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Indian Journal of

CLINICAL PRACTICE 481-532 Pages

February 2011

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Volume 21, Number 9

Rosai-Dorfman Disease: A Rare Cause of Chronic Lymphadenopathy in Children

Dr KK Aggarwal

Group Editor-in-Chief

Head Office: 39 Daryacha, Hauz Khas Village, New Delhi, India. e-Mail: emedinews@gmail.com, Website: www.ijcpgroup.com

emedinews is now available online on www.emedinews.in or www.emedinews.org From the Desk of Editor in Chief Padma Shri and Dr BC Roy National Awardee

Dr KK Aggarwal

President, Heart Care Foundation of India; Sr Consultant and Dean Medical Education, Moolchand Medcity; Member, Delhi Medical Council; Past President, Delhi Medical Association; Past President, IMA New Delhi Branch; Past Hony Director. IMA AKN Sinha Institute, Chairman IMA Academy of Medical Specialities & Hony Finance Secretary National IMA; Editor in Chief IJCP Group of Publications & Hony Visiting Professor (Clinical Research) DIPSAR

7th February 2011, Monday Women with PCOS may have Four Times the Prevalence of Type 2 Diabetes According to a review and meta-analysis published online in the journal Human Reproduction Update, women with polycystic ovary syndrome (PCOS) have a four–fold increased prevalence of type 2 diabetes, independent of body mass index (BMI).

After including 35 studies in the systematic review and 30 in the meta–analysis, the study found that women with PCOS had a 4.48-, 2.48- and 2.88-fold increased prevalence of type 2 diabetes, impaired glucose tolerance (IGT), and the metabolic syndrome, respectively, compared with controls. And, in BMI-matched studies, the corresponding prevalence’s were increased a respective 4.00-, 2.54-, and 2.20-fold.

Infertility Update What Advice do You have for Young Women to Prevent Possible Future Fertility Problems?

Sexually transmitted diseases (STDs) can be a major cause of future infertility, so young women should ALWAYS have protected sex.

Also, women should consult with their Ob/Gyn if they have irregular menstrual cycles or have painful periods or ovulation. If your doctor is dismissive and does not offer to find a cause and solution to your problems, find a physician who will. Unfortunately, many couples’ biggest barrier to conception is an Ob/Gyn who is unfamiliar with the latest technology to treat the causes’ of infertility even though the woman may not presently be trying to conceive.

Dr KK Aggarwal Editor in Chief ————————————————————————————

Medicolegal Update What is Touch DNA?

Insulin Resistance Increases Risk of Heart Disease Much research points to the fact that diabetes is related to coronary heart disease, but it is unclear what causes this link. Therefore, a group of researchers set out to determine whether heart disease in those with diabetes is caused by increased insulin resistance, changes in metabolic factors, or other symptoms of diabetes. The researchers used a tool called the Archimedes model to estimate the proportion of heart attacks that could be prevented by keeping insulin at healthy levels versus keeping other metabolic functions at healthy levels. They found that approximately 42% of heart attacks would be prevented if insulin resistance levels were normal. This led researchers to conclude that the link between heart disease and diabetes is primarily insulin resistance. −Dr Monica and Brahm Vasudev

Dog Sniffs out Colorectal Cancer, Findings may Help Develop Volatile Organic Compounds-based Tests According to a study in the journal Gut, a Labrador retriever was at least 95% as accurate as colonoscopy when smelling breath samples, and 98% accurate when sniffing stool samples. The dog’s sense of smell was especially effective in early-stage cancer; and the canine could discern polyps from malignancies, which colonoscopy can’t.

Surgery may Reduce EDS Associated with Obstructive Sleep Apnea Excessive daytime sleepiness in people with obstructive sleep apnea, improves greatly after surgery for the disorder, according to findings presented at a recent Triological Society meeting in Arizona.

Women with PAD may Experience Faster Decline in Function, Mobility Compared with Men Among patients with peripheral arterial disease (PAD), women appear to experience a faster decline in function and mobility compared with men, according to a study published in the Journal of the American College of Cardiology.

LVADs may Help Certain Patients Recover Heart Function WebMD (1/31, Goodman) reported that an implantable pump that assists with the work of a weakened heart may, in rare cases, help some people recover a significant amount of heart function, according to research published the Journal of the American College of Cardiology. The study summarizes international research on recipients of left ventricular assist devices, or LVADs, including1,092 LVAD patients enrolled in a government-funded registry.

