of enrollment for biochemical parameter testing, which was done in in-hospital pathology laboratory following good laboratory practices. Biochemical parameters assessed included serum glucose, serum urea, serum creatinine, SGPT, serum total cholesterol, serum triglyceride and serum high-density lipoprotein

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CARDIOLOGY (HDL) cholesterol, serum low-density lipoprotein (LDL)cholesterol, serum potassium (K+) and serum sodium (Na+). DATA ANALYSIS The data were analyzed by finding mean ± standard error of mean (SEM) for numerical and ordinal data while percent of number (n) of patients for nominal data. Chi-square test was used to find difference of statistical significance in categorical measurements amongst three groups. For parametric numerical data, results were obtained by applying Student’s t-test to find the change in characteristics from baseline levels. Analysis of variance (ANOVA) was used for numerical data to find the significant difference amongst three treatment groups. Difference amongst groups and hence treatment, was considered statistically significant if ‘p’ value was found to be <0.05 (p < 0.05). Post-hoc power analysis was done using GPower software. The power of the study (1-b) has been presented along with the respective level of significance. RESULTS Baseline biographic characteristics, risk factor association and biochemical variables were similar among three groups (Tables 1-3). There was no significant (p < 0.05) difference in CAD characteristics, medication affecting cardiac function other than ACE inhibitors, hemodynamics (such as heart rate, systolic and diastolic blood pressure) and baseline 2D echocardiography

characteristics amongst three groups (Tables 4-7). After 1, 3 and 6 months of ACE inhibitor administration following CABG, 2D echocardiography showed a significant (p < 0.05) improvement in LV contractility from baseline levels (i.e., levels at the time of enrollment) in captopril and ramipril groups. In perindopril treatment group, the increase in LVEF was found to be statistically significant after 1 and 3 months of treatment. Increase in LVEF in terms of percent change from baseline levels in individual patients did not differ significantly amongst three groups; however, the increase was greater and persistent in perindopril group (Table 7 and Fig. 1). There was a significant decrease in LVEDd from baseline levels in captopril and perindopril groups after 3 months, which increased after 6 months, but remained below pretreatment levels in both the groups. In ramipril group, not much change in this parameter was observed from baseline levels after 3 and 6 months of treatment (Table 7 and Fig. 2). After 3 months of treatment, LVEDs was significantly decreased in captopril and perindopril groups as compared with baseline levels. However, after 6 months, there was an increase in this parameter in both the groups. In ramipril-treated patients, no significant decrease in LVEDs was observed after 3 as well as 6 months of treatment. Decrease in LVEDs in terms of percent change from baseline levels did not differ significantly amongst three groups; however, it was more persistent in perindopril group (Table 7 and Fig. 3). Mitral-valve regurgitation- grade did not differ significantly from baseline levels within the groups

Table 1. Baseline Biographic Characteristics of Patients Parameter

Group II (Perindopril) (n = 43)

Group III (Ramipril) (n = 70)

Sex males (%)

(100%)†

38 (88.37%)

67 (95.71%)

Age (years)*

57.14 ± 1.84

60.25 ± 1.34

56.89 ± 1.07

(kg/m2)*

26.36 ± 1.53

27.48 ± 1.13

25.31 ± 1.32

9 (33.33%)

3 (6.98%)

14 (20.0%)

Moderate

7 (25.92%)

15 (34.88%)

16 (22.86%)

Sedentary

11 (40.74%)

25 (58.14%)

40 (57.14%)

16 (59.26%)

23 (53.49%)

29 (41.43%)

2 (7.40%)

4 (9.30%)

2 (2.86%)

15 (55.55%)

22 (51.16%)

45 (64.29%)

BMI

Group I (Captopril) (n = 27)

Lifestyle (stress) Heavy

Symptoms Dyspnea on exertion Edema Chest pain

BMI = Body mass index; kg/m2 = Kilogram per square meter. *Mean ± SEM. †Values

in brackets are percent of total n in each group.

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CARDIOLOGY Table 2. Prevalence of Risk Factors in Patients at the Time of Enrollment Risk factor

Group I (Captopril) (n = 27)

Group II (Perindopril) (n = 43)

Group III (Ramipril) (n = 70)

Habit Alcoholism

1 (3.7%)*

0 (0%)

4 (5.71%)

5 (18.52%)

5 (11.63%)

18 (25.71%)

1 (3.7%)

6 (13.95%)

17 (24.28%)

10 (37.03%)

21 (48.83%)

36 (51.43%)

7 (25.92%)

17 (39.53%)

29 (41.43%)

DM + HT

3 (11.11%)

10 (23.26%)

17 (24.29%)

IHD

7 (25.93%)

8 (18.6%)

24 (34.28%)

Past history of MI

18 (66.67%)

21 (48.84%)

42 (60.0%)

Smoking Tobacco chewing Disease

Positive family history

DM = Diabetes mellitus; HT = Hypertension; IHD = Ischemic heart disease; MI = Myocardial infarction. *Values in brackets are percent of total n in each group.

Table 3. Biochemical Parameters at Baseline Level Biochemical parameter

Group I (Captopril) (n = 27)

Group II (Perindopril) (n = 43)

Group III (Ramipril) (n = 70)

155.59 ± 10.82

149.01 ± 12.43

176.79 ± 7.55

Serum urea (mg%)*

29.59 ± 1.43

32.23 ± 1.39

34.34 ± 1.16

Serum creatinine (mg%)*

1.18 ± 0.08

1.19 ± 0.03

1.15 ± 0.03

SGPT (IU/L)*

28.58 ± 2.52

30.37 ± 1.51

33.4 ± 1.23

RBS (mg%)*

K+

4.47 ± 0.07

4.10 ± 0.08

4.32 ± 0.07

Serum Na+ (mEq/L)*

135.98 ± 1.47

135.89 ± 0.81

136.56 ± 0.54

Serum TC (mg%)*

112.0 ± 8.54

110.45 ± 4.59

117.65 ± 3.61

Serum TG (mg%)*

75.68 ± 6.46

99.53 ± 8.14

106.17 ± 7.49

Serum LDL-C (mg%)*

59.87 ± 6.55

54.56 ± 4.38

61.61 ± 2.96

Serum HDL-C (mg%)*

31.53 ± 1.52

27.96 ± 1.79

27.71 ± 1.22

Serum

(mEq/L)*

HDL-C = High-density lipoprotein cholesterol; IU = International unit; K+ = Potassium; LDL-C = Low-density lipoprotein cholesterol; mEq = Milliequivalence; mg = Milligram; Na+ = Sodium; RBS = Random blood sugar; SGPT = Serum glutamate pyruvate transaminase; TC = Total cholesterol; TG = Triglyceride. *Mean ± SEM.

as well as amongst three groups after 3 and 6 months of ACE inhibitor administration. At 6 months of ACE inhibitor administration, the percent improvement in MR-grade was greatest in captopril group as compared to that produced in perindopril and ramipril groups (Table 7). The NYHA class was significantly reduced (p < 0.05) from baseline levels in all three groups after 3 and 6 months suggesting significant improvement in functional status in all three groups (Fig. 4). Further, in ramipril group, the percent improvement in NYHA class was statistically significant as compared to those observed in other two groups. Two patients died in ramipril treatment group during post-hospital

course, one because of sudden fall in heart rate and the other because of recurrent MI. In remaining patients, no MACE was found in all three groups during 6-month follow-up. DISCUSSION Hyperactivated neurohormonal systems responsible for the cardinal effects in patients with LV dysfunction include mainly RAAS and sympathetic system. Amongst various drugs therapy, inhibitors of RAAS are at the top of the recommendations. Various components of RAAS play significant role in the development of LV remodeling; and hence in further deterioration of

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CARDIOLOGY Table 4. Angiographic Pattern of Stenosed Coronary Arteries as Revealed by Angiography Group I (Captopril) (n = 27)

Group II (Perindopril) (n = 43)

Group III (Ramipril) (n = 70)

Single vessel disease

0 (0%)*

1 (2.32%)

0 (0%)

Double vessel disease

4 (14.81%)

7 (16.28%)

8 (11.42%)

Triple vessel disease

23 (85.18%)

35 (81.39%)

62 (88.57%)

2 (7.41%)

8 (18.60%)

10 (14.23%)

Diffusely diseased artery

Diseased artery, lesion severity i.e., percent blockade of diameter LMCA (≥50%)

2 (7.41%)

7 (16.28%)

10 (14.23%)

LAD (100%)

17 (62.96%)

7 (39.53%)

30 (42.86%)

LAD (70-99%)

6 (22.22%)

20 (46.51%)

36 (51.43%)

LCx (100%)

3 (11.11%)

9 (20.93%)

7 (10.0%)

LCx (70-99%)

8 (29.63%)

16 (37.21%)

29 (41.43%)

RCA (100%)

9 (33.33%)

17 (39.53%)

28 (40.0%)

RCA (70-99%)

11 (40.74%)

13 (30.23%)

31 (44.29%)

LMCA = Left main coronary artery; LAD = Left anterior descending artery; LCx = Left circumflex artery; RCA = Right coronary artery. *Values in brackets are percent of total n in each group.

Table 5. Medication Affecting Cardiac Function Other than ACE Inhibitors Given to Patients Following CABG Medication

Group I (Captopril) (n = 27)

Group II (Perindopril) (n = 43)

Group III (Ramipril) (n = 70)

Digoxin

23 (85.18%)*

29 (67.44%)

49 (70.0%)

Diuretics

25 (92.59%)

37 (86.04%)

62 (88.57%)

b-adrenoceptor blocker

15 (55.55%)

17 (39.53%)

33 (47.14%)

ACE = Angiotensin-converting enzyme; CABG = Coronary artery bypass grafting. *Values in brackets are percent of total n in each group.

Table 6. Hemodynamic Levels in Patients at Baseline (At the Time of Enrollment) and at 1, 3 and 6 Months of Treatment Parameters

Group I (Captopril) (n = 27)

Group II (Perindopril) (n = 43)

Group III (Ramipril) (n = 70)

Baseline

79.60 ± 1.42

85.72 ± 2.49

82.71 ± 2.13

1 month

83.0 ± 1.34

83.92 ± 0.84

83.85 ± 0.99

3 months

81.0 ± 2.45

79.0 ± 1.32

82.4 ± 1.24

6 months

84.0 ± 1.62

82.0 ± 1.12

86.67 ± 1.56

Baseline

125.4 ± 3.69

122.89 ± 2.82

123.75 ± 2.10

1 month

119.0 ± 1.98

125.81 ± 2.74

119.84 ± 1.44

3 months

121.0 ± 3.17

125.67 ± 4.11

127.0 ± 2.86

6 months

126.25 ± 2.45

126.78 ± 3.24

122.0 ± 1.59

Baseline

76.24 ± 1.42

78.19 ± 1.58

79.75 ± 1.16

1 month

76.18 ± 1.59

80.84 ± 1.08

78.01 ± 0.90

3 months

83.0 ± 4.62

83.33 ± 0.83

80.8 ± 1.34

6 months

81.34 ± 2.56

80.0 ± 1.27

83.33 ± 0.70

HR (beats/min)*

SBP (mmHg)*

DBP (mmHg)*

DBP = Diastolic blood pressure; HR = Heart rate; mmHg = Millimeters of mercury; SBP = Systolic blood pressure. *Mean ± SEM.

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CARDIOLOGY

Baseline

1 month 45

3 months

LVEF (%)

6 months

* *

30 25 20 15 10 5 0 Captopril (n = 27)

Perindopril (n = 43)

Ramipril (n = 70)

Captopril (% change)

Perindopril (% change)

Ramipril (% change)

Figure 1. Effect of ACE inhibitors on LV contractility measured as LVEF in patients with LV systolic dysfunction and undergoing CABG. *Significantly different from baseline (p < 0.05). Power (1-b) = 0.546 at a = 0.4.

65 Baseline 60 55

1 month

3 months 6 months

50 45 40

LVEDd (mm)

35 30 25 20 15 10 5 0 -5 -10

Captopril (n = 27)

Perindopril (n = 43)

Ramipril (n = 70)

Captopril (% change)

Perindopril (% change)

Ramipril (% change)

Figure 2. Effect of ACE inhibitors on LVEDd in patients with LV systolic dysfunction and undergoing CABG. *Significantly different from baseline (p < 0.05).

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CARDIOLOGY Table 7. 2D Echocardiography and Color Doppler Characteristics and NYHA Class for HF in Patients at the Time of Enrollment (Baseline) and at 1, 3 and 6 Months of ACE Inhibitor Treatment Parameters 2D echocardiography and color Doppler

Group I (Captopril) (n = 27)

% change from baseline in individual patients

Group II (Perindopril) (n = 43)

% change from baseline in individual patients

Group III (Ramipril) (n = 70)

% change from baseline in individual patients

LVEF (%)* Baseline

25.89 ± 0.84

24.91 ± 1.07

1 month

31.68 ±

1.95‡

29.44 ±

2.65‡

3 months

33.25 ±

2.36‡

26.11 ± 7.22

35.43 ±

2.60‡

6 months

36.25 ± 2.51‡

39.42 ± 9.49

30.38 ± 7.23

28.5 ± 3.42

25.21 ± 0.57 26.12 ± 6.44

30.29 ± 1.14‡

17.74 ± 5.09

36.61 ± 7.68

32.59 ±

1.49‡

35.28 ± 6.72

39.2 ± 7.92

33.03 ± 1.58‡

25.61 ± 6.34

LVEDd (mm)* Baseline

55.86 ± 1.60

1 month

52.18 ± 2.80 2.03‡

3 months

50.5 ±

6 months

53.98 ± 1.47

57.25 ± 1.23 7.67 ± 3.99

58.56 ± 2.06

6.3 ± 3.84 -2.55 ± 2.07

54.82 ± 0.90 10.97 ± 9.49

52.28 ± 1.53

2.01‡

3.18 ± 3.86

55.39 ± 1.96

2.99 ± 1.32

54.93 ± 2.65

4.81 ± 1.16

54.14 ± 1.07

2.87 ± 2.05

53.83 ±

-1.9 ± 2.81

LVEDs (mm)* Baseline

44.17 ± 1.57

1 month

41.35 ± 2.72

3 months 6 months

44.37 ± 1.40

43.18 ± 1.07

6.37 ± 4.85

47.02 ± 2.32

-2.62 ± 4.36

39.93 ± 1.64

-0.7 ± 4.01

38.28 ±

2.31‡

5.67 ± 1.05

1.86‡

7.39 ± 5.94

41.83 ± 2.00

7.30 ± 2.75

39.91 ±

1.28‡

2.52 ± 3.11

7.73 ± 3.43

40.28 ± 1.37

4.93 ± 3.22

38.18 ±

44.3 ± 2.87

MR-grade* 0.46 ± 0.08†

0.7 ± 0.08

Baseline

0.77 ± 0.11

1 month

0.82 ± 0.1

-24.55 ± 38.41

0.49 ± 0.16

41.67 ± 13.14

0.6 ± 0.16

-77.14 ± 58.04

3 months

0.6 ± 0.15

50.0 ± 13.87

0.36 ± 0.12

-2.22 ± 41.87

0.7 ± 0.11

-48.75 ± 53.27

6 months

0.5 ± 0.16

50.0 ± 17.41

0.73 ± 0.2

-68.0 ± 53.4

0.68 ± 0.12

-89.09 ± 64.3

NYHA class for HF* Baseline

2.91 ± 0.18

2.94 ± 0.15

1 month

2.18 ±

0.22‡

0.26‡

25.0 ± 10.8

2.0 ± 0.24‡

28.7 ± 6.07

3 months

2.0 ± 0.17‡

34.72 ± 13.14

1.95 ± 0.14‡

27.45 ± 4.89

2.17 ± 0.15‡

17.86 ± 5.65

6 months

2.67 ± 0.16

6.67 ± 10.64

2.43 ± 0.20‡

4.17 ± 2.73

2.25 ± 0.15‡

36.46 ± 3.14†

5.0 ± 13.41

1.89 ±

3.0 ± 0.15

2D = Two-dimensional; HF = Heart failure; LVEDd = Left ventricular end-diastolic diameter; LVEDs = Left ventricular end-systolic diameter; LVEF = Left ventricular ejection fraction; MR = Mitral-valve regurgitation; NYHA = New York Heart Association. *Mean ± SEM. †Significantly

different as compared with other two groups (p < 0.05); ‡Significantly different from baseline (p < 0.05).

LV dysfunction caused by ischemia and/or infarction. Thus, suppression of these components has potentialabsolute and synergistic in sustaining the beneficial effects brought about by surgical revascularization. It is recommended that all HF patients with established LV systolic dysfunction should be treated with ACE inhibitor, until there are contraindications to these agents.18 By inhibiting ACE- systemic and tissue as well, ACE inhibitors reduce afterload and systolic stress too.23,24

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These subsequently increase stroke volume due to facilitated stroke work.24,25 By improving renal hemodynamics and by reducing aldosterone secretion, ACE inhibitors prevent blood volume overload. Consequently, preload and diastolic wall stresses are diminished.26 However, different ACE inhibitors may vary in their activity and thus superiority. Pfeffer et al (1992) found captopril treatment (at about 3.5 years of captopril administration) to be more beneficial, as compared with placebo, in patients having

CARDIOLOGY

Baseline

1 month

* *

LVEDs (mm)

3 months

6 months

Captopril (n = 27)

-10

Perindopril (n = 43)

Ramipril (n = 70)

Captopril (% change)

Perindopril (% change)

Ramipril (% change)

Figure 3. Effect of ACE inhibitors on LVEDs in patients with LV systolic dysfunction and undergoing CABG. *Significantly different from baseline (p < 0.05).

Baseline

1 month 45

3 months 6 months

NYHA class for HF

30 25 20 15 10 5

†

0 Captopril (n = 27)

Perindopril (n = 43)

Ramipril (n = 70)

Captopril (% change)

Perindopril (% change)

Ramipril (% change)

Figure 4. Effect of ACE inhibitors on functional status as per NYHA class for HF in patients with LV systolic dysfunction and undergoing CABG. *Significantly different from other groups (p < 0.05); †Significantly

different from baseline (p < 0.05).

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CARDIOLOGY Baseline

1 month

3 months

6 months

30 20 10

0 -10 -20 MR-grade

-30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160

Captopril (n = 27)

Perindopril (n = 43)

Ramipril (n = 70)

Captopril (% change)

Perindopril (% change)

Ramipril (% change)

Figure 5. Effect of ACE inhibitors on mitral-valve regurgitation (MR) in patients with LV systolic dysfunction and undergoing CABG. *Significantly different from other groups (p < 0.05).

LV dysfunction after an MI.10 They found captopril to significantly reduce mortality from cardiovascular cause with 21% risk reduction and also the incidence of major cardiovascular events, defined in terms of development of severe HF (37% reduction), congestive HF (CHF) requiring hospitalization (22% reduction) and recurrent MI (25% reduction). In EUROPA (EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease), perindopril was compared with placebo in patients with stable CAD.20 At average follow-up of 4 years, perindopril was found to produce a 20% relative risk reduction in primary endpoints viz. cardiovascular death, MI or cardiac arrest.20 The Heart Outcomes prevention Evaluation (HOPE) trial reported that ramipril, when compared with placebo at 5 years of administration, significantly reduced the incidences of MI (relative risk 0.8), stroke (relative risk 0.68) or death from cardiovascular causes (relative risk 0.74).19 In this trial, the patient group included those having vascular diseases or diabetes plus another

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cardiovascular risk factor but low EF or HF.19 Thus, various large randomized placebo-controlled clinical trials have shown the absolute beneficial effects of chronic administration of ACE inhibitors on mortality and major cardiovascular events in patients having CAD with or without LV dysfunction.27,28 Captopril, as compared with enalapril in patients with acute MI (AMI), is comparable in terms of improving LV function and survival.29 Ramipril and captopril are also similar for their effects on serum creatinine, serum K+, cardiac events such as arrhythmias and mortality as well in patients with CHF, though ramipril significantly controls the blood pressure with longer duration of action.30 Three-month treatments with captopril and perindopril have been reported to produce similar effects on heart rate, systolic function and LV mass, although less number of patients in perindopril group as compared with captopril group required add-on therapy with thiazides to normalize the blood pressure.31 Chu-Pak et al (2002) reported no difference in mortality

CARDIOLOGY rates after 6 months of treatment with captopril and perindopril in patients with AMI, though perindopril treatment showed better short-term tolerance than captopril treatment did, with significantly less acute hemodynamic changes and fewer withdrawals.32 Pilote et al (2008) found a possible 10-15% increase in mortality with captopril and enalapril compared with ramipril among patients with CHF.33 However, following adjustment for differences in used dosages, all ACE inhibitors had similar clinical efficacy administered in patients after MI.34 Thus, ours is probably the only research that has compared, in one subset of patient-population, the effects of captopril, perindopril and ramipril in patients with LV systolic dysfunction and who were undergoing CABG. We found an improvement in LV contractility in all three groups treated with different ACE inhibitors. There was an increase in LVEF at 1, 3 and 6 months of ACE inhibitor administration. The beneficial effects on LV performance observed after 1 month of CABG may be mainly due to revascularization.35 It is possible that at 3 and 6 months, the observed improvements may be an influence of ACE inhibitor. In the presented research, the percent improvement in LVEF from baseline levels was not statistically significant among three groups, though it was slightly greater in perindopril and ramipril groups after 3 months as compared to captopril group and in captopril and perindopril groups at 6 months as compared to ramipril group. The improvement in overall cardiac function could be because of better coronary blood flow due to inhibition of sympathetic coronary vasoconstriction by ACE inhibitors and due to inhibition of endothelial as well as adventitial ACE providing better hemodynamic control by ACE inhibitors.36-38 This property of ACE inhibitors helps enhance coronary circulation and myocardial perfusion through newly placed grafts too. In our earlier findings, we reported captopril and perindopril more efficient for improving LV contractility as compared to ramipril, lisinopril and losartan.21 Captopril and perindopril were found to produce a significant increase in percent LVEF as compared to other ACE inhibitors and losartan. There was a significant correlation between decreases in blood glucose as well as insulin levels with improvements in LVEF.21 In the presented work, the sustained and greater improvements observed in perindopril group could be secondary to improved glucose utilization by cardiac myocytes. Moreover, greater improvement in arterial compliance and thus reduction in afterload by perindopril might be responsible for the improvement

in LV contractility. Afterload inversely affects LV contractility and has direct correlationship with peripheral vascular resistance which is a measure of arterial compliance. Various ACE inhibitors viz. captopril, lisinopril and perindopril have been shown to increase arterial compliance.39-41 However, perindopril is the ACE inhibitor that has been reported to reduce media to lumen ratio of small arteries with significantly correlated LV mass reduction.42,43 Increasing the compliance (elasticity) of even larger arteries, in addition to reduction in peripheral resistance, is also an important documented property of perindopril.44 Perindopril has also been reported to improve patientâ&#x20AC;&#x2122;s hemodynamic status by improving the elasticity of resistance vessels in heart disease patients too.45,46 Furthermore, the improved compliance of conduits (by significant improvement in endothelial nitric oxide synthase expression and activity) and repair of coronary arterioles by perindopril could also be the contributing factor for greater improvement in LVEF.46-48 Besides indirect effects, direct effects of ACE inhibitors are of significance in patients with LV systolic dysfunction. ACE inhibitors prevent ventricular dilation and thereby reduce work load of heart with further improvement in its function. In our findings, the reduction in LV systolic and diastolic diameters was observed in all three groups without any significant difference at 3 and 6 months of ACE inhibitor administration. Evidences have shown that ACE inhibitors attenuate LV remodeling.16,17,25,49 The greater beneficial effects of perindopril on both diastolic and systolic diameters as compared to captopril and ramipril group is consistent with earlier report of Masuelli et al (2002), which reported that perindopril reversed LV remodeling and improved functional status significantly in HF patients who had been switched over from enalapril treatment.50 The significant reduction in LVEDs by perindopril might be due to its direct effect on Tei index.51 Perindopril has a distinguished characteristic of suppressing cardiac aldosterone production, which is activated in failing ventricles, by suppressing cardiac ACE activity.52 We found perindopril and ramipril treatments to produce negative effects on MR-grade after 3 and 6 months while captopril treatment showed favorable effects on this parameter after both 3 and 6 months of ACE inhibitor administration. Captopril is efficacious in reducing functional MR in dilated left ventricles, however, the doses used are high.53 Mitral-valve regurgitation results from a complex interaction of very small geometric and temporal changes and can occur as a result of multiple mechanisms which can not be simply overcome by inhibiting ACE.

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CARDIOLOGY All the ACE inhibitors used in our research (captopril, perindopril and ramipril) were found to be effective in improving functional status. There was reduction in NYHA class in all three groups from baseline levels. However, percent improvement in NYHA class at 6 months of ACE inhibitor treatment was significant in ramipril group only. This might be because of an increase in skeletal muscle perfusion during exercise and ability of ACE inhibitors to enhance endurance performance and muscle energy metabolism.54-57 Further, various ACE inhibitors have been proved to significantly improve NYHA class for HF in patients with moderate-to-severe LV systolic dysfunction.9,58-60 CONCLUSIONS Our findings show that all three ACE inhibitors (i.e., captopril, perindopril and ramipril) produce statistically comparable effects on heart in patients with LV systolic dysfunction undergoing CABG. While perindopril clinically produces a marginal superiority in cardiac function, ramipril produces the greatest improvement in functional capacity. REFERENCES 1. Kalorama. Congestive Heart Failure: Worldwide Drug and Medical Device Markets. SMi Publishing Pharmaceuticals, March 2002. 2. American Heart Association. Heart and Stroke Statistical Update, 2001. 3. McDonagh TA, Morrison CE, Lawrence A, Ford I, Tunstall-Pedoe H, McMurray JJ, et al. Symptomatic and asympatomatic left-ventricular systolic dysfunction in an urban population. Lancet 1997;350:829-33. 4. Blackledge HM, Newton J, Squire IB. Prognosis for South Asian and white patients newly admitted to hospital with heart failure in the United Kingdom: historical cohort study. BMJ 2003;327:526-31. 5. Eagle KA, Guyton RA, Davidoff R, Edwards FH, Ewy GA, Gardner TJ, et al. American College of Cardiology/ American Heart Association 2004 guidelines update for coronary-artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, 2004. Available from http://www.acc.org/qualityandscience/ clinical/guidelines/cabg/index.pdf. [Accessed 23 July 2013]. 6. Nishina T, Nishimura K, Yuasa S, Miwa S, Nomoto T, Sakakibara Y, et al. Initial effects of the left ventricular repair by placation may not last long in a rat ischemic cardiomyopathy model. Circulation 2001;104 (Suppl I): I-241-5.

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7. Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang CS, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A Substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 1990;82:1724-9. 8. Dzau VJ. Tissue rennin-angiotensin system in myocardial hypertrophy and failure. Arch Int Med 1993;153:937. 9. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 1991;325: 293-302. 10. Pfeffer MA, Braunwald E, MoyĂŠ LA, Basta L, Brown EJ, Cuddy TE, et al; The SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial. N Engl J Med 1992;327(10):669-77. 11. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995;273:1450-6. 12. Swedberg K, Pfeffer M, Granger C, Held P, McMurray J, Ohlin G, et al. Candesatan in heart failure: assessment of reduction in mortality and morbidity (CHARM): rationale and design. J Card Fail 1999;5:276-82. 13. Flather MD, Yusuf S, Kober L, Pfeffer M, Hall A, Murray G, et al; ACE-inhibitor Myocardial Infarction Collaborative Group. Long-term ACE-inhibitor therapy in patients with heart failure or left ventricular dysfunction: a systematic overview of data from individual patients. Lancet 2000;355:1575-81. 14. Maggioni AP, Anand I, Gottlieb SO, Latini R, Tognoni G, Cohn JN. Effects of valsartan on morbidity and mortality in heart failure patients not receiving ACE inhibitors. J Am Coll Cardiol 2002;40:1414-21. 15. Banerjee A, Talreja A, LeJemtel TH. Evolving rationale for angiotensin converting enzyme inhibitor therapy in chronic heart failure. Mt Sinai J Med 2003;70:225-31. 16. Pfeffer MA, Lamas GA, Vaughan DE, ParisiAF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988;319(2):80-6. 17. Konstam MA, Kronenberg MW, Rousseau MF, Udelson JE, Melin J, Stewart D, et al; The SOLVD Investigators. Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dilatation in patients with asymptomatic systolic dysfunction. Circulation 1993;88:2277-83. 18. Hunt SA, Abraham WT, Mancini DM, Chin MH, Michl K, Feldman AM, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the

CARDIOLOGY 2001 Guidelines for the Evaluation and Management of Heart Failure). Available from http://circ.ahajournals.org/ cgi/content/ full/112/12/e154. [Accessed 23 July 2013]. 19. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G; The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-convertingenzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-53. 20. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003;362:782-8. 21. Goyal RK, Prajapati DV, Jain AR, Mallya BS. Effect of CABG and ACE inhibitors on cardiac function in diabetic patients. J Mol and Cell Cardiol 2001;33:A52.

efficacy and acceptability in an Italian mutlicenter trial. Am J Med 1992;92(4):S79-S83. 32. Chu-Pak L, Hung-Fat T, William N, Kwok-Keung C, ShuKin L, Kin-Kwan K, et al. Comparison of perindopril versus captopril for treatment of acute myocardial infarction. Am J Cardiol 2002;89(2):150-4. 33. Pilote L, Abrahamowicz M, Eisenberg M, Humphries K, Behlouli H, Tu JV. Effect of different angiotensinconverting-enzyme inhibitors on mortality among elderly patients with congestive heart failure. CMAJ 2008;178(10):1303-11. 34. Hansen ML, Gislason GH, Køber L, Schramm TK, Folke F, Buch P, et al. Different angiotensin-converting enzyme inhibitors have similar clinical efficacy after myocardial infarction. Br J Clin Pharmacol 2008;65(2):217-23.

23. Zimmerman BG, Sybertz EJ, Wong PC. Interaction between sympathetic and rennin-angiotensin system. J Hypertens 1984;2:581-7.

35. Cheitlin MD, Armstrong WF, Aurigemma GP, Beller GA, Bierman FZ, Davis JL, et al. ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography), 2003.

24. Dzau VJ. Mechanism of action of angiotensin-converting enzyme (ACE) inhibitors in hypertension and heart failure: Role of plasma versus tissue ACE. Drugs 1990;39(2):11-6.

36. Magrini F, Shimizu M, Roberts N, Fouad FM, Tarazi RC, Zanchetti A. Converting enzyme inhibition and coronary blood flow. Circulation 1987;75(1):I168-74.

25. Greenberg B, Quinones MA, Koilpillai C, Limacher M, Shindler D, Benedict C, et al. Effects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction: Results of the SOLVD echocardiography substudy. Circulation 1995;91:2573-81.

37. Perondi R, Saino A, Tio RA, Pomidossi G, Gregorini L, Alessio P, et al. ACE inhibition attenuates sympathetic coronary vasoconstriciton in patients with coronary artery disease. Circulation 1992;85:2004-13.

22. Kossman CE; The Criteria Committee of the New York Heart Association. Diseases of the Heart and Blood Vessels: Nomenclature and Criteria for Diagnosis. 6th edition. Little Brown: Boston, Massachusetts; 1964:p.110-4.

26. Dzau VJ. Renal effects of angiotensin converting enzyme inhibition in cardiac failure. Am J Kidney Dis 1987;10: 74-80. 27. Dickstein K, Kjekshus J, The OPTIMAAL Steering Committee, for the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet 2002;360:752-60. 28. McMurray JJ, Solomon S, Pieper K, Reed S, Rouleau J, Velazquez E, et al. The effect of valsartan, captopril, or both on atherosclerotic events after acute myocardial infarction an analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT). J Am Coll Cardiol 2006;47(4): 726-33. 29. Foy SG, Crozier IG, Turner JG, Richards AM, Framptom CM, Nicholls MG, et al. Comparison of enalapril versus captopril on left ventricular function and survival three months after acute myocardial infarction (the ‘PRACTICAL’ study). Am J Cardiol 1994:73(16):1180-6.

38. Zhuo JL, Froomes P, Casley D, Liu JJ, Murone C, Chai SY, et al. Perindopril chronically inhibits angiotensin converting enzyme in both the endothelium and adventitia of the internal mammary artery in patients with ischemic heart disease. Circulation 1997;96:174-82. 39. Asmar RG, Pannier B, Santoni JP, Laurent S, London GM, Levy BI et al. Reversion of cardiac hypertrophy and reduced arterial compliance after converting enzyme inhibition in essential hypertension. Circulation 1988;78(4):941-50. 40. Chau NP, Simon A, Vilar J, Cabrera-Fischer E, PithoisMerli I, Levenson J. Active and passive effects of anthihypertensive drugs on large artery diameter and elasticity in human essential hypertension. J Cardiovasc Pharmacol 1992;19(1):78-85. 41. Shimamoto H, Shimamoto Y. Lisinopril improves aortic compliance and renal flow: comparison with nifedipine. Hypertension 1995;25(3):327-34.

30. De Graeff PA, Kingma JH, Viersma JH, Wesseling H, Lie KI. Acute and chronic effects of ramipril and captopril in congestive heart failure. Inter J Cardiol 1989;23(1):59-67.

42. Thybo NK, Stephens N, Cooper A, Aalkjaer C, Heagerty AM, Mulvany MJ. Effect of antihypertensive treatment on small arteries of patients with previously untreated essential hypertension. Hypertension 1995;25(4 Pt 1): 474-81.

31. Agabiti-Rosei E, Ambrosioni E, Finardi G, Folino P, Gambassi G, Malini P, et al. Perindopril versus captopril:

43. Sihm I, Schroeder AP, Aalkjaer C, Holm M, Morn B, Mulvany M, et al. Normalization of structural

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CARDIOLOGY cardiovascular changes during antihypertensive treatment with a regimen based on the ACE-inhibitor perindopril. Blood Press 1995;4(4):241-8. 44. Hussar DA. New Drugs of 1999. J Am Pharm Assoc 2000;40(2):181-221. 45. Kool MJ, Lustermans FA, Breed JG, Struyker Boudier HA, Hoeks AP, Reneman RS, et al. The influence of perindopril and the diuretic combination amiloride + hydrochlorothiazide on the vessel wall properties of large arteries in hypertensive patients. J Hypertens 1995;13(8):839-48. 46. Schwartzkopff B, Brehm M, Mundhenke M, Strauer BE. Repair of Coronary arterioles after treatment with perindopril in hypertensive heart disease. Hypertension 2000;36:220-5. 47. Ghiadoni L, Magagna A, Versari D, Kardasz I, Huang Y, Taddei S, et al. Different effect of antihypertensive drugs on conduit artery endothelial function. Hypertension 2003;41:1281-6. 48. Comini L, Bachetti T, Cargnoni A, Bastianon D, Gitti GL, Ceconi C, et al. Therapeutic modulation of the nitric oxide: all ace inhibitors are not equivalent. Pharmacol Res 2007;56(1):42-8. 49. Onodera H, Matsunaga T, Tamura Y, Maeda N, Takumi H, Sasaki S, et al. Enalapril suppresses ventricular remodeling more effectively than losartan in patients with acute myocardial infarction. Am Heart J 2005;150(4):689. 50. Masuelli M, Brusca G, Pardo A, Pineiro D, Checkerdhemian S, Forcads P. ACE inhibitors in heart failure-switching from enalapril to Coversyl. Curr Med Res Opin 2002;18:296-302. 51. Nearchou NS, Tsakiris AK, Lolaka MD, Zarcos I, Skoufas DP, Skoufas PD. Influence of perindopril on left ventricular global performance during the phase of inferior acute myocardial infarction: assessment by Tei index. Echocardiography 2003;20(4): 319-27.

52. Mizuno Y, Yasue H, Yoshimura M, Fuji H, Yamamoto N, Nakayama M, et al. Effect of perindopril on aldosterone production in the failing human heart. Am J Cardiol 2002; 89(10):1197-200. 53. Seneviratne B, Moore GA, West PD. Effect of captopril on functional mitral regurgitation in dilated heart failure: a randomised double blind placebo controlled trial. Br Heart J 1994;72(1):63-8. 54. Mancini DM, Davis L, Wexler JP, Chadwick B, LeJemtel TH. Dependence of enhanced maximal exercise performance on increased peak skeletal muscle perfusion during long-term captopril therapy in heart failure. J Am Coll Cardiol 1987;10:845-50. 55. Willenheimer R, Rydberg E, Öberg L, Juul-Möller S, Erhardt L. ACE inhibition with ramipril improves left ventricular function at rest and post exercise in patients with stable ischaemic heart disease and preserved left ventricular systolic function. Eur Heart J 1999;20(22):1647-56. 56. Banerjee A, Talreja A, LeJemtel TH. Evolving rationale for angiotensin converting enzyme inhibitor therapy in chronic heart failure. Mt Sinai J Med 2003;70:225-31. 57. Bahi L, Koulmann N, Sanchez H, Momken I, Veksler V, Bigard AX, et al. Does ACE inhibition enhance endurance performance and muscle energy metabolism in rats? J Appl Physiol 2004;96:59-64. 58. Lamas GA, Vaughan DE, Parisi AF, Pfeffer MA. Effects of left ventricular shape and captopril therapy on exercise capacity after anterior wall acute myocardial infarction. Am J Cardiol 1989;63(17):1167-73. 59. Hutcheon SD, Gillespie ND, Crombie IK, Struthers AD, McMurdo ME. Perindopril improves six minute walking distance in older patients with left ventricular systolic dysfunction: a randomized double blind placebo controlled trial. Heart 2002;88(4):373-77. 60. Barrios AV, Pena PZ, Campuzano RR, Lombera RF, Peralta Y. Utility of perindopril in mild-moderate heart failure in daily clinical practice. Rev Clin Esp 2003;203(1):3-9.

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Intra-arterial Treatment Benefitial in Acute Ischemic Stroke A randomized trial in (N Engl J Med 2015;372(1):11-20) reports that intra-arterial treatment plus usual care within 6 hours of stroke onset was safe and effective in patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion of the anterior circulation. This finding is in contrast to results of other recent randomized controlled trials that did not report a benefit of intra-arterial treatment.

Sapien 3 Transcatheter Valve Superior A third-generation transcatheter heart valve, Sapien 3 transcatheter valve, addresses issues with earlier valves and was associated with improved ease of use, accuracy of positioning and paravalvular sealing, according to a new report published in J Am Coll Cardiol 2014;64:2235-2243. The rates of mortality and stroke with transfemoral access are among the lowest reported and support further evaluation as an alternative to open surgery in intermediate-risk patients.

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COMMUNITY MEDICINE

Quality Parameters for Ideal Clinic PARAM HANS MISHRA

WHAT IS A CLINIC

IMA Prayer

A clinic (or outpatient clinic or ambulatory care clinic) is a healthcare facility that is primarily devoted to the care of outpatients. Clinics can be privately operated or publicly managed and funded, and typically cover the primary healthcare needs of populations in local communities, in contrast to larger hospitals which offer specialized treatments and admit. Clinics are often associated with a general medical practice, run by one or several general practitioners or clinics are usually operated by physiotherapists and psychology clinics by clinical psychologists and so on for each health profession. Some clinics are operated in-house by employers, government organizations or hospitals and some clinical services are outsourced to private corporations, inpatients for overnight stays.

Every clinic should display the IMA prayer mentioned below:

Objectives of a Clinic Providing primary healthcare; provide high-quality integrated health services in a timely manner so as to ensure complete customer satisfaction.

Location Location should be easy accessible so, that large number of patients can come. No person shall run a clinical establishment unless it has been duly registered in accordance with the provisions of Clinical Establishment Act. For registration every clinical establishment shall fulfill the conditions namely: The minimum standards of facilities and services as may be prescribed, the minimum requirement of personnel as may be prescribed, provisions for maintenance of records and reporting as may be prescribed.

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May everybody be happy

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May everyone of us see to it

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That nobody suffers from any pain or sorrow

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I do not ask for crown nor Ι wish to be in heaven or reborn

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I only want to alleviate the suffering of those people

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Who are burning in fire of sorrow.

Doctor’s Prayer Every clinic should display the Doctors prayer mentioned below: Dear Lord. Thou great physician, Ι kneel before thee. Since every good and perfect gift must come from thee: I pray. Give skill to my hand, clear vision to my mind, kindness and sympathy to my heart. Give me singleness of purpose, strength to lift at least a part of the burden of my suffering fellow men and a true realization of the rare privilege that is mine. Take from my heart all guile and wordliness. That with the simple faith of a child Ι may rely on thee.

Size of Boards Size of the boards should be appropriate; they should not be very large.

No. of Boards Medical Superintendent Indian Spinal Injuries Centre Vasant Kunj, New Delhi Address for correspondence Dr Param Hans Mishra Medical Superintendent Indian Spinal Injuries Centre C-Block, Vasant Kunj, New Delhi -110 070 E-mail: drphmishra@rediffmail.com, drphmishra08@gmail.com, ms@isiconline.org

Maximum 2 boards (1 at residence, 1 at clinic).

Location of Boards Location of boards should be such that they are easily visible. It is improper for a physician to use an unusually large sign board and write on it anything other than his name, qualifications obtained from a

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COMMUNITY MEDICINE University or a statutory body, titles and name of his speciality, registration number including the name of the State Medical Council under which registered. The same should be the contents of his prescription papers. It is improper to affix a sign-board on a chemist’s shop or in places where he does not reside or work.

Display of Registration Numbers ÂÂ

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.

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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.

Instruments and Equipment to be Kept in Clinic

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Fees to be Charged No maximum limit, but it should be reasonable as per qualification and experience and affordable to majority of patient in nearby area. ÂÂ

A physician shall clearly display his fees and other charges on the board of his chamber and/or the hospitals he is visiting. Prescription should also make clear if the physician himself dispensed any medicine.

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A physician shall write his name and designation in full along with registration particulars in his prescription letter head.

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The name of the prescribing doctor must be written below his/her signature.

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The physician, engaged in the practice of medicine shall give priority to the interests of patients. The personal/financial interests of a physician should not conflict with the medical interests of patients. A physician should announce his fees before rendering service and not after the operation or treatment is under way. Remuneration received for such services should be in the form and amount specifically announced to the patient at the time the service is rendered. It is unethical to enter into a contract of ‘no cure no payment’. Physician rendering service on behalf of the state shall refrain from anticipating or accepting any consideration.

Stethoscope, BP apparatus, weighing machine, IV stand, height measuring tape tuning folk, hammer, system (Optional) for maintaining data.

Washbasin A clinic should have a washbasin.

Toilet Toilet is compulsory in a clinic.

Documentation ÂÂ

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736

Maintenance of medical records: Every physician shall maintain the medical records pertaining to his/her outdoor patients for a period of 3 years from the date of commencement of the treatment in a standard performa laid down by the Medical Council of India. If any request is made for medical records either by the patients/authorized attendant or legal authorities involved, the same may be duly acknowledged and documents shall be issued within the period of 72 hours. 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.

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Efforts shall be made to computerize medical records for quick retrieval.

Number of Patients that General Physician can See At least 5 minutes should be given to a patient, maximum 100 patients may be seen per day.

Obligations to the Sick ÂÂ

Though a physician is not bound to treat each and every person asking his services, he should not only be ever ready to respond to the calls of the sick and the injured, but should be mindful of the high character of his mission and the responsibility he discharges in the course of his professional duties. In his treatment, he should never forget that the health and the lives of those entrusted to his care depend on his skill and attention. A physician should endeavor to add to the comfort of the sick by making his visits at the hour indicated to the patients. A physician advising a patient to seek service of another physician is acceptable; however,

COMMUNITY MEDICINE in case of emergency a physician must treat the patient. No physician shall arbitrarily refuse treatment to a patient. However for good reason, when a patient is suffering from an ailment which is not within the range of experience of the treating physician, the physician may refuse treatment and refer the patient to another physician. ÂÂ

Medical practitioner having any incapacity detrimental to the patient or which can affect his performance vis-à-vis the patient is not permitted to practice his profession.

Qualification of Doctors ÂÂ Physician (Doctors with qualification of MBBS or MBBS with post graduate degree/diploma or with equivalent qualification in any medical discipline). ÂÂ A physician shall uphold the dignity and honor of his profession. ÂÂ The prime object of the medical profession is to render service to humanity; reward or financial gain is a subordinate consideration. Who-so-ever chooses his profession, assumes the obligation to conduct himself in accordance with its ideals. A physician should be an upright man, instructed in the art of healings. He shall keep himself pure in character and be diligent in caring for the sick; he should be modest, sober, patient, prompt in discharging his duty without anxiety; conducting himself with propriety in his profession and in all the actions of his life. ÂÂ No person other than a doctor having qualification recognized by Medical Council of India and registered with Medical Council of India/State Medical Council (s) is allowed to practice Modern system of Medicine or Surgery. A person obtaining qualification in any other system of medicine is not allowed to practice modern system of medicine in any form.

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Conduct in consultation: In consultations, no insincerity, rivalry or envy should be indulged in. All due respect should be observed towards the physician incharge of the case and no statement or remark be made, which would impair the confidence reposed in him. For this purpose, no discussion should be carried on in the presence of the patient or his representatives.

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Consultant not to take charge of the case: When a physician has been called for consultation, the consultant should normally not take charge of the case, especially on the solicitation of the patient or friends. The consultant shall not criticize the referring physician. He/she shall discuss the diagnosis treatment plan with the referring physician.

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Appointment of substitute: Whenever a physician requests another physician to attend his patients during his temporary absence from his practice, professional courtesy requires the acceptance of such appointment only when he has the capacity to discharge the additional responsibility along with his/her other duties. The physician acting under such an appointment should give the utmost consideration to the interests and reputation of the absent physician and all such patients should be restored to the care of the latter upon his/her return.

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Visiting another Physician’s Case: When it becomes the duty of a physician occupying an official position to see and report upon an illness or injury, he should communicate to the physician in attendance so as to give him an option of being present. The medical officer/physician occupying an official position should avoid remarks upon the diagnosis or the treatment that has been adopted.

Home Visits

What is Commission?

Proper protocol for home visits should be made. As charges for routine visit, charges for emergency visits, conveyance charges to the doctors, etc.

Referral of any patient to any other diagnostic clinic, centre hospital or any other practitioner with intention of getting any financial benefit is known as commission.

Precautions to be Taken Care, While Examining Female Patients

What is Not Commission?

It should be taken care that while examining a female patient a female attendant should be there.

Any cash or kind payment or gift in lieu of services offered for genuine ailment is not a commission.

Medications to be Dispensed or Not

Responsibilities of Physicians to Each Other A physician should consider it as a pleasure and privilege to render gratuitous service to all physicians and their immediate family dependants.

Any qualified registered practitioner registered with state Medical Council can dispense any medicine which is approved by Drug Controller of India. However, any crosspatch that is dispensing of homeopathy, ayurvedic, unani and jadi-buti is not allowed.

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COMMUNITY MEDICINE Hypothetical Oath I, -------------, do hereby swear on this solemn day that:

I shall not even by mistake say that “HIV=AIDS=death” or cancers cannot be treated.

I shall NOT prescribe unnecessary medicines and tests to my patients

I shall not frighten my patients with unnecessary comments, opinions or advice.

I shall NOT give false counseling

I still remember what Hippocrates said, namely, “Let diet be your medicine” and shall accordingly prescribe fresh fruits, vegetables and good diet to my patients, rather than tonics, syrups, synthetic multi-vitamins, specially to children.

I shall NOT overcharge and accept cuts and gifts I shall NOT prescribe lethal drugs, like antiretrovirals, chemotherapy or give electroconvulsive therapy (ECT) to my patients I shall NOT be afraid of any authority and fabricate medical records or give false evidence I shall NOT exploit students studying under me I shall NOT manipulate findings or results to win grants. I, -------------, further solemnly affirm that: If I cannot treat a disease, I shall not say that AIDS, cancers, diabetes has no cure, but will tell the patient to try other systems of medicine. I shall treat health practitioners of other systems with respect and not tell deliberate lies to prove my importance. I shall study holistic healing modalities to increase my knowledge and wisdom.

I shall NOT perform surgery, unless it is absolutely must and will not indulge in rackets like amniocentesis, cesarean section, silicon implant or liposuction. I shall work to ban the useless and cruel animal experiments in the name of medicine. I shall participate in periodic workshops, seminars and conferences at my expense or on scholarship (no pharma funding) to educate myself and speak from my conscience if I am called upon to speak or preside. Finally, I realize and aver that a great responsibility of people’s well-being is upon my shoulders and I shall carry on my onerous task with utmost dedication. This I swear in the name of God and I shall repeat this oath daily lest I forget that I am in a divine profession to heal the world.

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Avoid Food Poisoning by Thorough Washing and Proper Cooking Thorough washing and proper cooking of fruits and vegetables can eliminate most bacteria that cause food poisoning, food-borne illnesses or food poisoning usually occurs as a result of eating food tainted with bacteria or their toxins. Virus and parasites also can cause food poisoning. People have long known that raw meat, poultry and eggs can also harbor diseases causing microbes. But, in recent years most outbreaks of food-borne illnesses are due to fresh fruits and vegetables. Food poisoning can cause abdominal pain, nausea, headache, fatigue, vomiting, diarrhea and dehydration. Symptoms may appear several hours to several days after eating tainted food. For example, Salmonella bacteria will cause illness 12 hours to 3 days after ingestion lasting about 4-7 days. The most common way to treat food poisoning is to drink plenty of fluids. The sickness usually subsides within a few days.

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DENTISTRY

Nanotechnology and Nanoparticles: Small is Large JACOB KURIEN*, JAYASEKHARAN VP†, E ANURADHA SUNIL‡, EAPEN CHERIAN#

ABSTRACT Modern day dentistry involves evidence-based practice in clinical establishments and also in research activities. Latest innovative techniques have revolutionized the field of dentistry and implementation of various modalities promise to broaden the horizons of both patient and healthcare management systems. The results obtained with latest technologies so far have been exhilarating and provide a boon to mankind. Nanotechnology is a rapid evolving area of research in the field of agriculture, chemistry and medicine. Today, nanoparticles have been used to good effect in the field of dentistry and commendable results have been obtained. The use of nanoparticles has reached the level of diagnosis and management of certain conditions. This field has much more to offer as far as the future of the speciality is concerned. This review provides information on various intricate features of nanotechnology, nanoparticles and their implications and applications in dentistry.

Keywords: Nanotechnology, nanoparticles, nanorobotics, gene therapy, nanodiagnostics

he term ‘nanotechnology’ was coined by Prof. Kerie E. Drexler. It is derived from the Greek word for ‘dwarf’. It is the science of manipulating matter measured in the nanometer, roughly the size of 2 or 3 atoms. The basic idea of nanotechnology is to employ individual atoms and molecules to construct functional structures.1 Nanotechnology has a great consideration and potential which consists also of public awareness, ethics and the impact of this novel technique must be addressed before any actual molecular manipulative techniques is adopted for research activities. Nanodiagnostics is the application of the intricate details of these techniques for early diagnosis or predisposition at the molecular stage of the disease. In in vitro detection, nanomedicine could increase the

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

efficacy and reliability of the diagnostics using human fluids or tissues samples by using selective nanodevices. In general, nanotechnology is a research field of great biotechnologic potential comprising of engineering, medicine and biology for early detection, diagnosis and intervention of diseases and in specific scenarios, for the personalized treatment of cancer. Thus, this unique technology has a tremendous future in the field of dentistry and is on the right path for revolutionizing various methodologies adopted in the field.2 Nanoparticles are typically smaller than several hundred nanometers in size, comparable to large biological molecules such as enzymes, receptors and antibodies. With a size of about 100-10,000 times smaller than human cells, these nanoparticles can offer outstanding and unique interactions with biomolecules both on the surface of and inside the cells,2 which may revolutionize cancer diagnosis and treatment. The various aspects of nanotechnology and nanoparticles are briefly reviewed in this article. The many nanoparticles used are: ÂÂ

Nanopores

ÂÂ

Nanotubes

ÂÂ

Quantum dots

ÂÂ

Nanoshells

ÂÂ

Nanorods

ÂÂ

Fullerenes

ÂÂ

Nanospheres

ÂÂ

Nanowires

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DENTISTRY ÂÂ

Nanobelts

ÂÂ

Nanorings.3

Nanorods are useful in a restorative context. Enamelprism-like hydroxyapatite nanorods were synthesized that have exhibited self-assembly properties. Since, they are similar to the enamel rods that make up the basic crystalline structure of dental enamel, nanorods could contribute to a practical artificial approximation of such a naturally-occurring structure.4 Nanotubes of various types have been investigated for dental applications in a number of interesting directions. Titanium oxide nanotubes have been shown in vitro to accelerate the kinetics of bone-growth applications for dental implant coatings. Nanofibers and their uses for biomedical applications are established. Nanofibers have been used to generate ceramics. Nanofibrillar silicate crystals have also been recently studied in the capacity of reinforcement of dental composites. Added in the correct proportions and with uniform distribution of the fibers/crystals, nanofibers were demonstrated to improve the physical properties of these composites. Composite has been incorporated in nonagglomerated discrete nanoparticles that are homogeneously distributed in resins or coatings to produce nanocomposites. The nanofiller used includes an aluminosilicate powder having a mean particle size of 80 ran and a 1:4 M ratio of alumina to silica and a refractive index of 1.508.4 NANO IN ORAL ANESTHESIA In modern times, nanodentistry provides a suspension containing millions of active analgesics, which will be instilled on the patient’s gingiva. After contacting the surface of crown or mucosa, programmed nanodevices can actually reach the pulp via the gingival sulcus, lamina propria and dentinal tubules. Once installed in the pulp, the analgesic specialized devices and dental robots are commanded by the dentist to shut down all sensitivity in any particular tooth that requires treatment.5 After oral procedures are completed, the dentist orders the nanorobots to restore all sensation, to relinquish control of nerve traffic and further procedures if any are carried out to the final outcome. IMPRESSION COMPOUNDS Nanofillers are integrated in vinylpolysiloxanes, producing a unique addition of siloxane impression materials. The material has better flow, improved hydrophilic properties and enhanced detail precision.6

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NANOTECHNOLOGY ADVANCEMENTS IN TOOTH REPAIR Nanodental advancements for major tooth repair may evolve through several stages of technical details, first using genetic engineering, tissue engineering and regeneration and later involving the growth of whole new teeth in vitro and their installation. Ultimately, the manufacture of nanorobots and installation of a biologically autologous whole replacement that includes both mineral and cellular components,7 that is, complete dentition replacement therapy should become feasible within the time and economic constrains of a typical office visit, through the use of an affordable desktop manufacturing facility, which would fabricate the new tooth in the dentist’s office. HYPERSENSITIVITY OF DENTINAL TUBULES Naturally hypersensitive teeth have eight times higher surface density of dentinal tubules and diameter with twice as large than nonsensitive teeth. Reconstructive dental nanorobots, using native biological materials, could selectively and precisely occlude specific tubules within minutes, offering patients a quick and permanent cure.8 ORTHODONTIC MANAGEMENT Orthodontic nanorobots could directly manipulate the periodontal tissues, allowing rapid and painless tooth straightening, rotating and vertical repositioning within minutes to hours. Complete realignment has been possible with various methods and these approaches had the support of nanotechnology and nanoparticles in successful treatment of the given condition. Thus, this novel methodology also has a great influence on specialized areas like orthodontic correction. DURABILITY AND ESTHETICS Tooth durability and appearance may be improved by replacing upper enamel layers with covalently bonded artificial materials such as sapphire or diamond, which have 20-100 times the hardness and failure strength of natural enamel, or contemporary ceramic veneers as well as good biocompatibility. Pure sapphire and diamond are brittle and resist fracture as part of a nanostructure composite material that possibly includes embedded carbon nanotubes.9 NANODIAGNOSTICS In in vitro diagnostics, nanomedicine could increase the efficiency and reliability of the diagnostics using human

DENTISTRY fluids or tissue samples by using selective nanodevices, to make multiple analyses at subcellular scale.10 In in vivo diagnostics, nanomedicine could develop devices able to work inside the human body in order to identify the early presence of a disease, to identify and quantify toxic molecules, tumor cells etc. DIAGNOSTIC SALIVARY BIOMARKER Saliva is an inexpensive, noninvasive and easy-touse diagnostic medium containing proteomic and genomic markers for molecular disease identification. Exosomes are secreted by salivary gland epithelium and released into the salivary fluid via exocytosis.11 Malignancy and other diseases cause elevated exosome secretion and tumor antigen enrichment of exosomes associated with cancer cells. Various detection tools are also established in the proper diagnostic methods and treatment modalities concerned with each specialized zone of interest. ROLE OF GOLD NANOPARTICLES IN CANCER MANAGEMENT Worldwide oral cancer is the sixth most common cancer. Often, oral cancer is preceded by the presence of clinically identifiable premalignant changes and oral physicians can play a crucial role by identifying these changes for reducing the incidence and mortaility of cancer. Nanoparticles for oral cancer diagnosis are more accurate and less invasive to the body. Many cancer cells have a protein, epidermal growth factor receptor (EGFR), distributed on the outside of their membranes, noncancer cells have much less of this protein.12 By attaching gold nanoparticles to an antibody for EGFR, researchers have been able to bind the nanoparticles to the cancer cells. Once bound, the cancer cells manifest different light scattering and absorption spectra than benign cells. Gold and nanotechnology based treatment potentially provide localized targeted therapies with an aim to enhance efficacy, reduce side-effects and improve patientâ&#x20AC;&#x2122;s quality-of-life. Gold nanoparticles-based cancer therapy uses photothermal therapy for the destruction of cancer cells or tumor tissue. When irradiated with focused laser pulses of suitable wavelength, targeted gold nanospheres, nanorods, nanoshells can kill bacteria. Thus, the horizon of magnificient opportunities has steadily increased over a period of time and the advent of these techniques proves to be a boon to the future of dental research in dentistry.