−Dr. Kaberi Banerjee

• Locard’s Exchange Principle states that with contact between two items, there will always be an exchange. So, when a crime is committed, if the perpetrator deposits a sufficient number of skin cells on an item at the scene, and that item is collected as possible evidence.

• It is the DNA in skin cells that is left at a crime scene and may be sampled from a variety of items including gun grips, steering wheels, eating utensils, luggage handles, and clothing.

• Humans shed tens of thousands of skin cells each day, and these cells are transferred to every surface with which human skin comes into contact.

• Touch DNA is not Low Copy Number DNA (LCN DNA).

• LCN DNA profiling allows a very small amount of DNA to be analyzed, from as little as 10-30 cells.

• Touch DNA samples are processed exactly the same way as blood, semen, saliva etc, and can stand up to scrutiny in court much better than LCN DNA. • Touch DNA analysis may be able to link the perpetrator to the crime scene, by collecting the skin cells and analyzing them. −Dr. Aru Handa

Medi Finance Update FoInvesting a significant portion of your portfolio in one industry can be risky, especially if that industry falls on hard times. However, the upside can be equally as good if the industry performs well. (We have seen this in the technology sector.) However, if you have a diversified portfolio you may be able to reap some incremental returns by investing in an industry–specific fund.

Lab Update Protein C Formal name: Protein C Functional or Antigen; Protein S Free (Functional) or Antigen (Total). Tests for Protein C and Protein S are usually ordered to help diagnose the cause of a venous thromboembolism (VTE). Functional tests for Protein C and free Protein S are usually ordered, along with other tests for hypercoagulability, to screen for sufficient, normal, factor activity.

High Protein C and Protein S levels are not usually associated with medical problems. Low levels of Protein C or Protein S can result in excessive formation of blood clots. Low concentrations of Protein C and Protein S may be seen with vitamin K deficiency, liver disease, severe infections (inflammatory conditions), renal disease, cancers, disseminated intravascular coagulation (DIC), HIV, during pregnancy, immediately following a thrombotic episode, and with warfarin or heparin anticoagulant therapy. −Dr. Arpan Gandhi and Dr. Navin Danga

Indian Journal of

Online Submission

Clinical Practice

Volume 21, Number 9, February 2011

Contents

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

Dr KK Aggarwal CMD, Publisher and Group Editor-in-Chief Dr Veena Aggarwal Joint MD & Group Executive Editor Anand Gopal Bhatnagar Editorial Anchor

From the desk of group editor-in-chief

ACS Updates Prostate Cancer Screening Guideline

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KK Aggarwal

clinical Practice

Management of Acute Bronchitis in Children

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Rajiv Kumar Malik, KK Aggarwal

IJCP Editorial Board Dr Alka Kriplani Asian Journal of Obs & Gynae Practice Dr VP Sood Asian Journal of Ear, Nose and Throat Dr Praveen Chandra Asian Journal of Clinical Cardiology Dr Swati Y Bhave Asian Journal of Paediatric Practice Dr Vijay Viswanathan The Asian Journal of Diabetology Dr KMK Masthan Indian Journal of Multidisciplinary Dentistry Dr M Paul Anand, Dr SK Parashar Cardiology Dr CR Anand Moses, Dr Sidhartha Das Dr A Ramachandran, Dr Samith A Shetty Diabetology Dr Ajay Kumar Gastroenterology Dr Koushik Lahiri Dermatology Dr Georgi Abraham Nephrology Dr Sidharth Kumar Das Rheumatology Dr V Nagarajan Neurology Dr Thankam Verma, Dr Kamala Selvaraj Obs and Gyne Advisory Bodies Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

Review article

Role of Herbolax in the Management of Constipation and Preradiography Abdominal Preparation

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NS Sasi Kumar, Suprabha Hegde

Clinical review

Role of Prebiotics and Probiotics in Treatment of Irritable Bowel Syndrome (IBS)

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RT Borse, RM Barve

clinical diagnosis

A Study of Arginase Activity in Hepatocellular Damage as a Diagnostic Index

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NR Malukar, Ajay S Dabhi, M Vadivelan, HB Sirajwala

clinical study

Efficacy and Tolerability of Combination Therapy vs Monotherapy in GERD Patients Manoj Goyal, Harinder Singh Manesh, Rani Walia, MM Gupta

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Indian Journal of

Clinical Practice

Volume 21, Number 9, February 2011

Contents

Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Pvt. Ltd. and Published at Daryacha, 39, Hauz Khas Village New Delhi - 110 016 E-mail: editorial@ijcp.com

case report

Rosai-Dorfman Disease: A Rare Cause of Chronic Lymphadenopathy in Children

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

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PN Vinoth, S Muthamil Selvan, J Thanka, Rajendiran, Vaishanavi Ravi, J Julius Xavier Scott

Š Copyright 2011 IJCP Publications Pvt. Ltd. All rights reserved.