ADVENT OF NANOROBOTICS A programed or assisted nanorobot, could actually help in surgeries, on site when introduced into the body through vascular system or cavities. Axotomy of roundworm neurons was performed by laser surgery after which the axons are functionally regenerated. Femtolaser acts like a pair of nano-scissors by vaporizing tissue locally, while leaving adjacent tissue unharmed.5 Thus, use of nanotechnology helps the surgeon in invasive medical procedures in determining the correct localization of lesions and does not cause any injury to normal structures, which greatly reduces patient discomfort and agony.13 As far medical procedures or treatment is concerned, the chance of aggressive therapy is drastically reduced and a more conservative approach (using nanotechnology) improves patient healthcare management by a long margin. ADVANTAGES Numerous advantages have credited the purpose of increased utilization of nanotechnology and nanoproducts in recent years. The simplicity of the technique used and the fabrication of materials in a more convenient form is an important aspect. All the procedures are less invasive and less aggressive. Numerous research experiments and proposals have benefitted greatly from advancements in local drug delivery, therapeutic approach and specific treatment for preidentified targets. The nontoxic nature of the components also serves as a key factor in expanding the scope of this ever expanding technique. DISADVANTAGES The inability of the nanoparticles and components to reach certain specific targets is an area of concern. The inefficiency in use of some compounds have also been noted in recent years. Biocompatibility, in vivo kinetics also produces voids in research scenarios. Chronic toxicity presents itself as a hindrance in long-term procedures. Optical signals of gold nanoparticles may not be as strong as that of quantum dots. CONCLUSION Various innovative techniques have been embraced in the fields of medicine and dentistry at large over the past several years. Some of the advancements have truly and steadily broadened the base of research field in dentistry. This has lead to vast developments in clinical situations, diagnosis and treatment planning.

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DENTISTRY As a net result, the improvement in patient care over the last two decades has increased dramatically. Nanotechnology and nanoparticles are such a unique and one-of-a kind approach in dentistry and the results of their use have been promising. Vast concrete results of their implementation in various aspects has provided the fraternity with a strong base to further expand the horizon as far as treatment planning, diagnosis and management of specific cases are concerned. Combination of traditional techniques in addition with this advancement seems to be the way forward in every area of dentistry. REFERENCES 1. Rybachunk AV, Chelkman IS. Nanotechnology and nanoparticles in dentistry. Pharmacol Pharm 2009;1: 18-21. 2. Reddy PS, Ramaswamy P, et al. Role of gold nanoparticles in early detection of oral cancer. J Indian Acad Oral Med Radiol 2010; 22(1):30-3. 3. Kovvuru SK, Mahita VN. Nanotechnology: The emerging science in dentistry. J Orofac Res 2012;2(1):33-6. 4. Saunders SA. Current practicality of nanotechnology in dentistry. Part 1: Focus on nanocomposite restoratives and biomimetics. Clin Cosmet Investig Dent 2009;1: 47-61. 5. Mujoo S, Khan F, et al. Nanotechnology: A new era in dentistry. Indian J Dent Res Rev 2012;1:16-8.

6. Rao KVP, Kumar JS. Nanotechnology in dentistry. Kerala Dental J 2013;36(1):56-9. 7. Chandra Mouli PE , Manoj Kumar S, Prathiban S. Nanotechnology in dentistry - A review. Int J Biol Med Res 2012;3(2):1550-3. 8. Saravana KR, Vijayalakshmi R. Nanotechnology in dentistry. Indian J Dent Res 2006;17(2):62-5. 9. Chandki R, Kala M, Kumar KN, Brigit B, Banthia P, Banthia R. ‘Nanodentistry’: Exploring the beauty of miniature. J Clin Exp Dent 2012;4(2):e119-24. 10. Praetorius NP, Mandal TK. Engineered nanoparticles in cancer therapy. Recent Pat Drug Deliv Formul 2007;1(1):37-51. 11. Nagesha D, Laevsky GS, Lampton P, Banyal R, Warner C, DiMarzio C, et al. In vitro imaging of embryonic stem cells using multiphoton luminescence of gold nanoparticles. Int J Nanomedicine 2007;2(4):813-9. 12. Cai W, Gao T, Hong H, Sun J. Applications of gold nanoparticles in cancer nanotechnology. Nanotechnol Sci Appl 2008;2008(1). 13. Mitra SB, Wu D, Holmes BN. An application of nanotechnology in advanced dental materials. J Am Dent Assoc 2003;134(10):1382-90. 14. Parak WJ, Gerion D, et al. Biological applications of colloidal nanocrystals. Nanotechnology 2003;14:R15-R27. 15. Sokolov K, Follen M, Aaron J, Pavlova I, Malpica A, Lotan R, et al. Real-time vital optical imaging of precancer using anti-epidermal growth factor receptor antibodies conjugated to gold nanoparticles. Cancer Res 2003;63(9):1999-2004.

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Dental Implants Safe in Patients with Uncontrolled Diabetes Dentists can safely place dental implants in patients with uncontrolled diabetes, a new study shows. The finding contradicts common recommendations. "We failed to identify any association between elevated blood sugar and implant failure or implant complications," first author Thomas W. Oates Jr, DMD, PhD, told Medscape Medical News. Along with his colleagues, Dr Oates, a professor in the Department of Periodontics, School of Dentistry, University of Texas Health Science Center at San Antonio, published the article in the December issue of the Journal of the American Dental Association. After 1 year, none of the implants placed in 19 patients with uncontrolled diabetes failed.

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ENT

Comparing the Incidence of Hearing Impairment in Normal to High-risk Newborns MV SUBBA RAO*, BJ PRASAD†, MAHESHWAR REDDY‡

ABSTRACT Objectives: 1) Screening by otoacoustic emission (OAE), to study the incidence of hearing impairment in newborns; 2) to compare the incidence of hearing impairment in normal to high-risk newborns and 3) to study if the risk of hearing impairment increases as the number of risk factors increase. Material and methods: This was a prospective nonrandomized observational cohort study from November 2011 to December 2013. All newborns born in the hospital were included. Detailed history (pre- and postnatal) of each newborn pertaining to risk factors for hearing loss was taken and a detailed examination was done. Relevant serological tests were done. Newborns were screened for hearing impairment by OAEs and the result of the test was noted as PASS/REFER (FAIL). Results: Overall incidence of hearing impairment in newborns: 1.8%, incidence of hearing impairment in normal newborns: 0.7% and hearing impairment in high-risk newborns: 6.3%. Incidence of hearing impairment was significantly higher in high-risk newborns compared to normal newborns (p < 0.01). Conclusion: Though, the incidence of hearing impairment is significantly higher in high-risk newborns, targeted screening of high-risk newborns will result in missing a significant number of normal newborns with hearing impairment. Hence, there is a necessity for universal newborn hearing screening program.

Keywords: Hearing impairment, otoacoustic emissions, high-risk newborns

his study was done for identification and remediation of hearing loss in newborn infants who are hard of hearing before the age of 6 months to help them perform significantly higher on vocabulary, communication, intelligence, social skills and behavior.

Nine hundred fifteen were term and 137 were preterm. Eight hundred forty-six were normal neonates and 204 were found to be with high-risk factors, they were studied and compared (Table 1).

MATERIAL AND METHODS

A total of 19 neonates failed the otoacoustic emission (OAE) test among the 1,050 enrolled neonates (Table 2). Of the 19 neonates who failed the OAE test; six were from them normal newborn group and 13 from the high-risk newborn group.

This study was done in the postnatal ward of neonatal intensive care unit (NICU) of MediCiti Institute of Medical Sciences, Hyderabad. An informed consent was obtained from the parents or guardians of the infants. A total of 1,050 neonates were enrolled into the study. Five hundred sixty-two were male and 488 females.

RESULTS AND ANALYSIS

The overall incidence of hearing impairment among the enrolled neonates in this study was 1.8%. The incidence Table 1. Distribution of Newborns by Risk Factor for Hearing Impairment Risk factor for hearing impairment

*Professor and Head †Assistant Professor ‡Postgraduate Student Dept. of ENT MediCiti Institute of Medical Sciences, Ghanpur, Ranga Reddy District, Hyderabad Address for correspondence Dr MV Subba Rao Dept. of ENT MediCiti Institute of Medical Sciences Ghanpur, Ranga Reddy District, Hyderabad - 501 401 E-mail: matlapudi@yahoo.com

Total no. (N)

Absent

846

Present

204

Table 2. Result of Otoacoustic Emission Test Total no. of newborns screened 1,050

No. of newborns with ‘pass’ result

No. of newborns with ‘refer’ result

1,031

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ENT of hearing impairment in normal newborn group was 0.7% and the incidence of hearing impairment in highrisk newborn group was 6.3%. This study showed a significantly higher incidence of hearing impairment in the high-risk newborn group as compared to the normal newborn group with a p value of <0.01. The overall incidence of hearing impairment in various studies ranges from 0.56% to 8.2% and this comes within the range of the present study of 1.8%. Of the 69 neonates with a birth weight of <1.5 kg enrolled, a total of eight neonates failed the OAE test. With a p value of <0.01 for difference in incidence of hearing impairment between the normal and very low-birth-weight neonate groups, birth weight of <1.5 kg stands as a significant risk factor for hearing loss in this study. With no neonate in the group with history of intrauterine infection failing the test, there was no statistical significance for this risk factor as an independent risk factor for the hearing impaired. Statistical significance could not be established for family history of childhood sensorineural hearing loss as an independent risk indicator for hearing impairment in newborns. Eighty-one among the studied newborns had a history of use of ototoxic medications during hospital stay. Six had impaired hearing. The calculated difference in incidence of hearing impairment between this group and the normal newborn group had a p value of <0.01 making use of ototoxic drugs a significant risk factor. Apgar was significantly associated with hearing impairment. Five of 59 neonates failed the test with p value of <0.01. Four out of 24 newborns with a history of meningitis failed OAE with p value of <0.01. With a Table 3. Individual Risk Factor Distribution in High-risk Neonates Risk factor

No. of cases

Body weight <1.5 kg

Intrauterine infection

Family history of childhood hearing loss

Use of ototoxic medications

Apgar 0-4 (1 min), 0-6 (5 mins)

Meningitis

Mechanical ventilation ≥5 days

Neonatal hyperbilirubinemia at a level requiring exchange transfusion

Craniofacial abnormalities

Syndromic stigmata

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p value for difference in hearing impairment between normal and this group of neonates <0.01, mechanical ventilation of ≥5 days significantly increases the risk of hearing impairment. Neonatal hyperbilirubinemia at a level requiring exchange transfusion is significantly associated with risk of hearing impairment. Three out of 15 failed this test p value of <0.01, Statistical significance could not be established for craniofacial abnormalities and syndromic stigmata as risk factors for hearing impairment (Table 3). Prematurity (gestational age ≤37 weeks) was also associated with a risk of hearing impairment (p < 0.01). DISCUSSION Rughani et al (2010) studied a total of 100 neonates with risk factors for hearing impairment, body weight <1.5 kg, gestational age ≤34 weeks, birth asphyxia, hyperbilirubinemia requiring exchange transfusion, septicemia, mechanical ventilation, NICU stay ≥2 days, ototoxic drugs adminstration. Khairi et al (2001) from Malaysia suggested craniofacial malformations, very low-birth-weight, ototoxic medications, stigmata/syndromes associated with hearing loss and hyperbilirubinemia at a level of exchange transfusion were independent significant risk factors for hearing impairment, while poor Apgar scores and mechanical ventilation of >5 days were not. Hess et al (1998) from Germany suggested dysmorphism, prenatal rubella or cytomegalovirus (CMV) infection, family history of hearing loss, severe pre- and postnatal complications to be probable causes for hearing loss. Weichbold et al (2006) from Austria suggested that family history of hearing loss, meningitis, craniofacial malformations, persistent pulmonary hypertension, congenital CMV infection, extracorporeal membrane oxygenation, ototoxic therapy, gestational age <33 weeks increased the risk of hearing impairment. In this study, birth weight <1.5 kg, history of use of ototoxic medications, Apgar 0-4 (1 min) 0-6 (5 mins), meningitis, mechanical ventilation, neonatal hyperbilirubinemia at a level requiring exchange transfusion significantly increased the risk of hearing impairment. Risk of hearing impairment was higher in multiple risk factor group compared with single risk factor group. With single factor - 2.56%, 2 risk factors - 16% with 3 risk factors - 14.2%, 4 risk factors - 33.3%, 5 risk factors - 100%.

ENT Acknowledgment We thank the Principal, Superintendent, Management and the Dept. of Pediatrics, MediCiti Institute of Medical Sciences for help and support in conducting this study.

SUGGESTED READING 1. Yoshinaga-Itano C, Apuzzo ML. The development of deaf and hard of hearing children identified early through the high-risk registry. Am Ann Deaf 1998;143(5):416-24. 2. Ruben RJ. Effectiveness and efficacy of early detection of hearing impairment in children. Acta Otolaryngol Suppl 1991;482:127-31; discussion 132-5. 3. Erenberg A, Lemons J, Sia C, Trunkel D, Ziring P. Newborn and infant hearing loss: detection and intervention. American Academy of Pediatrics. Task Force on Newborn and Infant Hearing, 1998-1999. Pediatrics 1999;103(2):527-30. 4. Kliegman RM, Stanton BMD, St. Geme J, Schor N, Berham RE. Nelson Textbook of Pediatrics. 19th edition, Elsevier;2011:p.2189. 5. Early identification of hearing impairment in infants and young children. NIH Consensus Statement 1993;11(1):1-24. 6. Joint Committee on Infant Hearing 1994 Position Statement. American Academy of Pediatrics Joint Committee on Infant Hearing. Pediatrics 1995;95(1):152-6. 7. Yoshikawa S, Ikeda K, Kudo T, Kobayashi T. The effects of hypoxia, premature birth, infection, ototoxic drugs, circulatory system and congenital disease on neonatal hearing loss. Auris Nasus Larynx 2004;31(4):361-8. 8. Robinshaw HM. Early intervention for hearing impairment: differences in the timing of communicative and linguistic development. Br J Audiol 1995;29(6):315-34.

9. Norton SJ, Gorga MP, Widen JE, Folsom RC, Sininger Y, Cone-Wesson B, et al. Identification of neonatal hearing impairment: a multicenter investigation. Ear Hear 2000;21(5):348-56. 10. Lin HC, Shu MT, Lee KS, Lin HY, Lin G. Reducing false positives in newborn hearing screening program: how and why. Otol Neurotol 2007;28(6):788-92. 11. Clarke P, Iqbal M, Mitchell S. A comparison of transientevoked otoacoustic emissions and automated auditory brainstem responses for pre-discharge neonatal hearing screening. Int J Audiol 2003;42(8):443-7. 12. Nagapoornima P, Ramesh A; Srilakshmi, Rao S, Patricia PL, Gore M, Dominic M; Swarnarekha. Universal hearing screening. Indian J Pediatr 2007;74(6):545-9. 13. Rughani S, Vyas B, Sinha V, Shah M, Kapileshwar Y, Shah S. Hearing screening in newborns: a cross sectional study. World Articles in Ear, Nose and Throat. 2011; Vol. 4-1. 14. Jewel J, Varghese PV, Singh T, Varghese A. Newborn hearing screening – experience at a tertiary hospital in northwest India. Intern J Otolaryngol Head Neck Surg 2013;2:211-4. 15. Khairi MD, Din S, Shahid H, Normastura AR. Hearing screening of infants in Neonatal Unit, Hospital Universiti Sains Malaysia using transient evoked otoacoustic emissions. J Laryngol Otol 2005;119(9):678-83. 16. Hess M, Finckh-Krämer U, Bartsch M, Kewitz G, Versmold H, Gross M. Hearing screening in at-risk neonate cohort. Int J Pediatr Otorhinolaryngol 1998;46(1-2):81-9. 17. Weichbold V, Nekahm-Heis D, Welzl-Mueller K. Universal newborn hearing screening and postnatal hearing loss. Pediatrics 2006;117(4):e631-6.

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ÂÂ

A fundoplication technique using endoscopic submucosal dissection shows some promise in patients with refractory gastroesophageal reflux disease (GERD), according to a new study in the Scandinavian Journal of Gastroenterology. The endoscopic submucosal dissection narrows the hiatal opening. The resultant scarring narrows the lumen of the hiatal opening, suppressing gastric reflux.

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Patients with early-stage breast cancer treated with preventive or adjuvant chemotherapy have a cumulative risk of developing leukemia at 10 years of 0.5%, almost twice the rate reported in previous studies, as reported in a study in the Journal of Clinical Oncology.

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The US FDA has expanded the indication for tbo-filgrastim (Granix, Teva), now allowing it to be selfadministered by patients and their caregivers. Tbo-filgrastim, a granulocyte colony-stimulating factor (G-CSF) analog used to stimulate the proliferation and differentiation of granulocytes, was approved by the FDA in 2012 and has been commercially available in the United States since November 2013.

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Transfusion-related acute lung injury (TRALI) is more common than previously thought, and transfusionassociated circulatory overload (TACO) still presents a considerable mortality risk, according to two separate studies online now in Anesthesiology.

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The US FDA has approved a supplemental new drug application allowing use of ivacaftor (Kalydeco, Vertex Pharmaceuticals) in patients aged 6 years and older with cystic fibrosis (CF) who have the R117H mutation in the CF transmembrane conductance regulator (CFTR) gene.

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HEMATOLOGY

Rifampicin- and Pyrazinamide-induced Thrombocytopenia: A Rare Presentation PRAVEEN B GAUTAM*, SURESH KUMARâ&#x20AC;

ABSTRACT Drug-induced thrombocytopenia is an uncommon but serious side-effect of many drugs including antitubercular drugs. It is a difficult to diagnose but easy to prevent complication, which can be achieved by just stopping to the same drug. In some cases, it can prove fatal if not taken care of urgently. We report a case of rifampicin- and pyrazinamide-induced thrombocytopenia in a patient receiving antitubercular drugs.

Keywords: Thrombocytopenia, side-effect, rifampicin, pyrazinamide, antitubercular drugs

ost of the antitubercular drugs have sideeffects, but serious reactions to these drugs are not common. Thrombocytopenia is an uncommon but potentially life-threatening complication of certain antitubercular drugs and is characterized by rapid destruction of platelets, whenever an offending drug is taken by the susceptible person. The discovery of isolated thrombocytopenia in a patient taking several medications presents a challenging clinical problem.1 We present an even rare adverse effect, a case of thrombocytopenia with purpura, petechiae on forearm and trunk, followed by gum bleeding and melena caused by both rifampicin and pyrazinamide, which on Naranjo adverse drug reaction probability scale2 is definitely associated with these drugs. CASE REPORT A 22-year-old male, nonsmoker, nonalcoholic admitted to Rajan Babu Institute of Pulmonary Medicine and Tuberculosis (RBIPMT), Delhi on 01/04/14 with chief complaints of right submandibular lymph node since

*Senior Resident Dept. of Respiratory Medicine â&#x20AC; Chest Specialist Rajan Babu Institute of Pulmonary Medicine and Tuberculosis (RBIPMT) Kingsway Camp, Delhi Address for correspondence Dr Praveen B Gautam HN-727, Anand Vihar Colony, Rapti Nagar Gorakhpur - 273 003, Uttar Pradesh E-mail: pravingautom12@gmail.com

2 months, fever on and off, cough with expectoration since 1 month. There was no history of tuberculosis in the family, no history of drug reaction or allergic diathesis. On general and physical examination, patient was found to be normal. Vital signs were within normal limits. Blood examination revealed hemoglobin (Hb) - 13.2 g/dL, total leukocyte count (TLC) - 7,400/mm3, differential leukocyte count (DLC) - P63L25E06M06, platelet count 2.77 lac/mm3, sputum for acid-fast bacilli (AFB) were negative, blood sugar - 73 mg/dL, blood urea - 29 mg/dL, serum creatinine - 0.8 mg/dL, total bilirubin - 0.9 mg/dL, serum glutamic-oxaloacetic transaminase (SGOT) - 24 U/L, serum glutamic-pyruvic transaminase (SGPT) - 27 U/L, chest skiagram revealed patchy fluffy opacities in the left lower zone of the lung and fine-needle aspiration cytology (FNAC) of right submandibular lymph node revealed positive stain for AFB. The patient was put on ATT DOTS Cat 1 in standard doses. After 3 days patient developed acute onset of petechiae over forearm and trunk accompanied by itching, all ATT drugs were stopped. A provisional diagnosis of rifampicin-induced thrombocytopenia was made. Routine investigation (09/04/14) showed Hb - 12.0 g/dL, TLC - 8,200/mm3, DLC - P58L31E05M06, platelet count 60,000/mm3 and normal renal and liver function tests. The bleeding time was 7 minutes and clotting time was 5 minutes 30 seconds and the patient was seronegative for human immunodeficiency virus (HIVs). The patient was managed conservatively, petechiae subsided and platelet count reached 3.5 lac/mm3 after 7 days. On 8th day (17/4/14), after informed

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HEMATOLOGY

Figure 1. Petechiae on trunk and abdomen caused by rifampicin.

Figure 2. Purpura on forearm caused by rifampicin.

consent, antituberculosis therapy was restarted with injection streptomycin, isoniazid, ethambutol and pyrazinamide. After 3 days, the patient again had petechiae on forearm and leg, gum bleeding and melena also developed and platelet count decreased to 28,000/mm3. Treatment was again stopped and patient was managed conservatively and recovered after 10 days. On 01/5/14, platelet count was 3.0 lac/mm3. It was decided that patient will be exposed to antitubercular medicine one after the other. He was given only isoniazid 300 mg and treatment was uneventful. On 3rd day, he was given 750 mg of pyrazinamide under observation. Within 6 hours, the patient developed petechiae on forearm, gum

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Figure 3. Purpura on upper part of forearm caused by pyrazinamide.

bleeding and melena and platelet count decreased to 30,000/mm3, pyrazinamide was withdrawn and isoniazid continued. Patient recovered and it was assumed that hypersensitivity was because of pyrazinamide and not because of rifampicin. After monitoring the platelet count, the patient was given rifampicin 450 mg along with isoniazid 300 mg. Within 12 hours, patient developed patechiae on forearm and itching and platelet count decreased to 58,000/mm2. Rifampicin was then stopped and lesion subsided within 48 hours. After 3 days, patient was exposed to ethambutol and then streptomycin, with no adverse events. Patient continued with isoniazid 300 mg, ethambutol 800 mg and streptomycin 750 mg without any further complaints. After that patient was discharged on ND1 regimen. DISCUSSION Thrombocytopenia is a well-known complication following the administration of different drugs and is characterized by accelerated platelet destruction whenever the offending drug is taken by a sensitized individual.3 Destruction may be mediated by a nonimmunologic or immunologic mechanism. The latter is associated with drug-induced thrombocytopenia. Immunologically-mediated mechanism of platelet destruction is usually based on generation of antibodies directed against platelet membrane or to various immunogens, whose antibodies cross-react with platelet moieties.4 These platelets are subsequently removed by monocyte-macrophages in

HEMATOLOGY the liver and spleen. Drug induced thrombocytopenia can be caused by quinidine, sulfonamides, chemotherapeutic agents, penicillin, barbiturates, heparin, digoxin and estrogen. No antitubercular drug is without side-effects, but adverse reactions are rarely life-threatening.5 Adverse reaction to rifampicin are uncommon on daily regimens, but are relatively common with intermittent regimens.6 They include a cutaneous syndrome, respiratory syndrome, a flu syndrome, purpura and elevated transaminase serum level.7 Many mechanisms are involved in immune-mediated thrombocytopenia like hapten-dependent antibody formation, drugglycoprotein complex antibody formation, autoantibody formation, drug-specific antibody formation and immune-mediated antibody formation.8 Rifampicin is suggested to act as a hapten and antibodies age provided after combining with some molecules in the plasma. These antibodies against rifampicin are suggested to fix a compliment on the platelets in the presence of rifampicin resulting in platelet destruction.9 Pyrazinamide-induced thrombocytopenia is a very rare cause of drug-induced thrombocytopenia. The mechanism of thrombocytopenia caused by pyrazinamide is not yet clearly illustrated but suggested to be immunological.10 Although most of the patients recover within 7-10 days and do not require therapy, an occasional patient with platelet count below 10,000-20,000/mm3 can have severe hemorrhage and may require temporary support with glucocorticoids, platelet transfusion or plasmapheresis. Reuse of the offending drug have to be avoided in the future, since only minute amounts of drug are needed to setup subsequent immune reaction.11 ATT can induce severe thrombocytopenia, which can be life-threatening. In our case, both rifampicin

and pyrazinamide were diagnosed as a cause of thrombocytopenia. By timely withdrawal of these drugs and supportive treatment, serious complications were prevented. ATT was reintroduced without rifampicin and pyrazinamide and there was no recurrence of thrombocytopenia. REFERENCES 1. Wazny LD, Ariano RE. Evaluation and management of drug-induced thrombocytopenia in the acutely ill patient. Pharmacotherapy 2000;20(3):292-307. 2. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30(2):239-45. 3. Blajchman MA, Lowry RC, Pettit JE, Stradling P. Rifampicin-induced immune thrombocytopenia. Br Med J 1970;3(5713):24-6. 4. Ferguson GC. Rifampicin and thrombocytopenia. Br Med J 1971;3(5775):638. 5. Prasad R, Garg R, Verma SK. Isoniazid- and ethambutolinduced psychosis. Ann Thorac Med 2008;3(4):149-51. 6. A controlled trial of daily and intermittent rifampicin plus ethambutol in the retreatment of patients with pulmonary tuberculosis: results up to 30 months. Tubercle 1975;56(3):179-89. 7. Toman K. What is the toxicity of anti-tuberculosis drugs in tuberculosis case finding and chemotherapy Question and Answer 1989. 1st edition, Jaypee Brothers, New Delhi, 101. 8. Kenney B, Stack G. Drug-induced thrombocytopenia. Arch Pathol Lab Med 2009;133(2):309-14. 9. Poole G, Stradling P, Worlledge S. Potentially serious side effects of high-dose twice-weekly rifampicin. Br Med J 1971;3(5770):343-7. 10. Jain VK, Vardhan H, Prakash OM. Pyrazinamide induced thrombocytopenia. Tubercle 1988;69(3):217-8. 11. Handin RI. Disorder of the platelet and vessel wall. In: Harrison’s Principles of Internal Medicine. Vol. 2, 12th edition, McGraw-Hill, Inc, 1501.

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High-dose Oral Resveratrol (RES) Administration Effective in Alzheimer’s Disease High-dose oral resveratrol (RES) administration stabilized levels of amyloid-beta 40 (Aβ40) in cerebrospinal fluid (CSF) and plasma compared with placebo in patients with mild to moderate Alzheimer's disease (AD), suggested a phase 2 study presented at the 7th Clinical Trials Conference on Alzheimer's Disease (CTAD).