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

Photo Quiz

Skin Plaques in a Woman with Renal Disease

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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.

Research review

From the Journals...

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Emedinews Section

From eMedinewS

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

Editorial & Business Offices Delhi

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From the Desk of Group Editor-in-Chief From the Desk of Group Editor-in-Chief

ACS Updates Prostate Cancer Screening Guideline

Dr KK Aggarwal

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

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he American Cancer Society (ACS) has updated its prostate cancer screening guideline. Men should only be screened after they receive information about the uncertainties, risks, and potential benefits associated with prostate cancer screening.

Prostate-specific antigen (PSA) testing is now recommended with or without the digital rectal exam (DRE).

There is little evidence that the DRE adds significant benefit to the PSA test, except, perhaps, when the PSA is in the borderline range.

PSA value of 4.0 ng/ml be used as a reasonable threshold to trigger further evaluation.

There is a new recommendation for men with PSA values between 2.5 and 4.0 ng/ml. Twenty-five percent of men with PSA levels between 2.5 and 4.0 ng/ml harbor prostate cancer and physicians should consider an individualized risk assessment for these men.

An individual assessment should take into account non-PSA risk factors, such as race, family history, results of previous biopsies and DRE results.

ACS also now recommends that the PSA testing interval be reduced to every other year for men whose PSA level is under 2.5 ng/ml. Such a reduction in testing frequency will lead to significantly reduced false positives, unnecessary biopsies and overdiagnosis, with only a negligible increase in missed cancers.

Source: CA Cancer J Clin Published online March 3, 2010.

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clinical practice

Management of Acute Bronchitis in Children Rajiv Kumar Malik*, KK Aggarwal**

Abstract Lower respiratory infections are the most common cause of illness and death in children in the developing world. These acute respiratory illnesses are significant not only due to the associated morbidity and mortality but also because of longterm consequences, especially when they are recurrent. Acute bronchitis is generally caused by respiratory infections: Viral (90%) and bacterial (10%). Recurrent episodes of acute or chronic infectious bronchitis are unusual in children and should alert the clinician to the likelihood of asthma. Knowledge of the susceptibility pattern of bacteria most often involved in such infections is very important as sputum culture and susceptibility testing is not requested in most cases and empirical treatment is given.

Key words: Lower respiratory infections, acute bronchitis, antibiotics, cephalosporin

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ower respiratory infections (LRIs) continue to pose a threat to the health of children across the world and are exacerbated by global environmental problems such as air pollution. In the developing world where nutrition remains poor and access to healthcare is scarce, LRIs are the most common cause of illness and death in children. Outcomes of LRI illness are far better in developed countries; nevertheless, the overall morbidity of LRI is still high and may exceed that of other age groups.1 These acute respiratory illnesses are significant not only due to the associated morbidity and mortality but also because of long-term consequences, especially when they are recurrent. Low birth weight and preexisting small lungs are important determinants of future lung function, and there is increasing evidence that pulmonary events in early life impact on adult pulmonary function.2 Acute bronchitis is one of the most common infections reported in children under five years of age, and is a leading cause of hospitalization.3 Acute tracheobronchitis is a term used when the trachea is

*Senior Consultant, Dept. of Pediatrics **Senior Physician and Cardiologist Moolchand Medcity, New Delhi Address for correspondence Dr KK Aggarwal Senior Physician and Cardiologist Moolchand Medcity, New Delhi

Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

prominently involved.4 Chronic bronchitis may be caused by repeated attacks of acute bronchitis, which can weaken and irritate bronchial airways over time, eventually resulting in chronic bronchitis.5 A German study reported an overall increase in hospitalization for lower respiratory tract infection viz. laryngotracheobronchitis, bronchitis, wheezing bronchitis, bronchiolitis, bronchopneumonia, pneumonia among children from 1996 to 2000. The incidence rate of bronchitis in children in this study was 28%.5,6 Etiology Acute bronchitis is generally caused by respiratory infections; approximately 90% are viral in origin and 10% are bacterial.5 ď Ź Viral infections include the following: Adenovirus, influenza, parainfluenza, respiratory syncytial virus, rhinovirus, human bocavirus, coxsackievirus, herpes simplex virus ď Ź Bacteria that may cause acute bronchitis include: Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus influenzae (nontypeable), Chlamydia pneumoniae (Taiwan acute respiratory [TWAR] agent), Mycoplasma species. The most common bacterial pathogen that causes lower respiratory tract infections in children of all age groups is S. pneumoniae. Nontypeable H. influenzae and M. catarrhalis may be significant pathogens in preschoolers (age <5 years), whereas 487

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Mycoplasma pneumoniae may be significant in school-aged children (ages 6-18 years).5 Other causes: Allergies, chronic aspiration or gastroesophageal reflux and, fungal infection. It has been shown that in utero and postnatal household cigarette smoke exposure is strongly linked to asthma and recurrent bronchitis in children.

Pathophysiology Acute bronchitis often follows upper respiratory tract infection as a result of the inflammatory response of the mucous membranes within the bronchial passages of the lungs.5 Patients with acute bronchitis usually have a viral respiratory infection with transient inflammatory changes that produce sputum and symptoms of airway obstruction. The tracheobronchial epithelium is invaded by the infectious agent, leading to activation of inflammatory cells and release of cytokines leading to constitutional symptoms, such as fever and malaise, follow. The tracheobronchial epithelium may become significantly damaged or hypersensitized, causing protracted cough.4 A recurrent insult to the airway epithelium, such as recurrent aspiration or repeated viral infection, may contribute to chronic bronchitis in childhood. Following damage to the airway lining, chronic infection with commonly isolated airway organisms may occur.5 Clinical Picture Acute bronchitis is usually preceded by a viral upper respiratory tract infection. It is more common in the winter when respiratory viral syndromes predominate.4 In the absence of clear diagnostic signs or laboratory tests, the diagnosis of acute bronchitis is purely clinical.

The initial presenting symptoms are usually nonspecific upper respiratory infectious symptoms, such as rhinitis.

After 3-4 days, a frequent, dry, hacking cough develops that may or may not be productive. The sputum may become purulent after several days, indicating leukocyte migration but not necessarily bacterial infection.4 Children younger than five years rarely expectorate.

In this age group, sputum is usually seen in vomitus (i.e. post-tussive emesis) as many children swallow their sputum. Parents frequently note a rattling sound in the chest.4,5 Chest pain may be a prominent complaint in older children, exacerbated by coughing.

The mucus gradually thins, usually within 5-10 days, and then the cough gradually abates.4 488

Physical examination: Findings on physical examination vary with age of the patient and stage of the disease. Early findings are absent or may be found as low-grade fever and upper respiratory signs such as nasopharyngitis, conjunctivitis and rhinitis. In the early phase, chest auscultation may be unremarkable.

But, the breath sounds become coarse, with coarse and fine crackles and scattered high-pitched wheezing as the disease progresses and cough worsens. Chest X-rays are normal or may have increased bronchial markings.4 Generally, the clinical course of acute bronchitis is self-limited, with complete healing and full return to function.5 The entire episode usually lasts about two weeks and seldom longer than three weeks.4 Bronchitis and Asthma

Recurrent episodes of acute or chronic infectious bronchitis are unusual in children and should alert the clinician to the likelihood of asthma. Bronchitis is often repeatedly diagnosed in children in whom asthma has remained undiagnosed for many years.

Similarly, a family history of asthma in parents or siblings may be masked within a history of ‘recurrent bronchitis.’ The diagnosis of ‘asthmatic bronchitis’ or ‘wheezy bronchitis’ is simply asthma.5 Bronchitis and Immunodeficiency

Recurrent episodes of acute bronchitis may also be associated with immunodeficiency. The most common immunodeficiencies in pediatric patients include:5,7  Transient hypogammaglobulinemia of infancy (THI)  Immunoglobulin G (IgG) subclass deficiency  Impaired polysaccharide responsiveness (partial antibody deficiency)  Selective IgA deficiency (IgAD) Treatment of Acute Bronchitis Supportive Treatment

In acute bronchitis, medical therapy generally targets symptoms and includes use of analgesics and antipyretics.5 Cough suppressants may produce symptomatic relief but may also increase the risk of suppuration and inspissated secretions and, therefore, should be used judiciously. Antihistamines dry Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

clinical practice secretions and are not helpful; expectorants are likewise not indicated.4 Antimicrobial Treatment

Acute bronchitis is frequently treated with antibiotics in ambulatory practice to control infection. Untreated protracted bacterial bronchitis is likely a precursor to chronic suppurative lung disease and bronchiectasis,2 hence antibiotics may be indicated.