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Pineal Gland: The Third Eye V PADMA*, NN ANAND*, C RAMAKRISHNAN*

ABSTRACT Pineal gland is a small, pine cone-shaped organ, located in the midline, attached to the posterior end of the roof of the third ventricle in the brain. While the physiological function of the pineal gland has been unknown until recent times, mystical traditions and esoteric schools have long known this area in the middle of the brain to be the connecting link between the physical and spiritual worlds. The pineal gland controls the various biorhythms of the body. It works in harmony with the hypothalamus gland, which directs the body’s thirst, hunger, sexual desire and the biological clock that determines our aging process. When it ‘awakens’, one feels a pressure at the base of the brain. The pineal gland or epiphysis synthesizes and secretes melatonin, that communicates information about environmental lighting to various parts of the body. The light-transducing ability of the pineal gland has made people call the pineal the ‘third eye’. This review article will unravel some of the mysteries of pineal gland.

Keywords: Pineal gland, melatonin, third eye

ineal gland is a small, pine cone-shaped organ, located in the midline, attached to the posterior end of the roof of the third ventricle in the brain (Fig. 1). The gland varies in size-in humans it is around 1 cm in length, whereas in dogs it is around 1 mm long.

Histologically, the pineal is composed of ‘pinealocytes’ and glial cells. In older animals, the pineal often contains calcium deposits (‘brain sand’). In some parts of the brain and in particular the pineal gland, there are calcium structures, the number of which increases with age, called corpora arenacea (or ‘acervuli,’ or ‘brain sand’). Chemical analysis shows that they are composed of calcium phosphate, calcium carbonate,1 magnesium phosphate and ammonium phosphate.2 Pineal gland calcification may also contribute to the pathogenesis of Alzheimer’s disease and may reflect an absence of crystallization inhibitors.3 The pineal gland was originally believed to be a ‘vestigial remnant’ of a larger organ. In 1917, it was known that extract of cow pineals lightened frog skin. Dermatology professor Aaron B Lerner and colleagues at Yale University, hoping that a substance from the pineal might be useful in treating skin diseases, isolated and named the hormone melatonin in 1958.4 The substance did not prove to be helpful as intended,

*Professor Dept. of Medicine Sree Balaji Medical College, Bharath University Chromepet, Chennai - 600 044, Tamil Nadu

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Corpus callosum

Pineal gland

Third ventricle Pineal gland

Figure 1. Location of pineal gland in the brain.

but its discovery helped solve several mysteries such as why removing the rat’s pineal accelerated ovary growth, why keeping rats in constant light decreased the weight of their pineals and why pinealectomy and constant light affect ovary growth to an equal extent; this knowledge gave a boost to the then new field of chronobiology.5 The pineal gland appears calcified in X-rays, which is usually due to fluoride, calcium and phosphorus deposits that build-up with age. René Descartes, the 17th century French philosopher-mathematician concluded that the pineal gland was the seat of the soul. The gland is relatively large in children and begins to shrink with the onset of puberty. It has a rich supply of adrenergic nerves that greatly influence its function. The pineal gland receives a sympathetic innervation from the superior cervical ganglion. A parasympathetic innervation from the pterygopalatine and otic ganglia

INTERNAL MEDICINE acid tryptophan. Within the pineal gland, serotonin is acetylated and then methylated to yield melatonin. Synthesis and secretion of melatonin is greatly affected by light exposure to the eyes. The serum concentrations of melatonin are low during the daylight hours and increase to a peak during the dark. The secretion during the dark cycle is due to the rate-limiting enzyme in melatonin synthesis- serotonin N-acetyltransferase (NAT), which is low during daylight and peaks during the dark phase.

is also present. Further, some nerve fibers penetrate into the pineal gland via the pineal stalk (central innervation). Also, neurons in the trigeminal ganglion innervate the gland with nerve fibers. Pinealocytes: The pinealocytes consist of a cell body with 4-6 processes emerging. They produce and secrete melatonin. The pinealocytes can be stained by special silver impregnation methods. Their cytoplasm is lightly basophilic. With special stains, pinealocytes exhibit lengthy, branched cytoplasmic processes that extend to the connective septa and its blood vessels. Interstitial cells: Interstitial cells are located between the pinealocytes. They have elongated nuclei and a cytoplasm that is stained darker than that of the pinealocytes. Perivascular phagocytes: These are located close to the blood vessels. The perivascular phagocytes are antigen presenting cells.

Two melatonin receptors have been identified from mammals (Mel1A and Mel1B). These are G proteincoupled cell surface receptors. The highest density of receptors has been found in the suprachiasmatic nucleus of the hypothalamus, the anterior pituitary and the retina. Receptors are also found in other areas of the brain.

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Effects on reproductive function: The effect of melatonin on reproductive systems can be summarized by saying that it is antigonadotropic.8 Melatonin inhibits the secretion of the gonadotropic hormones luteinizing hormone and follicle-stimulating hormone, from the anterior pituitary. Much of this inhibitory effect seems due to inhibition of gonadotropin-releasing hormone from the hypothalamus, which is necessary for secretion of the anterior pituitary hormones. Its production is high in infancy and childhood and declines with age and abnormally high levels of melatonin in children are associated with delayed sexual development. More recent data showing an association between endogenous melatonin levels and the onset of puberty, as well as observations of elevated melatonin levels in both men and women with hypogonadism and/or infertility, but a regulatory role of melatonin has yet to be established conclusively.

One practical application of melatonin’s role in controlling seasonal reproduction is found in its use to artificially manipulate cycles in seasonal breeders. For example, sheep that normally breed only once per year can be induced to have two breeding seasons by treatment with melatonin. In several vertebrate species, pineal hormones influence sexual development, hibernation and seasonal breeding

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Effects on sleep and activity: Melatonin is probably not a major regulator of normal sleep patterns, but has some effect. Another sleep disorder is seen in shift workers, who often find it difficult to adjust to working at night and sleeping during

Peptidergic neuron-like cells: These cells have a paracrine regulatory function. There is a great deal of speculation as to what causes calcification of the pineal gland. Fluoride in water and toothpaste, any food additives including artificial sweeteners and radiation from cell phones has also been cited as a possible cause of calcification of the pineal gland. The human pineal gland grows in size until about 1-2 years of age, remaining stable thereafter.6 The abundant melatonin levels in children are believed to inhibit sexual development and pineal tumors have been linked with precocious puberty. When puberty arrives, melatonin production is reduced. FUNCTIONS OF PINEAL GLAND ÂÂ

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Light exposure to the retina is first relayed to the suprachiasmatic nucleus7 of the hypothalamus which coordinates biological clock signals. Fibers from the hypothalamus descend in the spinal cord and project to the superior cervical ganglia, from which post-ganglionic neurons ascend back to the pineal gland. Thus, the pineal is similar to the adrenal medulla as it transduces signals from the sympathetic nervous system into a hormonal signal. The pineal gland or epiphysis synthesizes and secretes melatonin, that communicates information about environmental lighting to various parts of the body. The light-transducing ability of the pineal gland has made people call the pineal the ‘third eye’. The precursor to melatonin is serotonin, a neurotransmitter that is derived from the amino

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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.

Drug Subsidy

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

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

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

BPL Card (If Card holder)

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

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

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

Free Diagnostic Facility

Free Education and Employment Facility

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

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

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

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

About Heart Care Foundation of India

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

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

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

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

Committee Members

Chief Patron

President

Raghu Kataria

Dr KK Aggarwal

Entrepreneur

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

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

Advisors Mukul Rohtagi Ashok Chakradhar

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

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

Rishab Soni

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

http://heartcarefoundationfund.heartcarefoundation.org

INTERNAL MEDICINE the day. Another condition involving disruption of circadian rhythms is jet lag. ÂÂ

Other effects of melatonin: While the physiological function of the pineal gland has been unknown until recent times, mystical traditions and esoteric schools have long known this area in the middle of the brain to be the connecting link between the physical and spiritual worlds. Considered the most powerful and highest source of ethereal energy available to humans, the pineal gland has always been important in initiating supernatural powers. Development of psychic talents has been closely associated with this organ of higher vision. The third eye controls the various biorhythms of the body. It works in harmony with the hypothalamus gland, which directs the body’s thirst, hunger, sexual desire and the biological clock that determines our aging process. When it ‘awakens’, one feels a pressure at the base of the brain. The pineal gland’s location deep in the brain seems to intimate hidden importance. In the days before, its function as a physical eye that could see beyond space-time was discovered, it was considered a mystery linked to superstition and mysticism. Today, it is associated with the sixth chakras (Fig. 2).6

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The pineal gland contains several neuropeptides and neurotransmitters, such as somatostatin, norepinephrine and serotonin.7

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In humans, exogenous melatonin has a soporific effect, but only when administered during the day or early evening, when endogenous levels are low. Some types of primary insomnia have been attributed to diminished melatonin production, particularly in the elderly, but evidence of a causal link is still inconclusive. Melatonin administration also has mild hypothermic and hypotensive effects.8

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Literature supports the involvement of melatonin in immune function, with high levels promoting and low levels suppressing a number of immune system parameters. Melatonin receptors are seen in various lymphoid organs and in lymphocytes suggesting multiple mechanisms of action.9 Melatonin has been shown to be a powerful antioxidant, and has oncostatic properties, both direct and indirect, the latter mediated by its effects on reproductive hormones.10 There are reports of abnormal daily melatonin level profiles in a number of psychiatric and neurological disorders, but the significance of such abnormalities is far from clear.11

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Drug metabolism: Studies on rodents have suggested that the pineal gland may influence the actions of recreational drugs, such as cocaine9 and antidepressants, such as fluoxetine. Melatonin can protect against neurodegeneration.10

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Cancer: Tumors involving the pineal gland are rare; most (50-70%) arise from sequestered embryonic germ cells. They most commonly take the form of socalled germinomas, resembling testicular seminoma or ovarian dysegerminoma. Other lines of germ cell differentiation include embryonal carcinomas; choriocarcinomas; mixtures of germinoma, embryonal carcinoma and choriocarcinoma and uncommonly, typical teratomas (usually benign). Whether to characterize these germ cell neoplasms as pinealomas is still a subject of debate, but most pinealophiles favor restricting the terms pinealoma to neoplasms arising from the pineocytes.

A pineal tumor can compress the superior colliculi and pretectal area of the dorsal midbrain, producing Parinaud’s syndrome. Pineal tumors also can cause compression of the cerebral aqueduct, resulting in a Crown chakra

Third eye pineal

Throat chakra

Heart chakra

Solar plexus Spleen chakra

Pelvic chakra (Cervical organ)

Sacral chakra

Figure 2. Association of pineal gland with the six chakras.

INTERNAL MEDICINE noncommunicating hydrocephalus. These neoplasms are divided into two categories, pineoblastomas and pineocytomas, based on their level of differentiation, which, in turn, correlates with their neoplastic aggressiveness. The clinical course of patients with pineocytomas is prolonged, averaging 7 years. The manifestations are the consequence of their pressure effects and consist of visual disturbances, headache, mental deterioration and sometimes dementia-like behavior. THIRD EYE The third eye (also known as the inner eye) is a mystical concept referring to an invisible eye, which provides perception beyond ordinary sight. In Hinduism, the third eye refers to the Ajna or Brow chakra.11 In theosophy, it is related to the pineal gland.12 The third eye is often associated with religious visions, the ability to observe chakras and auras,13 clairvoyance and out-of-body experiences. People who have the capacity to utilize their third eyes are known as seers. Taoism teaches that the third eye, also called the mind’s eye, is situated between the two physical eyes. Taoism claims that the third eye is one of the main energy centers of the body located at the sixth chakra, forming a part of the main meridian, the line separating left and right hemispheres of the body14 and is given the name ‘muddy pellet’. According to the Christian teaching of Father Richard Rohr, the concept of the third eye is a metaphor for nondualistic thinking; the way the mystics see. In Rhohr’s concept, mystics employ the first eye (sensory input from sight) and the second eye (the eye of reason, meditation and reflection referred to as ‘having the mind of Christ’.15 René Descartes, dedicating much time to the study of the pineal gland, called it the ‘principal seat of the soul’.16 He believed it to be the point of connection between the intellect and the body. Descartes attached significance to the gland because he believed it to be the only section of the brain to exist as a single part rather than one-half of a pair. He argued that, because a person can never have ‘more than one thought at a time,’ external stimuli must be united within the brain before being considered by the soul and he considered the pineal gland to be situated in ‘the most suitable possible place for this purpose,’ located centrally in the brain and surrounded by branches of the carotid arteries. Baruch de Spinoza criticized Descartes’ viewpoint for neither following from self-evident premises nor being ‘clearly and distinctly perceived’ (Descartes having previously asserted that he could not draw conclusions of this

sort), and questioned what Descartes meant by talking of ‘the union of the mind and the body.’17 The notion of a ‘pineal-eye’ is central to the philosophy of the French writer Georges Bataille, which is analyzed at length by literary scholar Denis Hollier in his study against architecture. In this work Hollier discusses how Bataille uses the concept of a ‘pineal-eye’ as a reference to a blind-spot in Western rationality, and an organ of excess and delirium.18 Numerous spiritual philosophies contain the notion of an inner third eye that is related to the Ajna chakra and also to the pineal gland, and to which is attributed significance in mystical awakening or enlightenment, clairvoyant perception and higher states of consciousness. This idea occurs historically in ancient Central and East Asia and also in contemporary theories relating to yoga, theosophy, hinduism and pagan religions and new age spiritual philosophies. IMPORTANCE OF ACTIVATING/DECALCIFYING PINEAL GLAND It is important to keep the pineal gland active. When it is active, the pineal gland helps you to get good sleep and helps you be awake during the day. An active pineal gland will also ensure that neurological signals are clearly transmitted to the endocrine system. In addition to other functions, this can help promote better hormonal control. Spiritually, an open third eye also brings to you bliss, intuition, concentration, clarity and decisiveness. With a highly functioning pineal gland, your physical and mental functioning will be improved. Steps to reduce pineal gland calcification are: ÂÂ

No fluoride in water and food: When possible, eat organic foods and drink liquids that do not have fluoride added to them.

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Raw apple cider vinegar: The apple cider vinegar supplement you buy should be raw and not processed.

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Oregano oil and neem extract: Oregano and neem extract5 may help decalcify the pineal gland, purify other parts of the endocrine system, fortify the immune system and act as a natural antibiotic in the body. In India, neem has been used to decalcify pineal gland, or open the third eye for thousands of years.

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Essentials oils: Essential oils like lavender, parsley, pine, sandalwood, pink lotus and frankincense may help to stimulate the pineal gland and decalcify it. These oils can be used in a diffuser or added to warm bath water.

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Regular meditation and chanting: Meditation, yoga and chanting may help decalcify the pineal gland by stimulating the gland through resonance in the nasal bones. As the calcium crystals are broken up in the gland, the increased secretions can wash away the calcification. It is desired to chant for at least 10 minutes daily or longer.

CONCLUSION The pineal gland controls the various biorhythms of the body. It works in harmony with the hypothalamus gland, which directs the body’s thirst, hunger, sexual desire and the biological clock that determines our aging process. When it ‘awakens’, one feels a pressure at the base of the brain. The pineal gland or epiphysis synthesizes and secretes melatonin, that communicates information about environmental lighting to various parts of the body. The light-transducing ability of the pineal gland has made people call the pineal the ‘third eye’. The pineal gland’s full purpose is still a bit of a mystery. But, research suggests that we’re getting closer to understanding the pineal gland—and more about the endocrine system as a whole. Activation of pineal gland by regular meditation would prevent illness and improve the quality-of-life of humam beings. REFERENCES 1. Luke J. Fluoride deposition in the aged human pineal gland. Caries Res 2001;35(2):125-8. 2. Bocchi G, Valdre G. Physical, chemical, and mineralogical characterization of carbonate-hydroxyapatite concretions of the human pineal gland. J Inorg Biochem 1993;49(3):209-20. 3. Mahlberg R, Walther S, Kalus P, Bohner G, Haedel S, Reischies FM, et al. Pineal calcification in Alzheimer’s disease: an in vivo study using computed tomography. Neurobiol Aging 2008;29(2):203-9. 4. Lerner AB, Case JD, Takahashi Y. Isolation of melatonin and 5-methoxyindole-3-acetic acid from bovine pineal glands. J Biol Chem 1960;235:1992-7.

5. Coates, Paul M. (2005). Encyclopedia of Dietary Supplements. Marc R. Blackman, Gordon M. Cragg, Mark Levine, Joel Moss, Jeffrey D. White. CRC Press. p. 457. ISBN 0-8247-5504-9. Retrieved 2009-03-31. 6. Schmidt F, Penka B, Trauner M, Reinsperger L, Ranner G, Ebner F, et al. Lack of pineal growth during childhood. J Clin Endocrinol Metab 1995;80(4):1221-5. 7. Lowrey PL, Takahashi JS. Genetics of the mammalian circadian system: Photic entrainment, circadian pacemaker mechanisms, and posttranslational regulation. Annu Rev Genet 2000;34:533-562. 8. Motta M, Fraschini F, Martini L. Endocrine effects of pineal gland and of melatonin. Proc Soc Exp Biol Med 1967;126(2):431-5. 9. Uz T, Akhisaroglu M, Ahmed R, Manev H. The pineal gland is critical for circadian Period1 expression in the striatum and for circadian cocaine sensitization in mice. Neuropsychopharmacology 2003;28(12):2117-23. 10. Manev H, Uz T, Kharlamov A, Joo JY. Increased brain damage after stroke or excitotoxic seizures in melatonindeficient rats. FASEB J 1996;10(13):1546-51. 11. Saraswati, Swami Satyananda Saraswati. Kundalini Tantra. Yoga Publications Trust. Bihar, India; 2001. ISBN 978-8185787152. 12. Helena Petrovna Blavatsky. The Secret Doctrine. Vol. II, Theosophical Publishing House: Wheaton, IL 1993:p.295. 13. Leadbeater CW. The Chakras Wheaton, Illinois, USA: Theosophical Publishing House, 1927:pgs 79. 14. Jefferson RB. The doctrine of the elixir. The Archaic Anatomy of Individual Organs (Chap. 4). Coombe Springs Press, 1982. 15. Richard R. The Naked Now: Learning to See as the Mystics See. The Crossroad Publishing Company, 2009. 16. D escartes R. “The Passions of the Soul” excerpted from “Philosophy of the Mind,” Chalmers, D. Oxford University Press, Inc.: New York, 2002. 17. Hollier D. Against Architecture: The Writings of Georges. Bataille, trans. Betsy Wing, MIT, 1989. 18. Bataille G. Visions of Excess: Selected Writings, 1927-1939 (Theory and History of Literature, Vol. 14), trans. Stoekl A, et al., Manchester University Press, 1985

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immunotherapy in Advanced Metastatic Melanoma Ettetric The durability of the responses seen with immunotherapy in advanced metastatic melanoma continues to impress. The latest data reported here at the Society for Melanoma Research (SMR) 2014 International Congress update results from several early trials and show that the some responses are maintained for years. Not long ago, the survival in these patients was measured in months. The longest-term data are available for ipilimumab (Yervoy, Bristol Myers Squibb), the first of the new immune checkpoint inhibitors, launched in the United States in 2011. Some patients treated with this drug are still alive 10 years later, Stephen Hodi, MD, assistant professor of medicine at the Dana-Farber Cancer Institute, Boston, Massachusetts, reported last year. He described a survival curve that plateaus after around 3 years, with about 20% of patients receiving responses, with the longest lasting up to 10 years.

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INTERNAL MEDICINE

Multisystem Involvement in Melioidosis: A Case Report PRIYADARSHINI GUNASEELAN*, SWAMIKANNU M†, VAIDEHI R‡, SARVESWARI KN#

ABSTRACT Melioidosis is an infection caused by facultative intracellular, aerobic, Gram-negative soil and water living bacterium Burkholderia pseudomallei, which was previously classified under Pseudomonas. Melioidosis is an uncommon yet fatal infection dreaded as a potential bio threat. The infection spreads by inoculation, inhalation or ingestion. Diabetes, alcohol abuse, chronic renal failure, pulmonary diseases are identified risk factors. We report a case of a 39-year-old male diagnosed as melioidosis who presented with splenic abscess, pulmonary consolidation, skin nodules and later developed cellulitis of the foot, which required incision and drainage.

Keywords: Melioidosis, Burkholderia pseudomallei, consolidation, splenic abscess, cellulitis

CASE REPORT A 39-year-old man with no known comorbid illnesses came to our emergency room (ER) with a long history for fever for 5 weeks. He was treated elsewhere with multiple antibiotics and a course of antimalarial. On examination, he was febrile, temperature of 103˚F, tachycardic and also had a palpable spleen. On further interrogation, he revealed a history of pilgrimage by barefoot for about 90 km, 3 weeks prior to the onset of initial symptom (around early August, which is monsoon in this part of India). Preliminary investigations showed a normal blood count with few neutrophilic band forms and raised erythrocyte sedimentation rate (ESR), normal renal and liver functions. Probable causes of fever like typhoid, malaria, scrub typhus were negative. Human immunodeficiency virus (HIV) enzymelinked immunosorbent assay (ELISA) was negative. Diabetes mellitus was detected after admission with

*Postgraduate Dept. of Family Medicine †Consultant Physician ‡Consultant Microbiologist #Consultant Dermatologist Sundaram Medical Foundation, Chennai, Tamil Nadu Address for correspondence Dr Priyadarshini Gunaseelan Postgraduate Dept. of Family Medicine Sundaram Medical Foundation, Chennai, Tamil Nadu

glycosylated hemoglobin (HbA1C) of 13.9%. Ultrasound of the abdomen was unremarkable except for an enlarged spleen of 13 cm. He was empirically started on ceftriaxone. Blood culture of the patient grew Gram-negative bacilli identified by Vitek system as Burkholderia cepacia (Fig. 1). Since, the patient’s immune system was not severely debilitated for B. cepacia infection the cultures were repeated. In the meantime, he continued to have fever spikes, developed pustules over the face and arm and lost significant weight (lost 6 kg since admission) (Fig. 2). Computed tomography (CT) showed consolidation of the lower zone of left lung and splenic

Figure 1. Blood culture plate showing wrinkled pink colonies.

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INTERNAL MEDICINE drainage was done and 30 mL of pus was drained, which also showed heavy growth of B. pseudomallei. We planned to continue ceftazidime for a total period of 6 weeks. Glycemic control was achieved with insulin. Blood cultures done at the end of 3, 4 and 6 weeks were sterile. Ultrasound showed resolution of the splenic abscess. Patient was discharged with oral eradication therapy with doxycycline 100 mg twice-daily and co-trimoxazole thrice-daily for 6 months and is under regular follow-up. DISCUSSION Melioidosis is an illness endemic to South-East Asia regions, Indian subcontinent and Northern Australia. Though, there were few monographs from Malaysia and Rangoon describing features similar to the disease in the early 20th century, the first case report came from Burma in 1911 described by Whitmore and Krishnaswami.1-3

Figure 2. Skin nodules.

The bacteria causing melioidosis was named as Pseudomonas pseudomallei. It was further classified under the new genus Burkholderia in 1992 by Yabuuchi et al. It is a soil and water pathogen. Stagnation of water in places like paddy fields and rainfall causes clustering of cases. The bacterium is found in the soil of almost all states of India.2,3 Bruce Short from Australia in his monograph states that melioidosis is a military problem - because deployments, where personnel on patrol through paddy fields are at particular risk.4

Figure 3. CT of abdomen demonstrates splenic abscesses that were not easily visualized on a sonogram. Thoracic imaging shows consolidation of the left lower zone.

abscesses of size 5 Ă&#x2014; 6 cm (Fig. 3). The repeat blood culture and swab culture from the pustules grew Burkholderia pseudomallei sensitive to most groups of antibiotics. Antibiotic therapy with ceftazidime was started at 2 g IV 8th hourly. Fever spikes gradually subsided, but patient developed pain and swelling of the dorsum of the right foot on the 9th day of specific antibiotic therapy. Deep-vein thrombosis (DVT) was ruled out; uric acid was 1.6 mg/dL. The swelling progressively increased in size and was warm and tender. The cellulitis failed to subside, with continuing antibiotic therapy, hence incision and

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Apart from the environmental risk factors, 80% of cases of melioidosis are documented to occur in individuals with some identified comorbidity.5 A prospective study done on 540 patients in Northern Australia for 20 years has identified diabetes and hazardous alcohol use as high-risk factors.6 In about 60% of cases, diabetes has been detected after presentation with melioidosis like in our patient.2 However, mortality is not determined by these conditions. An underlying malignancy, cardiac failure, chronic kidney disease and biofilm formation as in in-dwelling catheters are associated with higher mortality.7 The overall mortality rate of melioidosis is 14%.6 Melioidosis is transmitted through inoculation or inhalation or ingestion. A case of vertical transmission through breast milk from a mother suffering from mastitis has also been reported. The incubation period varies from 1 to 21 days. The shortest incubation period is reported in a case of near drowning leading to aspiration pneumonia. Melioidosis has a spectrum

INTERNAL MEDICINE of clinical presentation ranging from indolent asymptomatic disease to acute respiratory distress syndrome and septicemia. Various case reports include pneumonia, abscesses of skin, subcutaneous tissue, deep-seated visceral abscesses and lymphadenitis.7-11 Even rare cases of mycotic aneurysm, osteomyelitis and mastitis have been described in literature. Pneumonia carries the risk of rapidly progressing to respiratory failure.9 Significant weight loss is an important observation as in our patient. Because of the intracellular activity of the bacterium and its ability to form multinucleated giant cells, melioidosis mimicks tuberculosis.8,10 Whitmore described the autopsy lesions on the first ever reported case of melioidosis as ‘peculiar cheesy consolidation that was neither lobar pneumonia nor tubercular’. Challenges in diagnosis of melioidosis require a clinical suspicion and a strong laboratory support. There are no specific guidelines currently for the treatment of melioidosis. Various centres follow different antibiotic protocol depending on the organ involved. Ceftazidime remains the drug of choice in most centers. Use of ciprofloxacin, amoxicillin-clavulanic acid, etc. have also been reported. The duration of treatment varies from 2 to 8 weeks depending on the site of infection; deep-seated abscesses require longer duration of antibiotics followed by oral eradication therapy with co-trimoxazole and doxycycline. The organism exhibits characteristic resistance to aminoglycosides. A study in Malaysia on 146 isolates of B. pseudomallei revealed that all isolates were susceptible to ceftazidime and carbapenems, 88% sensitive to co-trimoxazole and 82% sensitive to ciprofloxacin.

REFERENCES 1. Whitmore A. An account of a Glanders-like disease occurring in Rangoon. J Hyg (Lond) 1913;13(1):1-34.1. 2. Puthucheary SD. Melioidosis in Malaysia. Med J Malaysia 2009;64(4):266-74. 3. Pandey V, Rao SP, Rao S, Acharya KK, Chhabra SS. Burkholderia pseudomallei musculoskeletal infections (melioidosis) in India. Indian J Orthop 2010;44(2):216-20. 4. Short BH. Melioidosis: an important emerging infectious disease - a military problem? ADF Health 2002;3:13-21. 5. Wiersinga WJ, Currie BJ, Peacock SJ. Melioidosis. N Engl J Med 2012;367(11):1035-44. 6. Currie BJ, Ward L, Cheng AC. The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study. PLoS Negl Trop Dis 2010;4(11):e900. 7. Jin JL, Ning YX. Septicemic melioidosis: a case report and literature review. J Thorac Dis 2014;6(2):E1-4. 8. Sugi Subramaniam RV, Karthikeyan VS, Sistla SC, Ali SM, Sistla S, Vijayaraghavan N, et al. Intra-abdominal melioidosis masquerading as a tubercular abdomen: report of a rare case and literature review. Surg Infect (Larchmt) 2013;14(3):319-21. 9. Redondo MC, Gómez M, Landaeta ME, Ríos H, Khalil R, Guevara RN, et al. Melioidosis presenting as sepsis syndrome: a case report. Int J Infect Dis 2011;15(3):e217-8. 10. Saravu K, Mukhopadhyay C, Eshwara VK, Shastry BA, Ramamoorthy K, Krishna S, et al. Melioidosis presenting with mediastinal lymphadenopathy masquerading as malignancy: a case report. J Med Case Rep 2012;6:28. 11. Wijekoon S, Prasath T, Corea EM, Elwitigala JP. Melioidosis presenting as lymphadenitis: a case report. BMC Res Notes 2014;7:364.