Role of Cefaclor in Acute Bronchitis Mechanism of Action

A bactericidal antibiotic, cefaclor binds to penicillinbinding proteins (PBPs) in the cytoplasm of bacteria and inhibits synthesis of bacterial cell wall (peptidoglycan) causing cell lysis and death.

Cefaclor, a b-lactam antibiotic like the penicillins, is mainly bactericidal. It inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific PBPs that are located inside the bacterial cell wall.

Antimicrobial Spectrum

Cefaclor has in vitro activity against a wide variety of organisms causing indicated community-acquired infections. It is active in vitro against many grampositive aerobes, gram-negative aerobes and selected anaerobic bacteria, including Staphylococcus aureus, S. pneumoniae, Streptococcus pyogenes and H. influenzae (including ampicillin-resistant strains).8 The spectrum of activity of cefaclor includes a wide range of gram-negative and gram-positive bacteria; in particular, Escherichia coli, Klebsiella spp., Proteus mirabilis, Salmonella spp. and H. influenzae are more susceptible to clinically achievable concentrations of cefaclor than cephalexin.9 Clinical Pharmacology

After oral administration of single doses, about 95% of cefaclor is absorbed following oral administration.

Peak serum concentration is attained about one hour after dosing in fasting subjects. Cefaclor is wellabsorbed when given with or without food. However, when taken with food, the peak concentration achieved is 50-75% of that observed in fasting subjects.

Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

The serum half-life of cefaclor in healthy subjects is independent of dosage form and averages approximately one hour. After oral administration, cefaclor is excreted unchanged in the urine.10 Clinical Efficacy

Cefaclor is used for the treatment of lower respiratory tract infections including acute bronchitis.

The efficacy of antibiotic treatment in bacterial lower respiratory tract infections is partly dependent on the levels reached by the drug and on the length of stay at the site of infection.11 Cefaclor penetrates well into bronchial mucosa

In a study, bronchial mucosal biopsy specimens were obtained during fiberoptic bronchoscopy in 30 patients receiving cefaclor; of these, 10 were given 250 mg, 10 had 500 mg and 10 had 1,000 mg every eight hours. In 10 patients (from all dosage groups) cefaclor was undetectable in the bronchial mucosa but in every case the serum concentration was low, suggesting incomplete absorption. The mean (SD) bronchial mucosal concentration after 250 mg was 3.78 (1.77) µg/g (range 2.1-5.8 µg/g, n = 4), after 500 mg 4.43 (2.04) µg/g (range 2.0-7.1 µg/g, n = 8) and after 1,000 mg 7.73 (2.76) µg/g (range 5.0-12.7 µg/g, n = 6). A significantly higher concentration in the bronchial mucosa was achieved with 1,000 mg than with 250 mg (p < 0.05) or 500 mg (p < 0.025). These concentrations are effective against S. pneumoniae, most strains being inhibited <1.0 µg/ml. The concentrations were within one dilution of the minimal inhibitory concentration (MIC) for H. influenzae, most strains being inhibited <4.0 µg/ml.12 A laboratory analysis was done on 466 isolates of respiratory tract pathogens collected from 13 laboratories to determine the antimicrobial activity of cefaclor against common respiratory tract pathogens concluded that resistance of respiratory tract pathogens to the second generation cephalosporin, cefaclor is very low. MIC90 of cefaclor against all three common respiratory tract pathogens is <2 µg, which indicates that cefaclor would be effective in >90% of cases infected with these bacteria.13 In an earlier study of children with acute respiratory tract infection showed 100% sensitivity to cefaclor 489

clinical practice as compared to 31% resistant to cotrimoxazole and 39% resistance to chloramphenicol.14 In 1993, the global surveillance study of cefaclor showed >90% susceptibility of common respiratory bacterial pathogens to this antibiotic.15 A large multicenter multinational collaborative study, the Alexander Project, involving 15 centers throughout the world evaluated the susceptibility of 6,385 community-acquired lower respiratory tract pathogens to 15 antimicrobial agents. Out of 818 isolates of M. catarrhalis 82% were b-lactamase producers and >90% isolates were susceptible to cefaclor.16 Cefaclor is safe and efficacious in the treatment of bacterial respiratory tract infections in children

A multicenter, open label and noncomparative study was done to evaluate the response in terms of symptoms (in vivo) and bacterial cultures (in vitro) to cefaclor amongst children with respiratory tract infection between the ages two months to 12 years.

Patients were evaluated on Day 0 (initial evaluation prior to commencement of study), Day 4 (during therapy assessment and confirmation of compliance) and Day 10 (end of therapy assessment and compliance evaluation). One hundred seven children completed the study as per protocol.

Cefaclor is an oral semi-synthetic cephalosporin, effective against various respiratory pathogens.13 It has proven efficacy in the management of respiratory tract infections due to its molecular stability, activity against the most prevalent gram-positive and gramnegative respiratory tract pathogens, rapid absorption, >90% bioavailability and good penetration into respiratory mucosa. After years of extensive use, cefaclor remains clinically effective in patients with respiratory tract infections, making it competitive with other cephalosporins and with macrolides and fluoroquinolones, including many newer agents used for respiratory tract infections. Cefaclor was welltolerated; the few adverse effects related to therapy with cefaclor are usually minor and transient, and that drug-drug interactions involving cefaclor are rare.18 References 1. Klig JE, Chen L. Lower respiratory infections in children.

Curr Opin Pediatr 2003;15(1):121-6.

2. Chang AB, Chang CC, Oâ&#x20AC;&#x2122;Grady K, Torzillo PJ. Lower respiratory tract infections. Pediatr Clin North Am 2009;56(6):1303-21.

The most common pathogen reported was b-hemolytic Streptococcus (group A, C, F, G) followed by S. aureus, H. influenzae and S. pneumoniae. The study found that sensitivity of cefaclor for bacteria commonly seen in the respiratory tract was >90% in most of the cases.

Evaluation of the 42 culture proven cases for patients who completed the study showed that cefaclor had a 93% efficacy for indicated bacteria and 54% for nonindicated bacteria. In vivo analysis of cefaclor (i.e. on the basis of symptomatic response) showed that 96% cases had a symptomatic response by the second visit, which improved to 97% by the third visit.17

3. Fleming DM, Elliot AJ. The management of acute bronchitis in children. Expert Opin Pharmacother 2007;8(4):415-26.

Conclusion

7. Stiehm ER. The four most common pediatric immunodeficiencies. J Immunotoxicol 2008;5(2): 227-34.

Respiratory tract infection is one of the most common diseases prevalent in the community with high mortality rates especially in developing countries. Knowledge of the susceptibility pattern of bacteria most often involved in such infections is very important because in most cases sputum culture and susceptibility testing is not requested and empirical treatment is given.

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The susceptibility pattern of common bacterial isolates serves as a guideline for the choice of appropriate antibiotics.13

4. Watts KD, Goodman DM. Wheezing, bronchiolitis, and bronchitis (Chapter 388). In: Kliegman: Nelson Textbook of Pediatrics. 18th edition, An Imprint of Elsevier, Saunders, 2007.

5. Carolan PL. Pediatric bronchitis. Available at: http:// emedicine.medscape.com/article/1001332 6. Weigl JA, Puppe W, Belke O, NeusĂźss J, Bagci F, Schmitt HJ. The descriptive epidemiology of severe lower respiratory tract infections in children in Kiel, Germany.

Klin Padiatr 2005;217(5):259-67.

8. Rodriguez WJ, Ross S, Schwartz R, Goldenberg R, Khan W. Cefaclor in the treatment of susceptible infections in infants and children. Postgrad Med J 1979; 55(Suppl 4):35-8.

9. Derry JE. Evaluation of cefaclor. Am J Hosp Pharm 1981;38(1):54-8.

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clinical practice 10. Glynne A, Goulbourn RA, Ryden R. A human pharmacology study of cefaclor. J Antimicrob Chemother 1978;4(4):343-8.

Anwar F, Granoff DM, et al. Antimicrobial resistance of pneumococci in children with acute lower respiratory infection in Pakistan. Lancet 1991;337:156-9.

11. Intrapulmonary penetration of antimicrobials and implications in the treatment of lower respiratory tract infections (Chapter 2). In: Antibiotics and the Lung.

Cazzola M, Blasi F, Ewig S, (Eds.), European Respiratory Society Monograph 2004;28:13-44.

15. Preston DA. The global surveillance of bacterial susceptibility to cefaclor. Clin Ther 1993;15(1): 88-96.

12. Marlin GE, Nicholls AJ, Funnell GR, Bradbury R. Penetration of cefaclor into bronchial mucosa. Thorax 1984;39(11):813-7.

13. Ahmed A, Hafiz S, Rafiq M, Tariq N, Abdulla EM, Hussain S, et al. Determination of antimicrobial activity of cefaclor on common respiratory tract pathogens in Pakistan. J Pak Med Assoc 2002;52(1):7-11.