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Herpes Vaccine Safe in Patients with Arthritis on Biologics The herpes zoster vaccine can be safely used in patients with rheumatoid arthritis, psoriatic arthritis, and spondyloarthropathies who are being treated with biologic agents, according to the results of a new study. This is particularly good news in light of a related study that showed that the rate of herpes zoster infection is almost twice as high in patients with autoimmune and inflammatory diseases as in the general population, and that the infection can be more severe and can occur at younger ages. Both studies were presented here at the American College of Rheumatology (ACR) 2014 Annual Meeting.

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A Rare Case of Natural Pregnancy at Advanced Maternal Age GAYATRI MATHURIYA*, DEEPIKA BANSAL†

ABSTRACT It is extremely rare for a women over the age of 45 to have a child with their own eggs and with no fertility treatments and most women begin to go through menopause around this age. The age at which women attain menopause varies, though and if you haven’t gone through menopause in your 50s yet, there still is a chance you can get pregnant; your chances of getting pregnant in your 50s are much lower than they were 20 years earlier, but are still possible. After age 55, it’s almost unheard of. It’s very rare, but we present here with a mother who got pregnant at the age of 55, completely unplanned.

Keywords: Menopause, advanced age, pregnancy, maternal and fetal complications

woman’s fecundity ends with menopause, which by definition is 12 consecutive months without having had a period. Perimenopause usually begins between ages 40 and 51, and fertility can and often does end at this stage also. During this period, the periods become irregular and eventually stop altogether, but even when periods are still regular, the egg quality of women in their 40s is typically dramatically lower than in younger women, making the likelihood of conceiving a healthy baby also significantly lower, particularly alter age 42.1 Men in contrast generally remain fertile throughout their lives,2 although the risk of genetic defects is greatly increased due to the paternal age effect.3

The risk of pregnancy complications increases as the mother’s age increases. Risk associated with childbearing over the age of 50 include an increased incidence of gestational diabetes, hypertension, delivery by cesarean section, miscarriage, pre-eclampsia and placenta previa.4,5 In comparison to mother’s between 20 and 29 years of age, mother’s over 50 are at almost three times the risk of low-birth-weight, premature

*Associate Professor †Resident Dept. of Obstetrics and Gynecology MGM Medical College and MY Hospital, Indore, Madhya Pradesh Address for correspondence Dr Gayatri Mathuriya 48, Kalindi Kunj, Indore - 452 001, Madhya Pradesh E-mail: drgayatrimathuriya@gmail.com

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birth, their risk of extremely low-birth-weight, small size for gestational age and fetal mortality was almost double.6 CASE REPORT A 55 years G4P3L3 female as shown in Figure 1 was admitted in emergency hours on 11 June 2013 as a high-risk case. On admission, she had difficulty in breathing and no other complaints. It was her second marriage. Her age was 29 years at second marriage and her husband’s age was 35 years. She had first child 2 years after marriage. Now, her first child is 23 years old. Her third child was 13 years old. After delivery of her third child, she had perimenopause for 5 years. She had menopause since then, that means had permanent cessation of menses. On examination, her vitals were within normal limits. On chest auscultation, bilateral, occasional fine crepts and rhonchi were present. She was severely anemic, her hemoglobin was 6.9 g/dL, respiratory rate was 24/min. No other significant finding was present. On per abdomen examination; uterus was full-term, lie was longitudinal, cephalic, head high floating, Floating-Harbor syndrome (FHS) present and regular. On per vaginal examination; pelvis was adequate and patient was not in labor. Urgent nebulization was done, higher antibiotics and injection deriphylline were given. Patient was examined by a physician. Chest ultrasonography (USG), serum electrolytes and all routine investigations, electrocardiography (ECG) were done; all were found to be within normal limits. On 12 June 2013, one packed-cell volume (PCV) was

OBSTETRICS AND GYNECOLOGY 3.5 kg as shown in Figure 2. Intraoperatively, no complication was encountered. Postoperatively, she was managed with strict vitals monitoring, nebulization and antibiotics. Her postpartum period was uneventful. DISCUSSION

Figure 1. Fifty-five years old pregnant female.

Menopause occurs when a woman’s menstrual cycle stops for 12 consecutive months. While, this is generally an indicator that the body has slowed or stopped production of estrogen and progesterone, some women will continue to produce enough hormones to have an egg implanted in the lining of the uterus. The change of life is more of a process than single event and some women can have fluctuating hormone levels for up to 5 years. At any point within this time frame, it is possible for a woman to have a pregnancy during menopause because hormone levels can be unpredictable.7 While most Western women go through menopause between the ages of 45 and 55, women as old as 60 occasionally still have periods and thus can theoretically become pregnant. Women in developing countries tend to go through menopause about 8 years earlier that is at 48 years. The oldest known ‘natural mother’, meaning she became pregnant without medical intervention was 59. The previous record holder has been 57, when she gave birth in 1956.8 But in India, ‘natural mother’ at 55 years of age was the first case which is extremely rare. Needless to say, natural pregnancy so late in life is extremely rare.8 REFERENCES 1. Female Age, Fertility and Infertility – Advanced Fertility Center of Chicago. Available from: http://www. advancedfertility.com/age.htm. 2. The Alfred Foundation. (n.d.) Men’s Health. Retrieved May 18, 2007. 3. Available at: http://www.mayoclinic.com/health/ pregnancy/PR00115. 4. Salihu HM, Shumpert MN, Slay M, Kirby RS, Alexander GR. Childbearing beyond maternal age 50 and fetal outcomes in the United States. Obstet Gynecol 2003;102(5 Pt 1):1006-14.

Figure 2. Female with her husband and their newborn baby.

5. Schienberg, Jonathan. New Age Mystic To Become Mom at 57. (November 9, 2004). CNN. Retrieved March 4, 2007.

transfused, medical fitness and preanesthetic check-up was done for surgery. But on 13 June 2013 at 3 am, she went into spontaneous labor. Immediately blood was arranged and she was taken for lower-segment cesarean section (LSCS). Cesarean section was done on 13 June 2013 at 5:15 am and one PCV was transfused intraoperatively. She delivered a female baby of

6. Lister Hill Center for Health Policy (October 31, 2003). Pregnancy After 50. More Risky Than We Thought ? Retrieved March 4, 2007. 7. Available at: http://www.christianet.com/menopause/ pregnancy after menopause.htm. 8. Can you Get Pregnant at 58 yrs old? By Evangeline Marzec, eHow Contributer. Available at: http://www. ehow.com/way_5380190_can-pregnant-yrs-old.html.

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Bicornuate Uterus: A Case Report G RAJATHI*, V VATHSALA*, WMS JOHNSON*

ABSTRACT The incidence of the uterine malformations is estimated to be 3-5% in the general population. Abnormal fusion of the paramesonephric duct (mullerian duct) during embryonic life results in a variety of congenital uterine malformations like septate uterus, unicornuate uterus and bicornuate uterus. In the present case, the patient had a history of one stillborn child and one first trimester abortion. She was 25 years old, married for 5 years. During routine antenatal scan, the cause for it was diagnosed to be bicornuate uterus. It was confirmed by hysterosalpingography.

Keywords: Paramesonephric duct, bicornuate uterus, congenital uterine malformation, ultrasonogram

ore than 50% of women with malformed uterus will stay completely asymptomatic. Only 15-25% of women with uterine anomalies have problems with fertility and reproduction. They have increased incidence of miscarriage, poor fetal growth, malpresentations and abnormal placental and ectopic pregnancies. The incidence of uterine malformations is estimated to be 3-5% in the general population. Bicornuate uterus is considered as an high-risk for recurrent pregnancy loss, dysmenorrhea, dyspareunia, preterm labor and congenital defects in the fetus. It is a type of congenital uterine malformation, where the uterus is composed of two horns separated by septum. The fusion process of the upper part of the mullerian duct (paramesonephric duct) is altered leading to bicornuate uterus. It is usually diagnosed incidentally during routine obstetric scan. The incidence is estimated to be 0.4%. Because of better availability of diagnostic modalities (i.e., transvaginal sonography, hysterosalpingography and laparoscopy) better detection of anomalies is possible. Reproductive outcomes can be improved with better treatment.

scan done at Dept. of Obstetrics and Gynecology, Sree Balaji Medical College, Chennai (Fig. 1). Pregnancy was continued normally, but fetus was stillborn at 7th month. Fetus appeared to be normal externally, mother didnâ&#x20AC;&#x2122;t have any associated complication and was discharged with regular follow-up. Second pregnancy ended up in spontaneous abortion at the 2nd month of pregnancy. She underwent thorough check-up. All blood tests showed normal including thyroid profile. She did not have any history of consanguineous marriage and there were no family history of any abnormal pregnancy. Her motherâ&#x20AC;&#x2122;s antenatal history was uneventful. Her age at menarche was 14 years. Menstrual history was uneventful. There was no history of diabetes, hypertension, Rhesus (Rh) incompatibility and Rubella infection.

CASE REPORT A 25 years female, G2P1L0A1 was found to have bicornuate uterus, single cervix in the routine dating

*Sree Balaji Medical College and Hospital Bharath University, Chromepet, Chennai, Tamil Nadu Address for correspondence Dr G Rajathi E-mail: rajathi1010@gmail.com

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Figure 1. Ultrasound picture showing bicornuate uterus.

OBSTETRICS AND GYNECOLOGY DISCUSSION Uterine anomalies were identified in 1 in 594 fertile women (0.17%) and in 1 in 29 infertile women (3.5%). The prevalence of uterine anomalies in the general population was 1 in 201 women (0.50%). Their distribution was: 7% arcuate, 34% septate, 39% bicornuate, 11% didelphic, 5% unicornuate and 4% hypoplastic/aplastic/solid and other forms.1 Bicornuate uterus is a congenital uterine anomaly that results from defective lateral fusion of the paramesonephric ducts around the fundus, at about the 10th week of intrauterine life.

Organogenesis The differentiation of the different parts of the female genital tract starts from the 7th week of development. In the absence of anti-müllerian hormone, the Wolffian ducts regress and mullerian ducts will develop. This development consists of three phases: ÂÂ

Migration müllerian ducts to the urogenital sinus (6-9th week)

ÂÂ

Apposition of the lower-third of the müllerian ducts form the uterus and the upper two thirds of the vagina (9-13th week)

ÂÂ

Resorption of (13-17th week).

the

inter-müllerian

Class III (didelphys uterus) (Fig. 3) results from complete nonfusion of both müllerian ducts. The individual horns are fully developed and almost normal in size. Two cervices are inevitably present. A longitudinal or transverse vaginal septum may be noted as well. Didelphys uteri have the highest association with transverse vaginal septa, but septa also may be observed in other anomalies. Consider metroplasty; however, since each horn is almost a fully developed uterus, patients have been known to carry pregnancies to full-term. Class IV (bicornuate uterus) (Fig. 4) results from partial nonfusion of the müllerian ducts. The central myometrium may extend to the level of the internal cervical os (bicornuate unicollis) or external cervical os (bicornuate bicollis). The latter is distinguished from didelphys uterus because it demonstrates

partition

The detection of congenital uterine anomalies are bound to increase because of heightened physician awareness and improved diagnostic modalities. Failure of the paramesonephric duct to fuse may cause a variety of uterine defects. American Fertility Society (AFS) classification scheme: Class I (hypoplasia/agenesis) includes entities such as uterine/cervical agenesis or hypoplasia. The most common form is the Mayer-Rokitansky-Kuster-Hauser syndrome, which is combined agenesis of the uterus, cervix and upper portion of the vagina. Patients have no reproductive potential aside from medical intervention in the form of in vitro fertilization of harvested ova and implantation in a host uterus. Class II (unicornuate uterus) (Fig. 2) is the result of complete, or almost complete, arrest of development of one müllerian duct. If the arrest is incomplete, as in 90% of patients, a rudimentary horn with or without functioning endometrium is present. If the rudimentary horn is obstructed, it may come to surgical attention when presenting as an enlarging pelvic mass. If the contralateral healthy horn is almost fully developed, a full-term pregnancy is believed to be possible.

Figure 2. Unicornuate uterus. Note the failure of the development of one-half of the uterus. This form may be associated with a rudimentary horn arising from the contralateral müllerian duct.

Figure 3. Didelphys uterus. Note the complete separation but full development of each müllerian duct.

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OBSTETRICS AND GYNECOLOGY some degree of fusion between the 2 horns, while in classic didelphys uterus, the 2 horns and cervices are separated completely. In addition, the horns of the bicornuate uteri are not fully developed; typically, they are smaller than those of didelphys uteri. Some patients are surgical candidates for metroplasty.

loss and the complications found in other subtypes. Class VII (diethylstilbestrol [DES] -related anomaly) (Fig. 8) has occurred in several million women who were treated with DES, an estrogen analog prescribed

Class V (septate uterus) (Fig. 5) results from failure of resorption of the septum between the 2 uterine horns. The septum can be partial or complete, in which case it extends to the internal cervical os. Histologically, the septum may be composed of myometrium or fibrous tissue. The uterine fundus is typically convex, but may be flat or slightly concave (<1 cm fundal cleft). Women with septate uterus have the highest incidence of reproductive complications. Differentiation between a septate and a bicornuate uterus is important because septate uteri are treated by using transvaginal hysteroscopic resection of the septum, whereas if surgery is possible and/or indicated for the bicornuate uterus, an abdominal approach is required to perform metroplasty.

Figure 5. Septate uterus.

Midline septum can be of variable length and can be muscular or fibrous (Fig. 6). In the diagram, the septum is shown as an extension of the uterine myometrium. Class VI (arcuate uterus) (Fig. 7) has a single uterine cavity with a convex or flat uterine fundus, the endometrial cavity, which demonstrates a small fundal cleft or impression (>1.5 cm). The outer contour of the uterus is convex or flat. This form is often considered a normal variant because it is not significantly associated with the increased risks of pregnancy

Figure 4. Bicornuate uterus. Note the partial fusion of the

lower uterine segment and persistently separated upper uterine segments. Of key importance is the prominent fundal cleft (>1 cm), which distinguishes the anomaly from septate uterus.

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Figure 6. Midline septate is thin and linear as expected in the fibrous type. Since, the composition of the septum varies, whether it is composed of muscle or fibrous tissue is not a means to distinguish septate from other forms of uterine anomalies.

Figure 7. Arcuate uterus mild-thickening of the midline fundal myometrium resulting in fundal cavity indentation but normal outer fundal contour. Some authors consider it a normal variant. It is not associated with an increased risk of obstetric/gynecologic complications.

OBSTETRICS AND GYNECOLOGY with a transverse fundal incision for reunification of the uterine cavity certainly improves the obstetric outcome in women with bicornuate uterus, who have suffered earlier pregnancy losses. CONCLUSION

Figure 8. DES-related anomaly.

to prevent miscarriage from 1945 to 1971. The drug was withdrawn once its teratogenic effects on the reproductive tracts of male and female fetuses were understood. The uterine anomaly is seen in the female offspring of as many as 15% of women exposed to DES during pregnancy. Affected female fetuses have a variety of abnormal findings that include uterine hypoplasia and a T-shaped uterine cavity. Patients also may have abnormal transverse ridges, hoods, stenoses of the cervix and adenosis of the vagina with increased risk of vaginal clear cell carcinoma. Imaging findings are pathognomonic for this anomaly. MANAGEMENT

Before Pregnancy The management of the uterine malformations before pregnancy comprises the surgical treatment if possible and necessary. In the bicornuate uterus, hysteroplasty is theoretically possible in case of symptomatic malformation.

Surgical Management It is important to rule out other causes of abortion prior to embarking on any corrective surgery for anomalies. Strassman utriculoplasty 1952 operation

Women with uterine anomalies have poorer reproductive outcomes and lower pregnancy rates with all conceptions. They are known to have a higher incidence of infertility, repeated first, second trimester spontaneous abortions, intrauterine growth retardation, fetal malpositions, preterm labor, prelabor preterm rupture of membranes and retained placenta. Early diagnosis and proper antenatal care is required to successfully manage a pregnancy with bicornuate uterus. SUGGESTED READING 1. Nahum GG. Uterine anomalies. How common are they, and what is their distribution among subtypes? J Reprod Med 1998;43(10):877-87. 2. Raga F, Bauset C, Remohi J, Bonilla-Musoles F, Simón C, Pellicer A. Reproductive impact of congenital Müllerian anomalies. Hum Reprod 1997;12(10):2277-81. 3. Poncelet C, Aissaoui F. Malformations utérines et reproduction. Gynecol Obset Fertil 2007;35:821-5. 4. Strassmann EO. Plastic unification of double uterus; a study of 123 collected and five personal cases. Am J Obstet Gynecol 1952;64(1):25-37. 5. Woelfer B, Salim R, Banerjee S, Elson J, Regan L, Jurkovic D. Reproductive outcomes in women with congenital uterine anomalies detected by three-dimensional ultrasound screening. Obstet Gynecol 2001;98(6):1099-103. 6. Martínez-Frías ML, Bermejo Sánchez E, Rodríguez-Pinilla E, Martínez Santana S, Paisán Grisolía L, Egüés Jimeno J, et al. Epidemiological aspects of children of women with bicornuate uterus. An Esp Pediatr 1998;48(2):159-62. 7. Hua M, Odibo AO, Longman RE, Macones GA, Roehl KA, Cahill AG. Congenital uterine anomalies and adverse pregnancy outcomes. Am J Obstet Gynecol 2011;205(6): 558.e1-5.

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Adding Estrogen Along with Progesterone as Luteal Phase Support, Enhances Outcomes in ART Cycles: A Randomised Control Study ARITRA PRADHAN*, SURABHI TOMAR SHARMA*, RIDHI KATHURIA†

ABSTRACT Human embryo implantation has a pivotal role in determining the success of assisted reproductive technology (ART). Receptivity of the uterus is dependent on the hormonal status of the endometrium at the time of implantation. Luteal phase supplementation (LPS), after controlled ovarian stimulation (COS) for IVF, has been a routine practice in IVF – embryo transfer (ET) because stimulated IVF cycles are associated with a defective luteal phase in almost all patients. There are controversial reports about adding oestrogen to progesterone supplementation as LPS. In the present study, the effect of adding oral estradiol to progesterone for luteal phase support was compared to progesterone alone. The results suggested that adding oral E2 improved the chemical and clinical pregnancy rates.

Keywords: Implantation, assisted reproductive technology, luteal phase supplementation, estradiol progesterone

he success rate of an IVF/ICSI cycle are of prime importance to a practitioner. These depend on various factors including oocyte quality and receptivity of endometrium.1 An important factor out of these is implantation. It has a pivotal role in determining the success of assisted reproductive technology (ART) because after the transfer of high quality embryos, the pregnancy rate may still be relatively low.2 Human embryo implantation is a three-stage process involving coordination between a receptive endometrium and a functional blastocyst.3 Receptivity of the uterus is dependent on the hormonal status of the endometrium at the time of implantation.1 Oestrogen causes proliferation of endometrial cells in the basal layer and increases progesterone receptors. Progesterone induces secretion from endometrial glandular cells and decidualization of the stromal layer.

*Assistant Professor †Resident Dept. of Obstetrics and Gynecology National Institute of Medical Sciences, Jaipur, Rajasthan Address for correspondence Dr Ridhi Kathuria C/O Vijay Nursing Home F - 24/25, Sector - 3, Rohini -110 085, New Delhi E-mail: ridhi.kathuria@yahoo.com

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Therefore adequate concentrations of these hormones are essential for adequate endometrial maturation before embryo implantation.1 Ovarian stimulation for IVF results in supraphysiological steroid levels and is associated with very low luteinizing hormone (LH) concentrations during the luteal phase.4 Luteal phase supplementation (LPS), after controlled ovarian stimulation (COS) for IVF, has been a routine practice in IVF – embryo transfer (ET) because stimulated IVF cycles are associated with a defective luteal phase in almost all patients.5,6 There exists a major controversy over the ideal LPS that can be used in ART cycles.7 Also the thoughts on the doses to be used, the duration and the time of starting and stopping it, vary widely.8 It is well established that luteal support with progesterone improves implantation in ART cycles.9 Under progesterone supplementation, however, it has been shown that mid-luteal estradiol (E2) levels decrease in a proportion of patients and that this might be associated with a concomitant decrease in pregnancy rates.10 There are controversial reports about adding oestrogen to progesterone supplementation as LPS.1,7,11-13 In the present study, the effect of adding oral estradiol to progesterone for luteal phase support was compared to progesterone alone.

OBSTETRICS AND GYNECOLOGY MATERIAL AND METHODS

phase support were discontinued.

In this prospective case control study, infertile women under 40 years old who were candidates for IVF/ICSI cycles at NIMS Fertility and Research Centre (Jaipur) were enrolled. The study was performed between the period of July 2013 to June 2014.

Statistical Analysis

Exclusion criteria consisted of age >40 years, polycystic ovary syndrome (PCOs), endometriosis, co-existing pathologies like fibroids or adhesion in uterus, and body mass index (BMI) more than 30 kg/m2 or less than 18 kg/m2. All patients signed an informed consent form. A long GnRH agonist and gonadotrophins protocol was used for pituitary suppression and ovarian stimulation. In this protocol, the women had first been down-regulated with a GnRH analogue which was administered 0.5 mL subcutaneously from the 21st day of the previous menstrual cycle. When pituitary suppression was achieved (on the second day of the menstrual cycle follicle-stimulating hormone (FSH) ≤5 IU/mL, LH ≤5 IU/mL, progesterone ≤1 ng/mL, estradiol ≤50 pg/mL), its dose was reduced to 0.25 mL, together with either 150-225 IU human menopausal gonadotropin or 150-225 IU recombinant FSH was administered intramuscularly from the 2nd day of the menstrual cycle daily. After 3 or more follicles had reached 18 mm in diameter, 10,000 IU human chorionic gonadotropin was used to induce ovulation. Oocytes were aspirated trans-vaginally with ultrasound guidance 35-36 hours post ovulation trigger. Then IVF and or ICSI was done. Uterine embryo transfer was performed 48-72 hours after oocyte retrieval. Serum beta hCG was checked two weeks after embryo transfer. Clinical pregnancy was defined as the presence of at least one gestational sac with detectable fetal heart activity by transvaginal sonography. For luteal phase support, patients were randomly divided into two groups: Group 1 (control) consisted of patients who received vaginal administration of progesterone supplementation 400 mg twice a day starting on the day after oocyte retrieval and continued until the tenth week if the chemical pregnancy test was positive (‘P’ group). In Group 2 (estradiol + progesterone group), 2 mg of estradiol valerate was added orally with progesterone (‘P + E2’ group). In both groups, when the pregnancy test was negative or pregnancy loss occurred, the drugs used for luteal

The online program ‘Graphpad Instat’ was used for analysis of data. Two-tailed t test was used. Results are interpreted as mean ± standard error (SE). ‘P’ value less than 0.05 was considered significant. RESULTS In this study, 100 women were selected and randomly studied as ‘P’ group (N = 50) receiving progesterone supplementation 400 mg twice a day and ‘P + E2’ group (N = 50) receiving 2 mg of estradiol valerate orally in addition to progesterone supplementation. The mean age of patients was 31.01 ± 0.70 in the control group and 32.29 ± 0.57 years in the estradiol group (P >0.05). There were no statistically significant differences between the two groups with respect to cause of infertility (Table 1 and Fig. 1) and type of infertility (primary or secondary). The mean duration of infertility was 5.42 ± 0.55 years in the control group and 6.31 ±1.37 years in the estradiol group, but this difference was not statistically significant (P >0.05). The mean number of retrieved oocytes, number of transferred embryos were however not different significantly, but the chemical and clinical pregnancy rate were significantly different between the two Table 1. Causes of Infertility in P and P+E2 Groups Causes of infertility

P group (N = 50)

P + E2 group ‘p’ value (N = 50)

Male factor

34 (68%)

30 (60%)

Female factor

10 (20%)

8 (16%)

Male + female

5 (10%)

12 (24%)

Unexplained

1 (2%)

Table 2. Chemical and Clinical Pregnancy Rates in P and P+E2 Groups Variable

P group (N = 50)

P + E2 group ‘p’ value (N = 50)

No. of retrieved oocytes

9.47 ± 0.67

7.65 ± 0.68

No. of transferred embryos

2.78 ± 0.15

2.91 ± 0.15

Chemical pregnancy rate (%)

16 (32%)

24 (48%)

Clinical pregnancy rate (%)

12 (24%)

22 (44%)

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OBSTETRICS AND GYNECOLOGY

P group P + E2 group

70 60

Use of GnRH agonists may be associated with decreased production of E2 and progesterone in the luteal phase, a reduction in the length of the luteal phase, and impairment of endogenous gonadotropin secretion caused by persistent pituitary suppression.15

50 40 30

34 30

20 10

12 5 1

0 Male factor

Female factor Male + Female Unexplained factor

Figure 1. Causes of infertility in P and P+E2 Groups

P group P + E2 group

40 35 30 24

15 10

9.47 7.67

2.78 2.91

0 No. of retrieved oocytes

No. of transfered embryos

Chemical pregnancy rates

Clinical pregnancy rates

Figure 2. outcome rates in P and P+E2 groups.

groups (Table 2 and Fig. 2). In the estradiol group, 24 out of 50 women had a positive β hCG test, 22 women had an intrauterine gestational sac with detectable fetal heart. In the ‘P’ group, 16 women had a positive β hCG test and 12 progressed to clinical pregnancy detected by sonography. DISCUSSION Many areas of LPS used in ART cycles remain controversial. One of the subjects of debate in this regard is adding E2 to progesterone. In the present study, the use of oral estradiol supplementation in combination with vaginal progesterone was evaluated and compared to progesterone alone during ART cycles where a long GnRH agonist protocol was used for controlled ovarian stimulation in all studied women. The results suggested that adding oral E2 improved the chemical and clinical pregnancy rates. It is accepted that luteal function is suppressed in IVF cycles using GnRH agonists. This compromised function could potentially be attributed to ovarian

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stimulation and the resultant altered hormone levels, the process of oocyte retrieval and direct effect of the GnRH agonist on the corpus luteum.14

Indian Journal of Clinical Practice, Vol. 25, No. 8, January 2015

There have been different clinical trials studying the effect of adding E2 to progesterone during LPS in ART cycles, these trials were different with regard to the type of estradiol (oral, transdermal), its dose (2 mg or 6 mg), type of COS used (long or short GnRH agonist, GnRH antagonist) and type of progesterone used (intramuscular, vaginal). Some studies showed a positive effect of adding E2 in ART cycles. Farhi et al. studied the effect of adding E2 to progesterone supplementation during the luteal phase in IVF cycles with different GnRH agonist protocols (short or long). Their results showed that patients who received E2 supplementation and were treated with the long GnRH analogue protocol had significantly higher pregnancy and implantation rates.11 In another study, Gorkemli et al. evaluated patients treated with a long ovulation induction protocol in two groups: group I used only 600 mg/day of progesterone vaginally and group II used 100 μg/day of transdermal oestradiol in addition to progesterone. They showed that adding estradiol to progesterone in ICSIET cycles may increase implantation and pregnancy rates.12 Other studies showed no benefits of adding E2. Engmann et al. evaluated the effect of E2 supplementation via the vaginal route on the overall probability of conception in subgroups of patients using the GnRH agonist suppression, GnRH antagonist, or microdose GnRH agonist protocol. Their findings suggested that the use of luteal phase vaginal E2 supplementation does not improve the overall clinical pregnancy rates but may increase the risk of biochemical miscarriage.1 Serna et al. evaluated the effect of transdermal E2 administered after embryo transfer on cycle outcome. They found no difference between these luteal phase supports.7 Although adding estradiol is a subject of debate in LPS, another controversy concerns the dose of estradiol. Lukaszuk et al. in their prospective clinical trial evaluated the influence of different E2 supplementation doses (2 and 6 mg daily) during the luteal phase on implantation and pregnancy rates in women undergoing ICSI cycle. In their findings, significantly higher implantation rate and pregnancy rate were found

OBSTETRICS AND GYNECOLOGY in patients who received low dose E2 supplementation compared with no E2 supplementation, but the best outcomes were found significantly in the group with high dose E2 supplementation. They suggested that for women undergoing a long GnRH analogue protocol, addition of a high dose of E2 to daily progesterone supplementation significantly improves the IVF-ET outcomes.16 Different doses of estradiol were not compared in the present study and this may be one of its limitations. In conclusion, the present study showed that the addition of oral estradiol with a dose of 2 mg daily to vaginal progesterone supplementation as luteal phase support enhances the chemical and clinical pregnancy rates of IVF/ICSI cycles. Further studies with a larger sample size and using different doses of estradiol are recommended. BIBLIOGRAPHY 1. Engmann L, DiLuigi A, Schmidt D, Benadiva C, Maier D, Nulsen J. The effect of luteal phase vaginal estradiol supplementation on the success of in vitro fertilization treatment: a prospective randomized study. Fertil Steril 2008;89:554-61. 2. Valbuena D, Jasper M, Remohí J, Pellicer A, Simón C. Ovarian stimulation and endometrial receptivity. Hum Reprod 1999;14:107-11. 3. Achache H, Revel A. Endometrial receptivity markers the journey to successful embryo implantation. Hum Reprod Update 2006;12:731-46. 4. Tavaniotou A, Albano C, Smitz J, Devroey P. Comparison

of LH concentrations in the early and mid-luteal phase in IVF cycles after treatment with HMG alone or in association with the GnRH antagonist Cetrorelix. Hum Reprod 2001;16:663-7. 5. Kolibianakis EM, Devroey P. The luteal phase after ovarian stimulation. Reprod Biomed Online 2002;5:26-35. 6. Pabuccu R, Akar ME. Luteal phase support in assisted reproductive technology. Curr Opin Obstet Gynecol 2005;17:277-81. 7. Serna J, Cholquevilque JL, Cela V, Martínez-Salazar J, Requena A, Garcia-Velasco JA. Estradiol supplementation during the luteal phase of IVF-ICSI patients: a randomized controlled trial Fertil Steril 2008;90:2190-5. 8. Aboulghar M. Luteal support in reproduction: when, what and how? Curr Opin Obstet Gynecol 2009;21:279-84. 9. Pritts EA, Atwood AK. Luteal phase support in infertility treatment: a meta-analysis of the randomized trials. Hum Reprod 2002;17:2287-99. 10. Sharara FI, McClamrock HD. Ratio of oestradiol concentration on the day of human chorionic gonadotrophin administration to mid-luteal oestradiol concentration is predictive of in-vitro fertilization outcome. Hum Reprod 1999;14:2777-82. 11. Farhi J, Weissman A, Steinfeld Z, Shorer M, Nahum H, Levran D. Estradiol supplementation during the luteal phase may improve the pregnancy rate in patients undergoing in vitro fertilization – embryo transfer cycles. Fertil Steril 2000;73:761-6. 12. Gorkemli H, Ak D, Akyurek C, Aktan M, Duman S. Comparison of pregnancy outcomes of progesterone or progesterone + estradiol for luteal phase support in ICSIET cycles. Gynecol Obstet Invest 2004;58:140-4.

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Two Steroid Courses Safe After Preterm Membrane Rupture Two courses of antenatal corticosteroids can be administered to pregnant women with preterm premature rupture of membranes (PROM) without increasing the risk for neonatal sepsis, according to an article published online October 6 in Obstetrics & Gynecology. Since 2000, the recommendation from the Eunice Kennedy Shriver National Institute of Child Health and Development has been to limit administration to a single course of steroids. However, the data supporting that recommendation are thin, according to Cynthia Guamfi-Bannerman, MD, and Moeun Son, MD, from the Department of Obstetrics and Gynecology at Columbia University Medical Center, New York City.

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PEDIATRICS

Management of Dry Cough in Pediatric Population: Role of Pholcodine SRIDHAR GANAPATHY

ABSTRACT Cough is one of the commonest manifestations of respiratory tract infections and is a frequent reason for children visit to the primary care. Although etiology and pathogenesis of cough vary widely, early diagnosis, as well as appropriate treatment for the same is crucial for effective clinical outcome. In children, dry cough is a frequent complaint and acute viral infection is the commonest cause of cough. Dry cough, which is usually associated with distress and discomfort could be symptomatically treated with antitussive preparations. Codeine, pholcodine and dextromethorphan are commonly used antitussive agents. Although, the efficacy of codeine has never been questioned, it is not recommended in pediatric population. In this context, the use of pholcodine or dextromethorphan is considered safe. The objective of this review is to highlight the impact of cough in children, pathogenesis of cough, types of cough and management options. The article also describes the current evidences evaluating the comparative safety and efficacy of pholcodine-based formulations with other antitussive formulations in the treatment of dry cough in children.

Keywords: Dry cough, children, pholcodine, codeine, dextromethorphan

n children, cough is the most frequent symptom that needs presentation to general practitioners and persistent cough is one of the most common complaints for which children visit pediatricians for further investigation and treatment.1

Although, cough can be the only presenting symptom of a serious respiratory or systemic illness, ignoring cough can lead to progression of the underlying disease and increased morbidity.1,2 It has been reported that cough occurs in about 35% of preschool children in any given month.3 In children, chronic cough is also associated with a significant burden of recurrent doctor visits and parental stress. In an epidemiological study evaluating the burden of persistent cough, it was observed that >80% of children studied have had â&#x2030;Ľ5 consultations for a chronic cough during the 12-month period.2

Consultant Pediatrician Shri Siddhi Vinayak Clinic, Mumbai Address for correspondence Dr Sridhar Ganapathy Visiting Pediatrician and Pediatric Sleep Consultant Shri Siddhi Vinayak Clinic Guru Nanak Hospital, Janani Hospital, Mumbai, Maharastra E-mail: sridhar.ganapathy@rediffmail.com

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PATHOGENESIS OF COUGH Cough is an important protective reflex that clears excessive secretions and airway debris from the respiratory tract and prevents entry of particulate matter or foreign bodies into the airways.4 Usually, cough is initiated by stimulation of receptors located in the respiratory tract from the larynx to the segmental bronchi.4 Sensitization of the cough reflex through several mechanical and inflammatory changes in the airways and/or inhalation of mechanical and chemical irritants initiate an impulse. This impulse travels via afferent nerves (primarily vagus) to the cough centers in the medulla oblongata and pons, and by two-way communication with higher centers to the brain cortex. Hence, cough can be caused voluntarily and involuntarily.5 TYPES OF PEDIATRIC COUGH Pediatric cough can be categorized based on the duration of cough, type of an underlying disease or quality of cough (Fig. 1).6 Based on the duration, cough in children can be divided into three categories: Acute cough that lasts 2 weeks or less, protracted acute cough that lasts 2-4 weeks and chronic cough that persists for more than 4 weeks. Based on underlying disease or process, cough in children can be categorized as expected cough (in which the presence of cough is

PEDIATRICS

Cough in children

Cough duration • Acute cough (<2 weeks) • Protracted acute cough (2-4 weeks) • Chronic cough (>4 weeks)

Underlying disease or Quality of cough process • Classically • Normal or expected recognized cough cough • Dry cough vs • Specific cough wet or productive • Nonspecific cough cough • Protracted bronchitis

Figure 1. Different types of cough in children.

expected; e.g., after acute respiratory tract infection), specific cough (the cause of cough is evident from coexisting signs and symptoms; e.g., bronchial asthma) and nonspecific cough (which is commonly dry in nature with no identifiable respiratory disease or known etiology).6 Classically recognized cough types usually have certain characteristics pointing to specific etiologies in children. These include barking or brassy cough (croup, tracheomalacia, habit cough), honking (psychogenic cough), paroxysmal with or without inspiratory ’whoop‘ (pertussis and parapertussis), staccato (Chlamydia infection in infants), cough productive of casts (plastic bronchitis/asthma) and chronic wet cough in mornings only (suppurative lung disease).6 In children with dry cough, airway secretions are not absent. They possibly present with minimal secretions. Furthermore, dry cough may become wet in children, if airway secretions increase.6 ETIOLOGY OF CHRONIC COUGH Several clinical and epidemiological studies have shown that causes of chronic cough differ in children compared to adults.7 In children, most common causes of chronic cough include post-viral cough, asthma and environment pollution, whereas less common causes of chronic cough include infections (Chlamydia, pertussis and tuberculosis), upper airway cough syndrome or postnasal drip, foreign body, gastroesophageal reflux disease and habit or psychogenic cough.8

Post-viral Cough The term ‘post-viral cough’ refers to the presence of cough after acute viral respiratory infection. It has been estimated that symptomatic upper respiratory tract infection with cough occurs typically about 7-10 times/ year in school children.1

Although post-viral cough usually goes away within 3 weeks, atypical lower respiratory tract infections due to species of Mycoplasma, Bordetella and Chlamydia and viruses (cytomegalovirus, rous sarcoma virus, adenovirus, etc.) can lead to chronic cough.5

Asthma Asthma is also a common cause of chronic cough in pediatric population. Although, cough is a common symptom of asthma in children, very few asthmatic children present cough as the sole symptom. Cough associated with asthma is usually dry in nature and often worsens at night.5

Environment Pollution Environmental factors as well as inhaled allergens are also represented as the main causes of chronic cough in children. Among environment pollutants, most significant cause of cough is being a passive smoker, as it can increase the chances of respiratory infections among children. Passive smoking may also increase the chances of asthma and other reactive diseases. Compared to paternal smoking, maternal smoking habits are far significantly associated with cough in children. Observation of improvement after avoiding child from exposure to potential allergens for at least 2 weeks may be helpful in diagnosing allergic cough.5 MANAGEMENT OF DRY COUGH IN CHILDREN Initial steps in the management of chronic cough in children are to exclude serious underlying illness through systemic approach and to establish the cause of cough.9 The management of specific etiologies of cough in children that encompass the entire spectrum of pediatric pulmonology is beyond the scope of this article. Irrespective of the cause of cough, whenever possible, consider eliminating the exposure to cigarette smoke.10 In children with nonspecific cough and risk factors for asthma, a short trial of anti-asthma medications may be warranted. Children should always be re-evaluated in 2-4 weeks of diagnostic trial of anti-asthma medication. If trial fails to show benefit, the anti-asthma medications should be discontinued.10 ROLE OF COUGH SUPPRESSANTS: FOCUS ON PHOLCODINE Antitussives (cough suppressants to prevent, control or eliminate cough) have a specific role in the management of dry cough in children. They are indicated when cough

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is no longer serving as useful in clearing the airways and ideally when cough disturbs the quality-of-life of children, including disturbance of sleep and feed.8 Antitussive therapy is often indicated for post-viral cough, allergic dry cough, post-nasal drip, whooping cough, habit cough and disturbing cough.8,9 Several antitussive agents are available in the market. Among these, codeine, pholcodine and dextromethorphan are the most commonly used agents. Use of pholcodine or dextromethorphan is considered safe in this context.8 However, it is important to note that dextromethorphan may cause serotonin syndrome when combined with monoamine oxidase inhibitor, such as linezolid or with methylphenidate, which is used in children with attention deficit hyperactivity disorder.11 In addition, dextromethorphan is quite often used among younger adolescents for recreational purpose, which is referred as robo-tripping.12,13 Pholcodine, a codeine derivative, is a centrally-acting antitussive agent. It is considered as an effective and safe antitussive agent in the treatment of dry cough in children. Although, animal studies have reported that pholcodine has depressant action on respiratory and cardiovascular systems, the same has not been reported in humans at therapeutic doses. In humans, unlike codeine, pholcodine is not metabolized to morphine. It gets metabolized and is eliminated slowly, and thereby considered as a safe drug in children and adults.14 Pholcodine has a longer plasma half-life (32-43 hours), which confers longer duration of action, less frequent dosing and greater patient compliance. On the other hand, dextromethorphan has a shorter half-life of 2.7-3.3 hours, and therefore requires more frequent dosing. It has been reported that dextromethorphan has abuse potential, while no significant liability has been observed with pholcodine on prolonged use.15 The safety and efficacy of pholcodine have been evaluated in two open-labeled, prospective, multicenter, randomized trials conducted in Indian population.14,16

Study 1: Pholcodine vs Dextromethorphan and Codeine Tripathi et al16 conducted a study with aim to compare the efficacy and safety of three formulations: Pholcodine and promethazine (CS1, n = 132), dextromethorphan and chlorpheniramine (CS2, n = 131), and codeine and chlorpheniramine (CS3, n = 109). A total of 418 children aged between 2 and 12 years suffering from dry cough associated with viral upper respiratory tract infections were included in the study. Of whom, 372 patients

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Time taken for complete dry cough relief (hours)

PEDIATRICS

132

140 120

p < 0.01 123.8

107

100 80 60 40 20 0

CS1

CS2 Groups

CS3

Figure 2. Time taken for complete dry cough relief (in hours) in all the three groups.

had completed the study. All the patients received respective treatment for a maximum period of 7 days. Findings of the study showed a significant reduction in cough frequency on Days 3 and 7 (p < 0.0001) compared to the baseline with all three formulations with comparable efficacy (p > 0.05). The change in the mean cough frequency was higher with CS1 (12.7) compared to that with CS2 (12.2) and CS3 (10.9). The frequency of night awakenings reduced with all the three formulations and was similar (p > 0.05). Mean frequency changes with night awakenings were 2.6 with CS1, 2.7 with CS2 and 2.3 with CS3. Playing activities, appetite and day-time behavior of the children improved with all the three formulations. However, time taken to provide complete symptomatic relief and number of doses to attain the same were comparatively less with CS1 than CS2 and CS3. The time taken to afford complete symptomatic relief from cough was 107 hours in CS1 as compared to 132 and 123.8 hours in CS2 and CS3 formulations, respectively (p < 0.01, Fig. 2). The total number of doses required to attain complete relief from cough was less with CS1 compared to CS2 and CS3 (14.1 ± 0.7 for CS1 vs 21.8 ± 1 for CS2 and 15.8 ± 0.8 for CS3, p < 0.05). The authors concluded that combination of pholcodine and promethazine was comparable to that of the other two formulations in terms of efficacy, tolerability and safety.

Study 2: Pholcodine vs Noscapine Mukaddam et al14 compared safety and efficacy of antitussive combination of pholcodine and promethazine with noscapine, ammonium chloride and sodium citrate in the treatment of children belonging to age group 2-12 years and those suffering from dry cough due to viral upper respiratory tract infections. The study had two treatment arms: CS1—pholcodine

PEDIATRICS Table 1. Global Assessment of Efficacy and Tolerability CS1

CS2

N (%)

P value

Global efficacy assessment by investigator Poor

0 (0.0)

Satisfactory

4 (5.48)

11 (14.29)

Good

9 (12.33)

32 (41.56)

Very good

21 (28.77)

10 (12.99)

Excellent

39 (53.42)

24 (31.17)

<0.001

Global tolerability assessment by parents Poor Satisfactory

0 (0.0)

2 (2.60)

6 (8.22)

20 (25.97)

Good

16 (21.92)

22 (28.57)

Very good

30 (41.10)

17 (22.08)

Excellent

21 (28.77)

16 (20.78)

1.5 mg + promethazine hydrochloride 1.5 mg (n = 94), and CS2窶馬oscapine 1.83 mg + ammonium chloride 7 mg + sodium citrate 0.67 mg (n = 99). Results of the study showed that both CS1 and CS2 showed similar efficacy in terms of clinical response and cough frequency, which are considered as primary endpoints. Clinical response was defined as a reduction in cough score by 75% within 7 days from the baseline score. Duration taken to achieve complete relief from cough was 4.81 ﾂｱ 1.09 days with CS1 compared to 5.16 ﾂｱ 1.14 days with CS2 treatment arm. The mean change from baseline for nocturnal awakenings due to cough was comparable between the two study arms. The global assessment of efficacy and tolerability was favorable for CS1 group, as more patients belonging to CS1 group reported the treatment as excellent and effective compared to patients from CS2 arm (Table 1). Adverse events of the drug, parameters such as vital signs and physical examination, were considered. The CS1 group did not report any adverse events, while CS2 group reported two adverse events, drowsiness (0.96%) and passage of hard stools (0.96%). The study concluded that efficacy of CS1 was comparable with CS2 with better tolerability profile. The combination drugs in CS1 were effective in providing complete relief from cough, reduce the distressing cough frequency and nocturnal awakenings in children affected with dry cough. CONCLUSION Cough is one of the commonest manifestations of respiratory tract infections and is a frequent reason

0.005

for visit to the primary care. Early diagnosis and appropriate treatment for the same are crucial for effective clinical outcome. In children, acute viral infections being the commonest cause of cough present usually as a dry cough. Dry cough, which is normally associated with distress and discomfort could be symptomatically treated with antitussive preparations. The randomized trials conducted in Indian population have confirmed that safety, efficacy and tolerability of antitussive combinations containing pholcodine are noninferior to other antitussive combinations. Furthermore, pholcodine-containing formulations have better side-effect profile. Hence, cough and cold preparations containing pholcodine could be considered a safe option in the treatment of dry cough in children. However, more extensive research is needed to establish combinations with pholcodine as the standard option for treatment of nonspecific dry cough in children.

Acknowledgments Received scientific help from Abbott Healthcare.

REFERENCES 1. Shields MD, Thavagnanam S. The difficult coughing child: prolonged acute cough in children. Cough 2013;9(1):11. 2. Marchant JM, Newcombe PA, Juniper EF, Sheffield JK, Stathis SL, Chang AB. What is the burden of chronic cough for families? Chest 2008;134(2):303-9. 3. Marchant JM, Masters IB, Taylor SM, Cox NC, Seymour GJ, Chang AB. Evaluation and outcome of young children with chronic cough. Chest 2006;129(5):1132-41.

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PEDIATRICS 4. Goldsobel AB, Chipps BE. Cough in the pediatric population. J Pediatr 2010;156(3):352-8. 5. Ghanaie RM, Fahimzad SA, Karimi A. Management of chronic cough in children. Arch Pediatr Infect Dis 2013;1(3):136-43. 6. Chang AB, Landau LI, Van Asperen PP, Glasgow NJ, Robertson CF, Marchant JM, et al.; Thoracic Society of Australia and New Zealand. Cough in children: definitions and clinical evaluation. Med J Aust 2006;184(8):398-403. 7. Chang AB. Cough: Are children really different to adults? Cough 2005;1:7. 8. Subramanyam L, Balachandran A. Management of cough. IJPP 2010;12(1):17-22. 9. de Jongste JC, Shields MD. Cough. 2: Chronic cough in children. Thorax 2003;58(11):998-1003. 10. Chang AB, Glomb WB. Guidelines for evaluating chronic cough in pediatrics: ACCP evidence-based clinical practice guidelines. Chest 2006;129(1 Suppl): 260S-283S. 11. Iqbal MM, Basil MJ, Kaplan J, Iqbal MT. Overview of serotonin syndrome. Ann Clin Psychiatry 2012;24(4):310-8.

12. Chary M, Park EH, McKenzie A, Sun J, Manini AF, Genes N. Signs & Symptoms of Dextromethorphan Exposure from YouTube. PLoS One 2014;9(2):e82452. 13. Boyer EW. Dextromethorphan abuse. Pediatr Emerg Care 2004;20(12):858-63. 14. Mukaddam Q, Khandeparkar P, Naik M, Prabhu M. A randomized, open label, multicentre study to evaluate the safety and efficacy of cough mixture CS1 (pholcodeine and promethazine-tixylix) versus CS2 (noscapine, ammonium chloride, sodium citrate) in treatment of children with dry cough. Ind Med Gaz 2012:p.237-8. 15. Dollery CT, Boobis AR, Burley DM. Therapeutic drugs. In: Therapeutic Drugs. 2nd edition, Dollery CT (Ed.), Churchill Livingstone: Edinburgh 1999:p.115-6. 16. Tripathi RK, Langade DG. Efficacy, safety and tolerability of pholcodeine and promethazine cough formulation in children suffering from dry cough: An open, prospective, comparative, multi-centre, randomized, controlled, parallel group, three-arm study. Indian Pract 2009;62(5):280-9.

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WHO Recommends Removal of Serotype 2 Poliovirus from OPV The World Health Organization's strategy for eradicating polio will remove serotype 2 poliovirus from the oral polio vaccine (OPV) because this component causes many of the few new cases, according to a new clinical report published online December 29 in Pediatrics. OPV consists of three serotypes of attenuated virus. Wild serotype 2 was last detected more than a decade ago, and wild serotype 3 has not been seen since 2012.

Early CUS in Premature Infants Harmful A new study in Pediatrics has questioned the value of early cranial ultrasonography (CUS) in premature infants born at less than 30 weeks' gestational age. In the largest study of its kind, researchers found that late CUS and near-term brain MRI were independently associated with neurodevelopmental impairment (NDI), independent of early CUS findings and other perinatal or neonatal factors.

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PHARMACOLOGY

Oxidative Stress in Hypercholesterolemic Patients and Antioxidant Status of Fluvastatin Md. ABU NASAR*, TARANNUM F SUBHANI†

ABSTRACT This study was an attempt to establish the extent of increased oxidative stress in hypercholesterolemic patients and to evaluate the effect of fluvastatin on the oxidative stress and antioxidant status. The blood samples of 15 subjects (age- and sex-matched) each from Group I (healthy subjects), Group II (hypercholesterolemic patients with fluvastatin treatment) and Group III (hypercholesterolemic patients without any hypolipidemic drug) were taken and centrifuged for separation of plasma. Plasma was used for the estimation of vitamin E. The separated cells were washed thrice with 0.9 % w/v cold normal saline and used for the assay of percentage hemolysis of red blood cells (RBCs), malondialdehyde, superoxide dismutase and hemoglobin. Levels of oxidative stress were higher in hypercholesterolemic in comparison to control and fluvastatin group. Levels of antioxidants were higher in fluvastatin group than hypercholesterolemic but were lower than controls. From these findings, it was concluded that there is an increase in oxidative stress in hypercholesterolemia, but it decreased significantly after 2 months of fluvastatin therapy and antioxidant status also improves in patients taking fluvastatin.

Keywords: Fluvastatin, oxidative stress, antioxidant effects, hypercholesterolemic patients

he statins like fluvastatin significantly reduce cholesterol synthesis through inhibition of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and are widely prescribed for hyperlipidemia to reduce the risk of atherosclerotic complications.1 Their efficacy in reducing cardiovascular morbidity and mortality has been demonstrated in large intervention trials.1 However, debate continues as to whether the beneficial effects of statins can be ascribed purely to their ability to reduce cholesterol or whether additional actions, independent of cholesterol-lowering, play a significant role.1-3 Studies have shown that oxidized low-density lipoprotein (LDL) is a major correlate of oxidative stress in hypercholesterolemic patients and statins may reduce oxidative stress by reducing enhanced plasma levels of

*Assistant

Professor Dept. of Biochemistry Nalanda Medical College, Patna, Bihar †Dept. of Biochemistry Hind Institute of Medical Sciences, Sitapur, Uttar Pradesh Address for correspondence Dr Md. Abu Nasar Assistant Professor Dept. of Biochemistry Nalanda Medical College, Patna - 800 026, Bihar E-mail: dmabu_nasar@rediffmail.com

LDL, which are more susceptible to peroxidation in hypercholesterolemia and change the LDL structure, making them more resistant to peroxidation.1,4,5 Some studies have further shown that statins may also inhibit NAD(P)H oxidase, thus decreasing the generation of reactive oxygen species (ROS), thereby adding or synergizing biological effects of antioxidants.4,6 Some studies have also shown that statins or their metabolites may act as antioxidants, directly or indirectly by removing ‘aged LDL’, which is more prone to oxidation from the circulation.7 On the basis of these findings, it is evident that among their properties statins also possess antioxidant activities.8-9 Therefore, the aim of the present investigation was to evaluate the scientific evidence of fluvastatin for such an effect and its possible clinical relevance. The antioxidant effect of statins contribute to inhibition of atherogenesis, stabilization of atherosclerotic plaque, inhibition of myocardial hypertrophy and remodeling and modulation of vascular tone.6 Based on these arguments, which formed the backbone of this study an attempt was made to find out if there really was an increased oxidative stress in hypercholesterolemics and was it relatively decreased following fluvastatin therapy when compared to normal individuals. In this study, the levels of malondialdehyde (MDA), percentage hemolysis and superoxide dismutase (SOD)

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PHARMACOLOGY in red blood cells and vitamin E in plasma were measured. Red blood cells were chosen as they are well-known to be subject to increased hazards of free radical damage. Moreover, these cells have a finite life span in circulation and their sequestration and disposal by macrophages may be related to the extent of peroxidative damage caused to their membrane lipids, cytoskeletal proteins and enzymes. EXPERIMENTAL

Study Population This study was conducted on three groups of 15 subjects each in the age group of 40-70 years. Both male and female subjects were taken in all groups. ÂÂ

ÂÂ

Group I: Consisted of 15 healthy subjects (8 males and 7 females) between the age group 40-70 years having normal lipid profile (control group). Group II: Consisted of 15 patients (8 males and 7 females) who were already diagnosed as hypercholesterolemic and who were given treatment with HMG-CoA reductase inhibitors (fluvastatin) for minimum of 2 months with a minimum dosage of l0 mg/day of fluvastatin. Treatment with simvastatin was given only in this group in order to compare the results with control and hypercholesterolemic group without any hypolipidemic drug. Group III: Consisted of 15 hypercholesterolemic patients (8 males and 7 females) diagnosed recently, but were not taking any of the lipid-lowering agents (hypercholesterolemic group).

Selection of Cases The test Group II and III for this study consisting of 15 individuals in each group were taken from the following hospitals in Patna, Bihar. ÂÂ

Nalanda Medical College and Hospital, Patna, Bihar

ÂÂ

Patna Medical College and Hospital, Patna, Bihar

ÂÂ

Rajeshwar Hospital, Patna, Bihar

ÂÂ

Alam Clinic, Patna, Bihar

ÂÂ

Care Hospital, Patna, Bihar.

While choosing the subjects for the test and control groups, care was taken to eliminate those with habits like smoking, tobacco chewing, alcohol consumption and also those with history of chronic inflammatory diseases like tuberculosis, rheumatoid arthritis, diabetes mellitus and malignancy all of which play a vital role in contributing to oxidative stress injury. Approval to carry out these studies on human subjects was obtained

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from Institutional Clinical Ethics Committee of Nalanda Medical College, Patna, Bihar and their guidelines were followed for the studies.

Sample Collection Five milliliter of venous blood was collected in ethylenediamine tetra acetic acid (EDTA) containers from the median cubital vein or basilic vein of the each study subjects under strict aseptic conditions. The blood samples were centrifuged at 3,000 rpm for 10 minutes within 3 hours of collection. Plasma was separated and used for the estimation of vitamin E. The separated cells were washed thrice with 0.9% w/v 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 refrigerator (4-5°C) and was used for the assay of: ÂÂ

Percentage hemolysis of RBCs at 0 and 2 hours (which represented before and after incubation with hydrogen peroxide, respectively).

ÂÂ

Malondialdehyde (MDA).

ÂÂ

Superoxide dismutase (SOD).

ÂÂ

Hemoglobin (Hb).

Lipid Peroxidation (MDA) Red cell lipid peroxidation was studied as thiobarbituric acid (TBA) reaction products. The method of Stocks and Dormandy was followed with certain modifications.10 The sample under test was heated with TBA at low pH and a pink chromogen, allegedly a (TBA)2 - MDA adduct was measured spectrophotometrically at wavelength of 535 nm.11 One milliliter of erythrocyte suspension was added to 8.5 mL of 0.9% w/v of normal saline and mixed well. Then 0.5 mL of 0.44 M H2O2 was added. From this mixture, 2.5 mL of aliquot was immediately taken, to which 1 mL of 28% trichloroacetic acid (TCA) in 0.1 M sodium meta-arsenite was added. This was mixed well and allowed to stand for 10 minutes, after which it was centrifuged. Three milliliter of the supernatant was then taken, to which 1 mL of 1% TBA in 50 mM NaOH was added. This was then kept in a boiling water bath for 15 minutes and later immediately cooled under tap water. The pink chromogen was determined spectrophotometrically at the wavelength of 535 nm. Values were expressed as nanomoles of MDA formed per dL of RBC, taking the molar extinction coefficient as 1.56 × 105.10 MDA (nanomoles/100 mL of RBC) was determined using the equation: AT × 109 × 100 × DF × V MDA = ε

PHARMACOLOGY Where AT is the absorbance of test sample, DF is dilution factor, V is volume RBC suspension and є is the extension coefficient.