14. Mastro TD, Ghafoor A, Nomani NK, Ishaq Z,

16. Schito GC, Mannelli S, Pesce A. The Alexander Project Group. Trends in the activity of macrolide and b-lactam antibiotics and resistance development. J Chemother 1997;9(Suppl 3):18-28.

17. Najam Y, Walla FL, Iqbal A, Khan MK, Aqil S, Sharif MW, et al. The efficacy and safety of cefaclor in respiratory infections amongst Pakistani children.

J Pak Med Assoc 2000;50(9):289-93.

18. Meyers BR. Cefaclor revisited. Clin Ther 2000;22(2): 154-66.

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Review article

Role of Herbolax in the Management of Constipation and Preradiography Abdominal Preparation NS Sasi Kumar*, Suprabha Hegde**

Abstract Constipation is a common medical disorder encountered in clinical practice. The etiology of constipation is multifactorial viz. immobility, inadequate fluid and dietary fiber intake, and drugs. The management of constipation includes symptomatic control, dietary advice, increased fluid intake, improvement in mobility and toileting for an effective outcome. Currently available treatment options for constipation have various limitations either due to the latency period of action or adverse effects. Herbolax, a polyherbal formulation, acts gently and ensures smooth evacuation of fecal matter without disturbing the fluid-electrolyte balance. It does not cause physiological dependence, and hence, is safe for long-term use.

Key words: Constipation, preradiography abdominal preparation, Herbolax

C

onstipation is a common medical disorder encountered in clinical practice. Various epidemiological studies report prevalence of constipation to be ~20%; ~50% patients in palliative care units report suffering from constipation.1,2 Constipation can be due to primary motor disorder or other systemic diseases, or an adverse effect of many drugs or chronic illness. It may be exacerbated by physical immobility as a bedridden patient is unble to respond to defecatory signals. Factors such as underlying illness, medications and dietary inadequacies also contribute to constipation these patients.3 Because the diagnosis of constipation relies on symptomatic criteria, a consensus was reached on the definition of functional constipation and it was recommended that “two or more of the following factors must be noted for at least three months: i) Straining with defecation at least one-fourth of the time ii) lumpy or hard stools or both, at least one-fourth of the time and (iii) sensation of incomplete evacuation at least one-fourth of the time, or two or fewer bowel movements in a week”.4 The etiology of constipation is multifactorial viz. immobility, inadequate fluid and dietary fiber intake, and drugs. Consumption of a fiber-depleted diet has been implicated in constipation and increased dietary fiber intake has been shown to

accelerate colonic transit and produce more frequent, bulky stools.5,6 Most drugs (opioids, antiemetics, anticholinergics-antispasmodics, antidepressants, neuroleptics, aluminium salts and nonsteroidal antiinflammatory drugs) cause constipation by increasing intestinal smooth muscle tone, suppressing forward peristalsis, raising anal sphincter tone and reducing the sensitivity to rectal distension. Other causes include congenital, irritable bowel syndrome, systemic disorder (endocrine, metabolic or neurologic), structural abnormality, slow transit constipation or pelvic floor dysfunction. Bowel management is a common problem in patients with spinal cord compression where a combination of immobility, loss of rectal sensation and poor anal tone may result in constipation with variable degrees of abdominal distension, nausea and vomiting. The term ‘functional constipation’ is used to indicate that no secondary cause for the symptoms can be identified.7 The most commonly associated symptoms of constipation include flatulence, bloating, abdominal pain, feeling of incomplete evacuation, anorexia and feeling of nausea and vomiting.

Hemorrhoids, anal fissures and endocrine dysfunction may be concurrently present. Constipation may be the most common gastrointestinal (GI) complaint in most diabetic persons.8

*Assistant Professor Dept. of Pharmacology, Mandya Institute of Medical Sciences, Mandya **Research Associate, The Himalaya Drug Company, Makali, Bangalore Address for correspondence Dr Suprabha Hegde Research Associate The Himalaya Drug Company, Makali, Bangalore - 562 123 E-mail: dr.suprabha@himalayahealthcare.com

Various tests are done to evaluate the anatomical and physiological abnormalities. Anorectal manometry provides information about resting anal sphincter tone and squeeze pressure including testing for the presence or absence of the rectoanal inhibitory reflex. Balloon expulsion is the single most useful screening test of

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Review ARticle pelvic floor function. Anorectal angle determination is useful in patients with symptoms of outlet dysfunction.