Oxidative Hemolysis of RBCs or Percentage Hemolysis of RBCs Oxidative hemolysis of erythrocytes was measured at 0 and 2 hours, which indicated before and after 2 hours incubation with H2O2, respectively by the method of Kartha and Krishnamurthy.12 Principle of this method is based on the fact that an accelerated form of nonenzymic breakdown can be induced in red cells on exposure to H2O2.10 One milliliter of RBC suspension was added to 8.5 mL of 0.9% w/v of normal saline and mixed well. Then 0.5 mL of 0.44 M H2O2 was added and incubated at 37°C. Immediately, aliquots of 0.5 mL each were withdrawn and put into two different centrifuge tubes labeled as ‘saline’ and ‘water’, respectively. To the centrifuge tube labeled ‘saline’, 4.5 mL of 0.9% w/v of normal saline was added and centrifuged. The supernatant was then separated and its absorbance (optical density) was determined at 520 nm in a colorimeter. This represented nonhemolyzed (NH) RBCs at 0 hour or before incubation with H2O2. To the centrifuge tube labeled ‘water’, 4.5 mL of distilled H2O was added and centrifuged. The supernatant was then separated and its optical density was determined at 520 nm in a colorimeter. This represented complete hemolysis (CH) of RBCs at 0 hour or before incubation with H2O2.

A correction was made for carotenoids after adding FeCl3. Reading was taken at 520 nm, exactly after 90 second.13,14 One mililliter of plasma was thoroughly mixed with 1 ML of redistilled 95% ethanol in a 15 mL stoppered tube. Three mililliter of petroleum ether was then added and the tube was shaken vigorously for 3 minutes. This was then centrifuged and 2 mL of clear supernatant was transferred to a clear dry cuvette. The optical density was measured at 450 nm in a colorimeter for carotenes, taking petroleum ether as blank. Petroleum ether was then evaporated off at room temperature and the residue was dissolved in 1 mL chloroform. One mL of 95% ethanol was then added followed by 1 mL of 0.2 % a, a- dipyridyl and 0.1 mL of 0.1 % FeCl3. Exactly after 1.5 minutes, absorbance was measured at 520 nm in a colorimeter. Concentration of vitamin E (mg/L) of plasma was determined using the equation: AT - AC C= AS Where AT, AC and AS are absorbance of test, carotene and standard sample, respectively.

Superoxide Dismutase The method of Beauchamp and Fridovich was followed for measurement of SOD. The enzyme SOD catalyzes the reaction: O2- + O2- + 2H+

[SOD]

2H2O2

The above procedure was again repeated after 2 hours incubation with H2O2 at 37°C. The centrifuge tubes labeled ‘saline’ and ‘water’ now represented NH and CH RBCs at 2 hours or after incubation with H2O2.

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 for the assay of SOD.15

Percentage hemolysis of RBCs at 0 hour and 2 hours was determined using the equation:

Preparation of Hemolysate

Hemolysis (%) =

O.D of NH (saline) O.D of CH (water)

× 100

Vitamin E (a-tocopherol) Plasma vitamin E was measured using the Emmorie Engel reaction. Emmorie Engel reaction is based on the reduction of ferric to ferrous ions by tocopherols, which then forms a red complex with a, a- dipyridyl. Tocopherol and carotenes were extracted into petroleum ether and the extinction at 450 nm was measured.

This was done by the method of McCord and Fridovich.16 To 1 mL of erythrocytes (washed with 0.9% w/v of normal saline), 1 mL of deionised water was added to lyse the cells. To this, 0.5 mL of distilled ethanol followed by 0.3 mL of chloroform was added, mixed well and allowed to stand for 15 minutes. Now added 0.2 mL of H2O and centrifuged at 4°C. 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 K-PO4- buffer. This was the final diluted hemolysate that was used in the procedure

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PHARMACOLOGY 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 K-PO4- 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’ 2.9 mL of same reaction mixture with NBT and 0.1 mL of K-PO4- 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 K-PO4- buffer (pH 7.8/0.05 M) was added. Each of the above parameters was now taken in a 10 mL beaker. The beakers were kept in an aluminium foil lined box fitted with a 15 W fluorescent lamp for 10 minutes. The absorbance was measured at wavelength of 560 nm in a spectrophotometer for all the four beakers. One unit of SOD activity was taken as that producing 50% inhibition of NBT reduction. The values were expressed as units per gm Hb. It was calculated using the equation: Unit/dL SOD (x) = SOD activity (units/g Hb) =

C-T ½C X Hb

3 0.5

2 0.1

100 0.1

[Units/g Hb of SOD]

Where X is units/dL SOD, C and T are absorbance of control and test, respectively.

Estimation of Hemoglobin The hemoglobin content of erythrocytes was determined by the cyanmethemoglobin method.17 Hemoglobin was treated with a reagent containing potassium ferricyanide, potassium cyanide and potassium dihydrogen phosphate (Drabkins Reagent). The ferricyanide oxidizes hemoglobin to methemoglobin, which is converted to cyanmethemoglobin by the cyanide. Absorbance was measured at 540 nm in a colorimeter. 20 mL of RBC suspension was added to 4 mL of ferricyanide reagent and allowed to stand for 4 minutes. The absorbance was measured at 540 nm against a reagent blank in a colorimeter. The absorbance of the standard solution was measured by directly taking 4 mL of the standard cyanmethemoglobin solution (60 mg/dL).18

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Hemoglobin (g/dL) was determined using the equation: Hemoglobin (g/dL) =

AT × dilution factor X AS conc. of std. (mg/dL) 1,000

Where AT and AS are absorbance of test and standard respectively.

Statistical Analysis All the biochemical parameters were compared using Fishers F test for analysis of variance (ANOVA) except hemolysis. Students paired t-test was used for hemolysis (0 hour and 2 hours). The statistical software “SPSS version 11” (statistical package for social sciences) was used for this purpose. RESULTS AND DISCUSSION In this study, the products of lipid peroxidation, hemolysis of RBCs and antioxidant levels were compared between those having high cholesterol level, those who were on treatment with fluvastatin for a minimum of 2 months (minimum dosage of 10 mg/day) and those who were normal individuals taken as controls having normal lipid profile and of the same age group. Free oxygen radicals and insufficient antioxidant enzymes have been implicated in the pathogenesis of hypercholesterolemia.2,4,19,20 Statins have been used effectively for the treatment of hypercholesterolemia.2,20,21 These facts formed the basis of this study i.e., to investigate the antioxidant system and oxidative stress in hypercholesterolemic patients as well as in patients who were treated with fluvastatin for a minimum of 2 months. The mean total cholesterol levels of the three groups are given in Table 1. In patients taking fluvastatin, the mean total cholesterol reduced after 2 months of treatment (246.66 ± 8.54 mg/dL) as compared to hypercholesterolemic patients (325.33 ± 11.23 mg/dL). Table 1. Mean Total Cholesterol Levels of the Three Groups (Control, Fluvastatin and Hypercholesterolemic) Group

Mean total cholesterol level (mg/dL)a

Control

161.25 ± 5.43

After minimum 2 months of fluvastatin therapy

246.66 ± 8.54

Hypercholesterolemic

325.33 ± 11.23

N = No. of subjects;

aMean

± SD; N = 15, SD = Standard deviation.

PHARMACOLOGY RBC Malondialdehyde As a measure of oxidative stress, MDA the endproduct of lipid peroxidation was estimated by the TBA method. RBC MDA levels were highest in hypercholesterolemic group (742.67 ± 74.10 μmol/L) and lowest in control group (545.63 ± 48.03 μmol/L). The values were statistically highly significant (p = 0.001) when hypercholesterolemic group was compared with control group and statistically significant (p = 0.034) when control group was compared with fluvastatin group as indicated in Table 2. High level of MDA in hypercholesterolemic group suggested increase oxidative stress in patients of hypercholesterolemia. Its relatively lower level in fluvastatin group suggested decreased oxidative stress. These findings further favor antioxidant properties of statins like fluvastatin.2

Percentage Hemolysis of RBCs and Vitamin E Percentage hemolysis of RBCs was measured as an indicator of damage to RBC membrane as a result of oxidative stress. Amongst the antioxidants, vitamin E was chosen because, despite its low molar concentration in membranes, it effectively serves as the major lipid-soluble, chain-breaking antioxidant.24 This study has shown increased hemolysis of RBCs in the hypercholesterolemic group (4.52 ± 1.06%) as compared to fluvastatin (2.48 ± 0.67%) and control groups (1.69 ± 1.04%), but in fluvastatin group it was more than control but less than hypercholesterolemic group, both before (2.48 ± 0.67%) and after incubation (3.52 ± 0.81%) with hydrogen peroxide (Table 3). The values were statistically highly significant both before and after incubation with hydrogen peroxide (p < 0.05). This could be explained on the basis of increased oxidative stress in hypercholesterolemia and effect of fluvastatin in reducing oxidative stress

Table 3. Percentage Hemolysis of RBCs before and after Incubation of the Three Groups (Control, Fluvastatin and Hypercholesterolemic) Group

Mean (%)

Remarks

Hemolysis before incubation Control

1.69

1.04

Fluvastatin

2.48

0.67

0.001

Hypercholesterolemic

4.52

1.06

0.001

Hemolysis after incubation Control

2.78

0.88

Fluvastatin

3.52

0.81

0.001

Hypercholesterolemic

6.01

1.12

0.001

Name of the test used - Fishers F-test.

Table 4. Plasma Vitamin E Levels of the Three Groups (Control, Fluvastatin and Hypercholesterolemic) Group

Mean (mg/dL)

Remarks

Control

9.31

1.36

Fluvastatin

7.74

1.05

0.001

Hypercholesterolemic

6.28

0.68

0.001

Name of the test used - Fishers F-test.

Table 5. RBC Superoxide Dismutase (SOD) Levels of the Three Groups (Control, Fluvastatin and Hypercholesterolemic) Group

Mean (units/mg)

Remarks

Control

8078.63

762.50

Fluvastatin

7432.69

657.92 0.001

Hypercholesterolemic

5281.79

525.19 0.001

Name of the test used - Fishers F-test.

Table 2. Mean RBC MDA Levels of the Three Groups (Control, Fluvastatin and Hypercholesterolemic) Group

Mean (μmol/L)

Control

545.63

48.03

Remarks

Fluvastatin

590.23

39.63

0.034

Hypercholesterolemic

742.67

74.10

0.001

Name of the test used - Fishers F-test -for analysis of variance (ANOVA), N = No. of subjects; SD = Standard deviation; p value = Probability; HS = Highly significant; S = Significant.

in hypercholesterolemic patients after 2 months treatment. Mean vitamin E levels were lower fluvastatin group (7.74 ± 1.05 mg/dL) and lowest hypercholesterolemic group (6.28 ± 0.68 mg/dL) compared to control group (9.31 ± 1.36 mg/dL) shown in Table 4.

of in in as as

The values were statistically highly significant (p < 0.05). These studies have shown that vitamin E plays a critical role in protecting polyunsaturated fatty

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PHARMACOLOGY acids of cell membranes against lipid peroxidation through its free-radical quenching activity at an early stage of free-radical attack, thus suppressing hemolysis.24 This has made it one of the important factors determining the susceptibility of red cells to auto-oxidation hemolysis.24 Vitamin E appeared to be highly efficient as an antioxidant and is accepted as a first-line of defense against lipid peroxidation.22-25 The popular finding that vitamin E is inversely related to the respective tissue MDA level fits here as MDA in this study was found to be highest in hypercholesterolemic group (742.67 ± 74.10 μmol/L) and lowest in control group (545.63 ± 48.03 μmol/L). The increased hemolysis of RBCs in hypercholesterolemic group could be further documented by the decreased levels of vitamin E, which is a first line of defense against membrane damaging lipid peroxidation.22-25 In fluvastatin group, the level of vitamin E was more than hypercholesterolemic group but less than control group (Table 4). The results of percentage hemolysis of RBCs were in the same order, it was least in control, more than control in fluvastatin group and highest in hypercholesterolemic group. The controls had highest level of vitamin E as they are considered to be the group with least oxidative stress due to normal lipid profile of their blood. It may be hypothesized that due to increased oxidative stress in hypercholesterolemic group, utilization of vitamin E, which is an antioxidant, might have increased. This agreed with the work of Moriel et al (2000).19

Superoxide Dismutase Superoxide dismutase was chosen in this study as it plays an important role in the removal of superoxide radicals (O2-) formed in red cells and because hemoglobin and SOD have been shown to be in close association with red cells. In addition to this, some studies have also been suggested 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 superoxide radicals (O2-), especially at higher concentrations.26-28 This study showed low levels of SOD in hypercholesterolemic group (6.28 ± 0.69 units/mg) as shown in Table 5. In fluvastatin group (7.74 ± 1.05 units/mg), SOD level was more than hypercholesterolemic but less than controls. The values were statistically highly significant (p < 0.05). The low levels of SOD in the cellular and extracellular fluids reduce their oxygen-derived free radical (ODFR) scavenging capacity making

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Indian Journal of Clinical Practice, Vol. 25, No. 8, January 2015

the tissues more vulnerable to ODFR damage.28 The low level of SOD in hypercholesterolemic patients is indicative of increased oxidative stress in patients of hypercholesterolemia (Table 5). Studies have shown that in hypercholesterolemia there, was reduced activity of SOD which improved after 3 months of treatment with fluvastatin, further strengthens the idea of increased oxidative stress in hypercholesterolemics and reduction of oxidative stress after the use of fluvastatin which inhibits superoxide anion production, preserves intracellular SOD and prevents the ROS permeation into lipoproteins.2,26,27 Thus, we can conclude that the trends seen in this study definitely suggest that there is an increased oxidative stress occurring as a result of hypercholesterolemia and after the use of fluvastatin, oxidative stress decreases for which there may be two reasons. First due to decreased cholesterol levels and secondly due to antioxidant effect of fluvastatin as shown by many studies. CONCLUSION This study was an attempt to establish the extent of increased oxidative stress in hypercholesterolemic patients and to evaluate the effect of fluvastatin on the oxidative stress and antioxidant status after 2 months of treatment. Levels of oxidative stress were higher in hypercholesterolemic in comparison to control and fluvastatin group. Levels of oxidative stress in fluvastatin group were lower than hypercholesterolemic but, were higher than control group. Levels of antioxidants were higher in fluvastatin group than hypercholesterolemic but were lower than controls. From these findings, we can conclude that there is an increase in oxidative stress in hypercholesterolemia, but it decreases significantly after 2 months of fluvastatin therapy and antioxidant status also improves in patients taking fluvastatin. REFERENCES 1. M ason JC. Statins and their role in vascular protection. Clin Sci (Lond) 2003;105(3):251-66. 2. Yilmaz MI, Baykal Y, Kilic M, Sonmez A, Bulucu F, Aydin A, et al. Effects of statins on oxidative stress. Biol Trace Elem Res 2004;98(2):119-27. 3. R osenson RS. Curr Cardiol Rep1999;1:228. 4. De Caterina R, Cipollone F, Filardo FP, Zimarino M, Bernini W, Lazzerini G, et al. Low-density lipoprotein level reduction by the 3-hydroxy-3-methylglutaryl coenzyme-A inhibitor simvastatin is accompanied by a related reduction of F2-isoprostane formation in

PHARMACOLOGY hypercholesterolemic subjects: no further effect of vitamin E. Circulation 2002;106(20):2543-9. 5. Shovman O, Levy Y, Gilburd B, Shoenfeld Y. Antiinflammatory and immunomodulatory properties of statins. Immunol Res 2002;25(3):271-85. 6. Beltowski J. Statins and modulation of oxidative stress. Toxicol Mech Methods 2005;15(2):61-92. 7. Mira R, TonyH, Khetam H, Aviram M. Lett Drug Des Disc 2004;1:269. 8. Norata GD, Pirillo A, Catapano AL. Circulation 2004;109:3164. 9. Ky B, Burke A, Tsimikas S, Wolfe ML, Tadesse MG, Szapary PO, et al. The influence of pravastatin and atorvastatin on markers of oxidative stress in hypercholesterolemic humans. J Am Coll Cardiol 2008;51(17):1653-62. 10. Stocks J, Dormandy TL. The autoxidation of human red cell lipids induced by hydrogen peroxide. Br J Haematol 1971;20(1):95-111. 11. Halliwell B, Chirico S. Lipid peroxidation: its mechanism, measurement, and significance. Am J Clin Nutr 1993;57(5 Suppl):715S-724S; discussion 724S-725S. 12. Kartha VN, Krishnamurthy S. Effect of hypervitaminosis A on hemolysis and lipid peroxidation in the rat. J Lipid Res 1978;19(3):332-4. 13. Bieri JG, Teets L, Belavady B, Andrews EL. Serum vitamin E levels in a normal adult population in the Washington, DC, Area. Proc Soc Exp Biol Med 1964;117:131-3. 14. Teitz NW. Textbook of Clinical Chemistry 1986:p.1285-8. 15. Fridovich I. Superoxide dismutases. Annu Rev Biochem 1975;44:147-59. 16. McCord JM, Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem 1969;244(22):6049-55.

17. Drabkin DL, Austin JH. J Biol Chem 1932;98:719. 18. van Assendelft OW, Zijlstra WG, van Kampen EJ, Holtz AH. Stability of haemiglobincyanide reference solutions. Clin Chim Acta 1966;13(4):521-4. 19. Moriel P, Plavnik FL, Zanella MT, Bertolami MC, Abdalla DS. Lipid peroxidation and antioxidants in hyperlipidemia and hypertension. Biol Res 2000;33(2):105-12. 20. Ng DS. The role of statins in oxidative stress and cardiovascular disease. Curr Drug Targets Cardiovasc Haematol Disord 2005;5(2):165-75. 21. Davì G, Romano M, Mezzetti A, Procopio A, Iacobelli S, Antidormi T, et al. Increased levels of soluble P-selectin in hypercholesterolemic patients. Circulation 1998;97(10):953-7. 22. Argani H, Ghorbani A, Rashtchizade N, Rahbaninobar M. Effect of lovastatin on lipid peroxidation and total antioxidant concentrations in hemodialysis patients. Lipids Health Dis 2004;3:6. 23. Garibaldi S, Fabbi P, Bertero G, Altieri P, Nasti S, Manca V, et al. Ital Heart J 2002;3:49. 24. Packer L. Protective role of vitamin E in biological systems. Am J Clin Nutr 1991;53(4 Suppl):1050S-1055S. 25. Simon E, Paul JL, Soni T, Simon A, Moatti N. Plasma and erythrocyte vitamin E content in asymptomatic hypercholesterolemic subjects. Clin Chem 1997;43(2): 285-9. 26. Oski FA. Vitamin E - a radical defense. N Engl J Med 1980;303(8):454-5. 27. Klatt P, Lamas S. Eur J Biochem 2001;267:4928. 28. G upta VK, Mallika V, Gupta Y, Srivastava DK. Ind J Clin Biochem 1992;7:3.

■■■■

ÂÂ ÂÂ ÂÂ ÂÂ ÂÂ ÂÂ ÂÂ ÂÂ ÂÂ ÂÂ ÂÂ ÂÂ

Do I Need Multivitamin Tablets? Multivitamin tablets are not needed unless there is a scarcity of a particular vitamin. If you include all seven colors and six tastes in your food, there is no need for vitamin supplementation. Wheat grass and barley grass juice contain folic acid and vitamin B12. Anything which is green contains vitamin B. Anything which is red contains lycopene. Citrus foods contain vitamin C. All dry fruits contain vitamin E. Sunlight is an excellent source of vitamin D. Carrots contain vitamin A. Folic acid is lost if the food is boiled and the water is discarded. Vitamin D is not absorbed if exposed to sunlight is through glass. Vitamin D is not absorbed through clothes if you are fully-clothed in sunlight.

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EXPERT VIEW

Golden Hours in Medical Practice KK AGGARWAL

ne should not ignore warning signals as ‘time is life’ in medical science. The three cardinal warning signals are: Anything which is unusual, anything which cannot be explained and any symptom appearing for the first time in life. Time is life is an old saying. In heart attack, time is muscle and in stroke, time is brain. Most acute emergencies will require emergent evaluation and treatment. Delay in treatment even of minutes can take away life. In emergency, one should not waste time to think, instead rush to a bigger hospital with full facilities and make sure that the person is attended to in time. Many hospitals may have ill-equipped emergency departments or may have inadequately trained staff. In nursing homes, the ER doctor may be from other systems of medicine. In emergency medicine, the golden hour refers to the first hour following traumatic injury being sustained by a casualty, during which there is the highest likelihood that prompt medical treatment will prevent death. If bleeding can be stopped and person can be infused enough fluids within first hour most trauma death can be avoided.

ÂÂ Platinum 10 minutes refer to first 10 minutes

after trauma and indicate importance of starting first aid within 10 minutes to reduce the chances of death. Effective time for CPR is <10 minutes. After 10 minutes chances of successful survival are negligible.

ÂÂ Door-to-ECG time is an important terminology

in the treatment of heart attack. One should get an ECG done within 10 minutes of chest pain. A prolonged door-to-ECG time is associated with an increased risk of clinical outcomes in patients with ST elevation heart attack.

Senior Physician and Cardiologist Moolchand Medcity, New Delhi

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Indian Journal of Clinical Practice, Vol. 25, No. 8, January 2015

ÂÂ Door-to-needle time in acute heart attack is the

time before which the clot dissolving drug should be given: In ST elevation heart attack recommended that the door-to-needle time should be <30 minutes.

ÂÂ Door-to-balloon time is for angioplasty. Primary

percutaneous coronary intervention is now preferred for most patients if it can be performed by an experienced operator with <90 minutes delay from presentation to the emergency department.

ÂÂ Door-to-Doctor time in stroke is another term. In

emergency department, arrival to initial physician evaluation should be <10 minutes in stroke; delay increases the mortality.

ÂÂ Door-to-neurologist time is for the specialist.

Emergency department arrival to Paralysis Stroke Team Notification time should be <15 minutes.

ÂÂ Door-to-CT scan time is the time before which

the CT should be done in suspected paralysis. Emergency department arrival to CT scan initiation in stroke should be <25 minutes.

ÂÂ Door-to-CT interpretation in stroke should be

<45 minutes.

ÂÂ Door to tPA time is the treatment window in

paralysis: 80% of eligible paralysis patients presenting to the emergency department should be treated with tPA clot dissolving drug within 60 minutes.

Door-to-antibiotic time in community-acquired pneumonia is the time to start antibiotics. Practice guidelines suggest that all patients hospitalized with CAP should receive antibiotics within 4 hours of admission. Door-to-antibiotic time in meningitis of >6 hours is linked to high mortality (8.64 times).

AROUND THE GLOBE

News and Views ÂÂ For women who are shown to have dense breasts

on mammography screening, the addition of ultrasound screening has little impact on outcome, increases harms, and dramatically increases costs, suggests a report published online December 8 in the Annals of Internal Medicine.

ÂÂ Vitamin D-3 absorption from a dietary supplement

can be significantly improved by taking it with a meal that contains fat, suggests new research published online in the Journal of the Academy of Nutrition and Dietetics.

ÂÂ Both single- and dual-hormone artificial pancreas

systems provide better glycemic control than the conventional insulin pump, suggests a report published online in The Lancet Diabetes & Endocrinology.

ÂÂ One-quarter of pregnant women with chronic

RSV-associated death, suggests a new study published online December 8 in Pediatrics. ÂÂ A new study published online in BMJ has stated

that prenatal and early-life exposure to antibiotics does not seem to cause asthma in children. Instead, genetic predisposition to respiratory infections and asthma, consultation patterns or other home and environmental factors, together with confounding by respiratory infections, seem to have biased previous results.

ÂÂ The injectable glucagon-like peptide 1 (GLP-1)

agonist liraglutide has received a positive opinion in the European Union for an additional indication: use in adults with type 2 diabetes and moderate renal impairment. If this label extension is endorsed in the European Union, liraglutide will become one of a few glucose-lowering agents sanctioned for use in this difficult-to-treat patient population.

hepatitis B virus (HBV) infection go on to develop increased liver inflammation after giving birth, although these flare-ups are typically asymptomatic and resolve within a year, suggests a new prospective study published online in Gut.

ÂÂ More than a quarter of patients with epilepsy are

ÂÂ Patients with wet age-related macular degeneration

ÂÂ Most patients with inflammatory bowel disease

(AMD) that becomes refractory to intravitreal ranibizumab therapy have improved outcomes with a dexamethasone intravitreal implant, points a new study published online in the British Journal of Ophthalmology.

ÂÂ Results from the AUGMENT HF trial, presented

at the American Heart Association (AHA) 2014 Scientific Sessions, have stated that an injection of the novel hydrogel Algisyl-LVR hydrogel into the left ventricular myocardium of patients with advanced heart failure was safe and improved functional and clinical end points over 6 months.

ÂÂ Emerging research is shedding new light on the

possible involvement of cardiac factors in sudden unexpected death in epilepsy (SUDEP). Increasing evidence suggests that cardiac arrhythmia precedes SUDEP. The findings were presented at the American Epilepsy Society (AES) 68th Annual Meeting.

ÂÂ Infants

with life-threatening or complex, chronic conditions are the most vulnerable to

prescribed opioids, which is significantly more than in the general population, reported a new study presented during the American Epilepsy Society (AES) 68th Annual Meeting. (IBD) do not receive screening for or vaccination against hepatitis B virus (HBV), suggested a new study published in the World Journal of Gastroenterology.

ÂÂ Contact lens wearers with “dry eye” and discomfort

may find relief from liposomal sprays or drops that add lipids back to the eye, suggests a new study published online in Optometry and Vision Science.

ÂÂ More than three quarters of patients with acute

lymphocytic leukemia (ALL) who had residual disease after chemotherapy and were subsequently treated with the novel immunotherapy blinatumomab experienced a complete eradication of minimal residual disease (MRD), suggested a new study presented at the American Society of Hematology (ASH) 56th Annual Meeting.

ÂÂ New research has pointed that differences in gene

expression suggest that defective maturation of the endometrium during the secretory phase and early pregnancy precedes the development of preeclampsia. The findings are published online in Hypertension.

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AROUND THE GLOBE ÂÂ Three new studies have reported that a chemical

called nitrate, found in green vegetables including spinach, lettuce and celery, may aid heart health and reduce the risk of obesity and diabetes. The studies are published in The FASEB Journal, The Journal of Physiology and Diabetes.

unilateral total-knee arthroplasty significantly reduced the risk of venous thrombosis compared with enoxaparin without increasing the risk of bleeding, reported a phase 2 study published online December 7 in the New England Journal of Medicine.

ÂÂ Recommendations by physician groups to avoid

ÂÂ The WHO fracture risk assessment tool FRAX is

bedsharing among mothers and their babies are intended to reduce sleep-related infant deaths. However, evidence suggests that the advice never to bedshare is unrealistic, and avoiding bedsharing may interfere with breastfeeding, according to an article published in Breastfeeding Medicine.

ÂÂ A new study has found a duplication of a short

stretch of the X chromosome in some people with a rare disorder that causes excessive childhood growth. Researchers pointed that a single gene within the region likely has a large influence on how much children grow. The study is published in the New England Journal of Medicine.

ÂÂ For most patients with drug-refractory epilepsy

who are eligible for surgical treatment, their outcomes end up better than continuing on medical therapy in most cases, as suggested by two new studies presented at the American Epilepsy Society’s (AES) annual meeting.

ÂÂ Children

who receive routine childhood immunizations are not more likely to develop allergies later in life, despite contrary claims from parents, and are even protected against allergic disease, reported a cohort study presented at the World Allergy Organization International Scientific Conference and Congress of the Brazilian Association of Allergy and Immunology.

ÂÂ Children who need maintenance hydration have

lesser odds of developing hyponatremia with isotonic fluid than with hypotonic fluid, suggests a new trial published online in The Lancet.

ÂÂ Patients who are allergic to penicillin can tolerate

aztreonam and carbapenems, suggest new findings published online in the Journal of Allergy and Clinical Immunology.

ÂÂ British scientists have found a brain mechanism

that may drive our desire for glucose-rich food; the discovery could lead to better treatments for obesity. The research is published in the Journal of Clinical Investigation.

ÂÂ Treatment with an antisense oligonucleotide that

inhibits factor XI in patients undergoing primary

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better than lumbar spine and femoral neck T-scores at identifying women with vertebral fractures, suggests new study published online in BMC Musculoskeletal Disorders.

ÂÂ The National Comprehensive Cancer Network

(NCCN) has updated prostate cancer guidelines. The 2015 update of the guidelines contains three major changes related to imaging, molecular testing, and the systemic treatment of castrationresistant disease. The guidelines are available on the NCCN website.

ÂÂ Screening asymptomatic persons with diabetes

using coronary computed tomographic angiography (CTA) may improve their cardiovascular risk profile by guiding them toward more aggressive therapy, but this may have little effect on mortality or nonfatal CV events over 4 years, reports a randomized trial presented at the American Heart Association (AHA) 2014 Scientific Sessions.

ÂÂ Chronic kidney disease (CKD) increases the risk of

stroke and systemic thromboembolism in patients with atrial fibrillation (AF) independently of other stroke risk factors, especially in those needing renal replacement therapy (RRT), suggests an observational cohort study published in the December 16 issue of the Journal of the American College of Cardiology Intranasal ketamine and fentanyl provide similar pain relief in children suffering from moderate to severe pain from limb injuries, suggests a study published online in Annals of Emergency Medicine.

ÂÂ Adolescents who are prescribed anxiolytics or

sleep medications are substantially more likely to misuse these medications for either sensationseeking or self-treating reasons as compared to their counterparts who have never been prescribed these agents, points new research published online in Psychology of Addictive Behaviors.

ÂÂ Plasma cytokine levels may be markers for, and

play a role in, alcoholism and common substance abuse behaviors, suggests new research presented at the American Academy of Addiction Psychiatry (AAAP) 25th Annual Meeting.

AROUND THE GLOBE ÂÂ The US Food and Drug Administration (FDA)

approved Gardasil 9, a human papillomavirus (HPV) vaccine that prevents cancers and other lesions caused by nine HPV types, five more than the original Gardasil protected against.

ÂÂ New

treatment recommendations appearing online in JAMA Dermatology state that treatment of nail psoriasis poses a clinical challenge and may ultimately require more than one approach.

ÂÂ The risk for prostate cancer is not increased

in hypogonadal men treated with testosterone therapy, suggest the results of a long-term registrybased study published in the January issue of the Journal of Urology.

ÂÂ Dentists can safely place dental implants in patients

with uncontrolled diabetes, reports a new study, thereby contradicting common recommendations. The report is published in the December issue of the Journal of the American Dental Association.

ÂÂ A new study states that children with autism

spectrum disorder are more than twice as likely to be born to mothers with preeclampsia during pregnancy, suggesting a link between the two. The study is published in the journal JAMA Pediatrics.

ÂÂ A new study indicates that current clinical

ÂÂ A small trial has shown pancreatic islet–cell

isolation can be performed in a location remote from surgery in patients undergoing total pancreatectomy followed by autologous islet–cell transplantation. The report is published online December 10 in JAMA Surgery.

ÂÂ Five years of tamoxifen continues to prevent breast

cancer from developing in women at high-risk for the disease, more than 15 years after they stopped taking it, suggest follow-up results from the IBIS-I (International Breast Cancer Intervention–I) trial presented at the San Antonio Breast Cancer Symposium.

ÂÂ Air pollution should be viewed as one of several

major modifiable risk factors in the prevention and management of cardiovascular disease, contends a European Society of Cardiology (ESC) position paper published online December 9, 2014 in the European Heart Journal, with lead author Dr David Newby (University of Edinburgh, Scotland). According to Dr Robert Storey (University of Sheffield, UK), air-pollution exposure should be part of the conversation with patients, who are often anxious to reduce their (CVD) risk in any way possible. We hope that our advice will help stimulate debate about improving cardiovascular health globally.

prediction rules used by physicians to determine whether children have “strep throat” caused by group A streptococcal infection may not be accurate. The study is published in the Canadian Medical Association Journal.

ÂÂ Subjective memory symptoms might be an early

ÂÂ Starting treatment with the opioid analgesic

has expanded the indication of ramucirumab to include the treatment of metastatic non-small cell lung cancer (NSCLC). The approval is based on findings from the phase 3 REVEL trial.

tramadol is associated with an increased risk for hypoglycemia requiring hospitalization, suggests a new study published online December 8 in JAMA Internal Medicine.

ÂÂ The antipsychotic ziprasidone and its generic

counterparts have been linked to a rare but potentially fatal skin reaction DRESS (drug reaction with eosinophilia and systemic syndromes), thus prompting the US Food and Drug Administration (FDA) to add a new warning to the drug’s label.

ÂÂ The administration of progesterone immediately

after acute traumatic brain injury (TBI) shows no benefit in improving functional outcomes, suggest two large, phase 3 randomized clinical trials published online December 10 in the New England Journal of Medicine.

indicator of stroke risk, especially in highly educated people, suggests a new study published online in Stroke on December 11.

ÂÂ The US Food and Drug Administration (FDA)

ÂÂ Medical comorbidities are linked to poor semen

quality, suggesting that current health condition and genetic factors affect sperm production, report the findings of a cross-sectional study published online December 9 in Fertility and Sterility.

ÂÂ Weight loss surgery may decrease the frequency and

severity of lower urinary tract symptoms, suggest two new studies published online December 8 in BJU International.

ÂÂ Routine measures of obesity are significantly

associated with an increased risk of sudden cardiac death (SCD) among middle-aged citizens who do not smoke, findings from the Atherosclerosis Risk

Indian Journal of Clinical Practice, Vol. 25, No. 8, January 2015

785

AROUND THE GLOBE in Communities (ARIC) study indicate. However, only the waist-to-hip ratio, an index of reflecting both subcutaneous and intra-abdominal fat, was directly associated with SCD, while measures of body mass index (BMI) and waist circumference were indirectly associated with SCD, apparently via effects on traditional CVD risk factors. The study was published online November 19, 2014 in Heart. ÂÂ In

compliant patients with true-resistant hypertension, renal denervation does not appear to reduce blood pressure more than intensified drug treatment and it is not ready to be used routinely yet, suggests new research from the Czech Republic published online in Hypertension.

ÂÂ Children whose mothers were exposed to higher

levels of phthalates, common chemicals in consumer products, in late pregnancy tend to score lower than other kids on intelligence tests at age seven, reported a new study published online December 10 in PLOS ONE.

ÂÂ Toddlers who sleep in the same bed as their

parents may be at increased risk of developing asthma, suggests a new study published in the European Respiratory Journal. Study authors noted that bed-sharing at 24 months was associated with increased risk of wheezing between the ages of 3 and 6 years old, and toddlers who bed-shared at this age were also at higher risk of being diagnosed with asthma at age 6.

ÂÂ A novel class of synthetic hallucinogens, being

sold as a cheaper, more readily available LSD substitute, or even as LSD itself, is emerging as a particularly fatal drug, especially for young males, suggests new research presented at the American Academy of Addiction Psychiatry (AAAP) 25th Annual Meeting.

ÂÂ Results from the large international Suppression

of Ovarian Function Trial (SOFT) are practice changing for the adjuvant treatment of premenopausal women with early-stage hormone receptor (HR)-positive breast cancer, and state that ovarian suppression with endocrine therapy has striking benefits for some of these patients. The results, presented at the San Antonio Breast Cancer Symposium (SABCS) 2014, have led to a new algorithm for the adjuvant treatment of premenopausal women with HR-positive breast cancer.

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ÂÂ Low levels of oxygen saturation during sleep and

reduced durations of slow-wave sleep are both associated with more brain pathology characteristic of dementia, points a new study published online December 10 in Neurology.

ÂÂ Drug clearance is not normal in patients with

chronic kidney disease (CKD), even for drugs that are only minimally cleared by the kidneys, and it varies by mode of dialysis, suggests a new study published in the American Journal of Kidney Diseases.

ÂÂ Allergens modified by carbamylation so that they

can be absorbed by the oral mucosa and given as sublingual immunotherapy may be effective in patients with rhinoconjunctivitis and allergic asthma caused by cat allergies, suggests a crosssectional survey presented at the World Allergy Organization International Scientific Conference and Congress of the Brazilian Association of Allergy and Immunology.

ÂÂ Outine measures of obesity are significantly

associated with an increased risk of sudden cardiac death (SCD) among middle-aged citizens who do not smoke, suggest the findings from the Atherosclerosis Risk in Communities (ARIC) study. Waist-to-hip ratio was directly associated with SCD, while measures of body mass index (BMI) and waist circumference were indirectly associated with SCD. The findings were published online in Heart.

ÂÂ A new study published online in Hypertension states

that systolic blood pressure levels tend to be higher in subjects drinking a beverage from bisphenol A (BPA) containing cans as compared to when they drank the same beverage from glass bottles.

ÂÂ For infants at high-risk for atopic dermatitis, the

daily application of a common moisturizer leads to fewer skin problems, including eczema, by 32 weeks of age, suggests a new study published in the Journal of Allergy and Clinical Immunology.

ÂÂ Two promising models that could help pinpoint

which children are at highest risk for subclinical seizures and should be prioritized for receiving continuous EEG monitoring (CEEG) were discussed at a press briefing during the American Epilepsy Society (AES) 68th Annual Meeting.

ÂÂ Liver fibrosis develops early after hepatitis C virus

(HCV) seroconversion and progresses quickly to cirrhosis in many patients, suggest new findings published online in JAMA Internal Medicine.

AROUND THE GLOBE ÂÂ For severe emphysema, lung volume reduction

treatment with the RePneu coil seems safe in the long-term, but there is a gradual lessening of clinical benefit over time for some patients, suggests the first long-term follow-up study published online in Respirology.

ÂÂ New correlative findings from the previously

reported CALGB 40603 trial suggest that bevacizumab works in breast cancer, specifically in subtypes of triple-negative breast cancer (TNBC), which is particularly difficult to treat. The data were presented at the San Antonio Breast Cancer Symposium (SABCS) 2014.

ÂÂ Physicians should avoid polysomnography (PSG)

in patients with chronic insomnia unless symptoms suggest a comorbid sleep disorder, advises the American Academy of Sleep Medicine (AASM) in its new “Choosing Wisely” list. The complete list can be found at www.aasmnet.org.

ÂÂ Rituximab treatment is associated with improved

disease activity in most patients with eosinophilic granulomatosis with polyangiitis (EGPA), suggests a new retrospective study published online in Annals of the Rheumatic Diseases.

ÂÂ An early intervention strategy in patients with non-

ST-segment-elevation ACS (NSTE-ACS) results in significant cost savings compared with a delayed intervention strategy for both high- and low-risk patients, suggests a Canadian analysis. The study was published online in the Canadian Journal of Cardiology.

ÂÂ A new research has identified novel lipid–derived

molecules associated with future coronary heart disease events. The approach, called metabolomics, has identified two lipid metabolites, lysophosphatidylcholine and sphingomyelin that reduced the risk of developing coronary heart disease, while monoglyceride was associated with increased risk of coronary heart disease. The report is published in the journal PLOS Genetics.

ÂÂ Children younger than two years who were

born prematurely are at increased risk of being hospitalized if they develop influenza, suggests a new systematic review and meta-analysis published online in Lancet Respiratory Medicine.

ÂÂ For treatment of juvenile recurrent parotitis (JRP),

ductal corticosteroid infusion (DCI) appears to work equally well as sialendoscopy with DCI, suggests a new retrospective study published online in JAMA Otolaryngology-Head & Neck Surgery.

ÂÂ A breast biopsy that results in a diagnosis of

atypical hyperplasia is considered a benign finding, but that description obscures the riskiness of the condition, according to a special report published in the January 1, 2015, issue of the New England Journal of Medicine. Dr Hartmann and coauthors from the Mayo Clinic in Rochester, Minnesota, have reported a cumulative incidence of breast cancer of almost 30% at 25 years of follow-up in their 698-patient cohort of women with atypical hyperplasia.

ÂÂ In latest guidance, the National Institute for

Health and Care Excellence (NICE) recommends dabigatran as an option for treating and preventing recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults.

ÂÂ According to a new study in the Journal of Clinical

Endocrinology and Metabolism, rituximab offers a number of advantages for Graves’ orbitopathy compared to IV methylprednisolone. It was found that Graves’ orbitopathy after rituximab therapy does not relapse, when compared to a relapse rate of about 20-25% after standard treatment with steroids, observed after discontinuation of intravenous methylprednisolone.

ÂÂ A self-directed exercise program can improve the

symptoms of arthritis, according to a study by Sara Wilcox, PhD, from the Dept. of Exercise Science, University of South Carolina, Columbia and colleagues published in 2015 issue of the American Journal of Preventive Medicine.

ÂÂ Removal of the fallopian tubes may help prevent

ovarian cancer, according to an opinion written by the American College of Obstetricians and Gynecologists’ Committee on Gynecologic Practice and published in the January 2015 issue of Obstetrics & Gynecology. The committee made the following recommendations:

In women at population risk for ovarian cancer, surgeons should discuss the potential benefits of salpingectomy. considering laparoscopic In women sterilization, physicians can discuss the fact that bilateral salpingectomy provides effective contraception, while pointing out that this procedure eliminates the option of tubal reversal. Prophylactic salpingectomy may prevent ovarian cancer in some patients.

Indian Journal of Clinical Practice, Vol. 25, No. 8, January 2015

787

AROUND THE GLOBE More randomized controlled trials are needed to support the use of salpingectomy in reducing ovarian cancer.

ÂÂ Researchers at the Stanford University School of

Medicine have developed a safe and effective skin patch to deliver a drug that enhances the healing of diabetes-related ulcers. The findings are published in the Proceedings of the National Academy of Sciences.

ÂÂ A combination of a cephalosporin and a beta-

lactamase inhibitor in an intravenous formulation has been approved for treating complicated intra-abdominal infections and complicated urinary tract infections in adults, the Food and Drug Administration announced on Dec. 19. The cephalosporin is ceftolozane and the beta-lactamase inhibitor is tazobactam; it will be marketed as Zerbaxa by Cubist Pharmaceuticals. This is the fourth antibacterial drug product approved by the FDA in 2014 and was designated as a Qualified Infectious Disease Product (QIDP) and was given priority review.

ÂÂ Researchers from the University of California-San

Diego have found that adipocytes under the skin protect the body against infection. The research, published in the journal Science, stated that adipocytes produce antimicrobial peptides that stave off pathogens.

ÂÂ A new study has found that binge drinking in

young, healthy adults significantly disrupts the immune system. The findings are published in the journal Alcohol.

ÂÂ A new study by the University of Oregon and

ÂÂ People with high intelligence may be less likely to

develop schizophrenia, especially those who have a genetic susceptibility to the condition, suggested a new study published in The American Journal of Psychiatry. ■■■■

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the Oregon Social Learning Center links physical violence against women by male partners to a disruption of an important steroid hormone cortisol that opens the door potentially to a variety of negative health effects. The results are published in the journal Psychoneuroendocrinology.

MEDILAW

Advertising and Medical Ethics KK AGGARWAL

Can a doctor advertise to solicit patients?

ÂÂ

On temporary absence from duty.

No, it is unethical for doctors to advertise in order to procure patients. Section 6.1 of the Code of Medical Ethics of the Medical Council of India (MCI) does not allow doctors to advertise.

ÂÂ

On resumption of another practice.

ÂÂ

On succeeding to another practice.

ÂÂ

Public declaration of charges.

6.1 MCI Act: Advertising

Can a doctor distribute leaflets to public regarding his/her professional activity?

6.1.1: Soliciting of patients directly or indirectly, by a physician, by a group of physicians or by institutions or organisations is unethical. A physician shall not make use of him/her (or his/her name) as subject of any form or manner of advertising or publicity through any mode either alone or in conjunction with others which is of such a character as to invite attention to him or to his professional position, skill, qualification, achievements, attainments, specialities, appointments, associations, affiliations or honours and/or of such character as would ordinarily result in his self-aggrandisement. A physician shall not give to any person, whether for compensation or otherwise, any approval, recommendation, endorsement, certificate, report or statement with respect of any drug, medicine, nostrum remedy, surgical or therapeutic article, apparatus or appliance or any commercial product or article with respect of any property, quality or use thereof or any test, demonstration or trial thereof, for use in connection with his name, signature or photograph in any form or manner of advertising through any mode nor shall he boast of cases, operations, cures or remedies or permit the publication of report thereof through any mode.

When can a doctor make a formal announcement in the press? 6.1.1 MCI Act: A medical practitioner is however permitted to make a formal announcement in press regarding the following: ÂÂ

On starting practice.

ÂÂ

On change of type of practice.

ÂÂ

On changing address.

Senior Physician and Cardiologist, Moolchand Medcity, New Delhi Member, Ethics Committee, Medical Council of India

No, a doctor cannot distribute leaflets to public regarding his/her professional activity. In a decision taken by Delhi Medical Council dated February 15, 2001, DMC/14/2/2001, the Council observed “Dr. X was soliciting patients through distributing unsolicited leaflets as is evident from the complaint and deposition of Mr MMP. As such, Dr. X has not complied with MCI Code of Medical Ethics. The Council issued a warning to Dr. X to refrain in future. Section 6.1.1 of MCI Act states: “Soliciting of patients directly or indirectly, by a physician, by a group of physicians or by institutions or organisations is unethical.”

Can an institution run by a physician be advertised? Should you advertise your medical practice? 7.12 MCI Act: An institution run by a physician for a particular purpose such as a maternity home, nursing home, private hospital, rehabilitation centre or any type of training institution, etc. may be advertised in the lay press, but such advertisements should not contain anything more than the name of the institution, type of patients admitted, type of training and other facilities offered and the fees.

Can a doctor print self-photograph? 6.1.2 MCI Act: Printing of self-photograph, or any such material of publicity in the letter head or on sign board of the consulting room or any such clinical establishment shall be regarded as acts of self-advertisement and unethical conduct on the part of the physician. However, printing of sketches, diagrams, picture of human system shall not be treated as unethical.

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MEDILAW Can a doctor use a sign board? Yes, a doctor can use a sign board. However, the MCI Code of Medical Ethics Regulations, 2002 have prescribed criteria for the information to be carried on the sign board in Section 7.13 as follows: 7.13 MCI Act: It is improper for a physician to use an unusually large sign board and write on it anything other than his name, qualifications obtained from a University or a statutory body, titles and name of his speciality, registration number including the name of the State Medical Council under which registered. The same should be the contents of his prescription papers. It is improper to affix a sign board on a chemist’s shop or in places where he does not reside or work.

Can a doctor pay another doctor whose services he/she has engaged? The AMA Code of Medical Ethics talks about this in Opinion 6.10 - Services Provided by Multiple Physicians: “…………It is ethically permissible in certain circumstances, however, for a surgeon to engage other physicians to assist in the performance of a surgical procedure and to pay a reasonable amount for such assistance, provided the nature of the financial arrangement is made known to the patient. This principle applies whether regardless of the assisting physician is the referring physician. (II)………………..”

Does contributing articles to the press amount to advertising? 7.11: A physician should not contribute to the lay press articles and give interviews regarding diseases and treatments which may have the effect of advertising himself or soliciting practices; but is open to write to the lay press under his own name on matters of public

health, hygienic living or to deliver public lectures, give talks on the radio/TV/internet chat for the same purpose and send announcement of the same to lay press.

Where can one complain about advertising? A complaint can be made to the: ÂÂ

State Medical Council

ÂÂ

Drug Controller General of India

ÂÂ

Advertising Standards Council of India

When can a complaint be filed with the Advertising Standards Council of India (ASCI) against an advertisement? The objectives of the ASCI are to monitor, administer and promote standards of advertising practices in India. A complaint can be filed with the ASCI if the advertisement: ÂÂ

Is not truthful

ÂÂ

Is not based or supported by independent research

ÂÂ

Is offensive

ÂÂ

Published without the permission of the person, firm or institution

ÂÂ

Misleading the consumer

ÂÂ

Contains any claim

ÂÂ

Describes products as free

ÂÂ

Claims that if one product is purchased another product will be provided free

ÂÂ

Contains terms such as guarantee up to ….years

ÂÂ

Claims treatment for diseases such as obesity, impotence, infertility, baldness, etc.

ÂÂ

Decrides any race, caste, colour, creed or nationality.

■■■■

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INSPIRATIONAL STORY

My Precocious and Precious Son

Paradoxically, life brought death in me – his coming into my life caused the death of my old habits and lifestyle, which were apparently less meaningful than the one I have now as a mum.

I don’t get to be with my son everyday (for I am away in the city during weekdays because of my job’s location), but whenever I am around to do my responsibility as a mum to him, I just get physically and mentally drained sometimes.

Despite the headaches and fury that I get during feeding time (and all other times when he turns the house upside–down) I still find myself staring at him for hours as he sleeps. And then I would realize how my love for him never diminished, even if he now belongs to the “Terrible Twos” phase in his life.

hen psychologists came up with the term “Terrible Twos” for toddlers, they sure knew what they were saying. My two-year-old sure is a living embodiment of such label, though I sometimes hate to admit it to myself.

This is not to say, though, that he is such a Dennis-themenace type of a kid. In fact, he behaves remarkably in places outside our house.

He is my son, and that’s all that matters.

I often hear hushed inspirational remarks from strangers whenever they see my son conducting himself very well in the church, or in the supermarket, or just anywhere else. That’s laudable, I know, for not all kids have that pleasing manner.

I have a friend named Monty Roberts who owns a horse ranch in San Ysidro. He has let me use his house to put on fund-raising events to raise money for youth at risk programs.

I’ve seen other kids romp around other people’s houses, break things, and go off wildly all over the place. But my son is definitely never like that. However, when at home, he can pester the people around him. He acts like a wild bull on the loose, and almost everything is out of their usual places after he leaves them. Yeah, it’s pretty much like a tornado just hit them. Immediately after giving birth to my son, it was definitely love at first sight that dawned in me. I never stopped loving him since. I remember when he was just weeks old, I would lie down beside him as he slept, and I would stare at him for hours, despite the fact that I barely had enough sleep to keep myself awake to gaze at him. I sacrificed everything for him, including me precious freedom as a single woman, my whims, and the luxury of sleeping until noon. His arrival caused a major rearrangement in my life. It was difficult, at first, but once I got the feel of things, I realized that his presence in my life is simply a gift. He might not know it now, but he has taught me so many things – to be patient (a trait I never practiced much), to be selfless, to be forgiving, and most importantly, to love unconditionally. It is so amazing how a helpless baby changed a multitude of aspects in me, something left untouched by years in school and experience at work.

KEEP YOUR DREAM

The last time I was there he introduced me by saying, “I want to tell you why I let Jack use my horse. It all goes back to a story about a young man who was the son of an itinerant horse trainer who would go from stable to stable, race track to race track, farm to farm and ranch to ranch, training horses. As a result, the boy’s high school career was continually interrupted. When he was a senior, he was asked to write a paper about what he wanted to be and do when he grew up. “That night he wrote a seven-page paper describing his goal of someday owning a horse ranch. He wrote about his dream in great detail and he even drew a diagram of a 200-acre ranch, showing the location of all the buildings, the stables and the track. Then he drew a detailed floor plan for a 4,000-square-foot house that would sit on a 200-acre dream ranch. “He put a great deal of his heart into the project and the next day he handed it in to his teacher. Two days later he received his paper back. On the front page was a large red F with a note that read, `See me after class.’ “The boy with the dream went to see the teacher after class and asked, `Why did I receive an F?’ “The teacher said, `This is an unrealistic dream for a young boy like you. You have no money. You come from an itinerant family. You have no resources. Owning a horse ranch requires a lot of money. You have to buy the land. You have to pay for the original

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INSPIRATIONAL STORY

“The boy went home and thought about it long and hard. He asked his father what he should do. His father said, `Look, son, you have to make up your own mind on this. However, I think it is a very important decision for you.’ “Finally, after sitting with it for a week, the boy turned in the same paper, making no changes at all.

and said, “I tell you this story because you are sitting in my 4,000-square-foot house in the middle of my 200acre horse ranch. I still have that school paper framed over the fireplace.” He added, “The best part of the story is that two summers ago that same schoolteacher brought 30 kids to camp out on my ranch for a week.” When the teacher was leaving, he said, “Look, Monty, I can tell you this now. When I was your teacher, I was something of a dream stealer. During those years I stole a lot of kids’ dreams. Fortunately you had enough gumption not to give up on yours.”

He stated, “You can keep the F and I’ll keep my dream.” Monty then turned to the assembled group

“Don’t let anyone steal your dreams. Follow your heart, no matter what.”

breeding stock and later you’ll have to pay large stud fees. There’s no way you could ever do it.’ Then the teacher added, `if you will rewrite this paper with a more realistic goal, I will reconsider your grade.’

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LIGHTER READING

HUMOR Boss: There are 50 bricks on an aeroplane. If you drop 1 outside. How many are left? Employee: That’s easy, 49. Boss: What are the three steps to put an elephant into a fridge? Employee: Open the fridge. Put the elephant in. Close the fridge. Boss: What are the four steps to put a deer into the fridge? Employee: Open the fridge. Take the elephant out. Put the deer in. Close the fridge. Boss: It’s lion’s birthday, all animals are there except one, why? Employee: Because the deer is in the fridge. Boss: How does an old woman cross a swamp filled with crocodiles? Employee: She just crosses it because the crocodiles are at the lion’s birthday.

an advanced high–tech communications network a hundred years earlier than the Italian’s. One week later, the Punjab Times, a local newspaper in India, reported the following: After digging as deep as 30 feet in his pasture near Amritsar, in the Indian state of Punjab, Dugdeep Singh, a self–taught archaeologist, reported that he found absolutely nothing. Dugdeep has therefore concluded that 300 years ago, India had already gone wireless. The world’s thinnest book has only one word written in it: “Everything”; and the book is titled: “What Women Want!”

QUOTES

“He who closes his ears to the views of others shows little confidence in the integrity of his own views.” –William Congreve

“A successful man is one who can lay a firm foundation with the bricks others have thrown at him.” –David Brinkley

Boss: Last question. In the end the old lady still died. Why? Employee: Ere.... I guess she drowned.... errr... Boss: No! She was hit by the brick fallen from the aeroplane. That’s the problem; you are not focused on your job.... You may leave now!

Dr. Good and Dr. Bad SITUATION: A patient with erectile dysfunction came with chest pain.

Moral: No matter how much you know or how much you are prepared. If your Boss has decided to screw you then you are surely screwed. HISTORY OF TELECOMMUNICATION

Its non cardiac

This pain can be cardiac in origin

After having dug to a depth of 10 feet last year, Italian scientists found traces of copper wire dating back 100 years and came to the conclusion, that their ancestors already had a telephone network more than 100 years ago. Not to be outdone by the Italians, in the weeks that followed, a Chinese archaeologist dug to a depth of 20 feet, and shortly after, a story in the China Daily read: ‘Chinese archaeologists, finding traces of 200 year old copper wire, have concluded their ancestors already had

©IJCP Academy

LAUGH-A-WHILE

Lighter Side of Medicine

LESSON: Men who present with erectile dysfunction may be at higher risk for subsequent development of cardiovascular events. KK Aggarwal

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Information for Authors Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767). Indian Journal of Clinical Practice strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so. The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript. Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper. Covering letter –

–

The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper. Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors. Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.

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

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

–

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

Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors. Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the departments and institutions where the work was performed,

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name of the corresponding authors, acknowledgment of financial support and abbreviations used. – The title should be of no more than 80 characters and should represent the major theme of the manuscript. A subtitle can be added if necessary. – A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included. – The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page. – A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text. Summary – The summary of not more than 200 words. It must convey the essential features of the paper. – It should not contain abbreviations, footnotes or references. Introduction – The introduction should state why the study was carried out and what were its specific aims/objectives. Methods – These should be described in sufficient detail to permit evaluation and duplication of the work by others. – Ethical guidelines followed by the investigations should be described. Statistics The following information should be given: – The statistical universe i.e., the population from which the sample for the study is selected. – Method of selecting the sample (cases, subjects, etc. from the statistical universe). – Method of allocating the subjects into different groups. – Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques. –

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.

Discussion –

This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.

References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses). At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution. Examples of common forms of references are: Articles Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes. Q. J. Expt. Physiol. 1955;40:89-111.

Figures – Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat. – All photomicrographs should indicate the magnification of the print. – Special features should be indicated by arrows or letters which contrast with the background. – The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen. – Color illustrations will be accepted if they make a contribution to the understanding of the article. –

Do not use clips/staples on photographs and artwork.

–

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

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected summary, etc.)_______________________________ 2. Total number of pages ________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________

Books

5. Special requests _____________________________

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

Indian 1.____________Foreign 1.________________

Articles in Books

2.____________ 2.________________

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

3.____________ 3.________________

4.____________ 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. –

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

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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