‘Radiopaque Marker Transit Test’ is a simple, readily available, well-validated test of overall colonic transit,9 which can also be measured scintigraphically.10 Sigmoidoscopy should be done in all cases of persistent constipation; for patients above 40 years, a barium enema examination is also indicated. Colonoscopy is preferable in the setting of iron deficiency anemia or if a first-degree relative has colon cancer.11 The management of constipation includes symptomatic control, dietary advice, increased fluid intake, improvement in mobility and toileting for an effective outcome. The use of laxatives for treating constipation is deeply rooted in medical and social traditions, but laxative abuse has been shown to be associated with various short- and long-term adverse effects.12,13 Laxatives aim to achieve comfortable defecation rather than achieve any particular frequency of evacuation. The choice of laxative depends on the nature of the stools, cause of constipation and patient acceptability. Oral laxatives are subgrouped as ‘predominantly softening surfactants’, ‘osmotic laxatives’, ‘bulking agents’, ‘saline laxatives’, ‘lubricants’ and ‘predominantly peristalsis stimulating agents’. ‘Softener laxatives’ increase stool bulk and lead to reflex stimulation of peristalsis; the ‘peristalsis stimulator laxatives’ enhance intestinal fluid secretion and so improve stool consistency. ‘Surfactant laxatives’ act as detergents, increasing water penetration and thus soften the stools.14 Currently available treatment options for constipation have various limitations either due to the latency period of action or adverse effects. Docusates have a latency of action of 5-7 days. Osmotic laxatives have latency upto five days and may cause bloating, colic and flatulence. Bulk forming agents are stool normalizers rather than true laxatives. Saline laxatives can produce an undesirable strong purgative action, while lubricants cause irritation with long-term use. A clear picture of the GI tract is an important prerequisite for accurate and unambiguous radiological diagnosis. Amongst the commonest causes of poor X-rays of the abdomen are fecal matter, gas or air in the GI tract. So all X-rays of the abdomen, lumbosacral spine, IVP, etc. should be done only after proper bowel preparation to eliminate intestinal gases or air and fecal matter to arrive at a proper diagnosis. Failure to do so may cause delay and increase cost for the patient. Repeated X-rays are also hazardous to the patient and staff.

Herbolax is a polyherbal formulation and has been found 494

to be efficacious in the treatment of constipation, and preradiographic preparation of abdomen for an accurate diagnosis by showing good contrast in the skiagram.

Composition Each Herbolax capsule contains active ingredients: Extracts Trivruth (Ipomoea turpethum) 70 mg Haritaki (Terminalia chebula) 50 mg Kasani (Cichorium intybus) 50 mg Kasamarda (Cassia occidentalis) 50 mg Kakamachi (Solanum nigrum) 40 mg Yasthi-madhu (Glycyrrhiza glabra) 40 mg Powders Sunthi (Zingiber officinale) 45 mg Vidanga (Embelia ribes) 10 mg Processed in Markandika (Senna), Kumari (Fresh Aloe), Bhringaraja (Eclipta alba), Aragvadha (Cassia fistula), Sunthi (Zingiber officinale), Anjira (Ficus carica), Draksha (Vitis vinifera), Shatapuspha (Foeniculum vulgare), Triphala and Satapatri (Rosa damascena).

Pharmacological Actions of Principal Herbs Ipomoea turpethum (Syn: Operculina turpethum): Glycosidic acid is the main constituent. It has purgative, laxative and anti-inflammatory activities.15-18 Terminalia chebula: It contains tannin, chebulinic acid and some purgative principles of the nature of anthraquinone. It has astringent, laxative and alterative activities.19 Its fruit is known to increase gastric emptying time. This action appeared to have protective effect on the gastrointestinal mucosa, with improvement in the secretory status of Brunner’s gland involved in the protection against duodenal ulcer, an additional property of the herb. It also has antioxidant activity. The trial also showed purgative activity of T. chebula oil. The short-term clinical trial with T. chebula extract showed that the herb had the property of completely evacuating the bowel. It has no adverse effects.20 Cichorium intybus: It contains saponins like cichoriin, esculetin and esculin. It has diuretic and laxative activities.21 Main therapeutic uses of C. intybus are as digestive, laxative, aperitif and antispasmodic.22 Chicory (C. intybus), by far the most commonly used source of inulin (later processed to have oligofructose) is a functional food ingredient as it affects physiological and biochemical processes in rats and human beings, resulting in better health and reduction in the risk of many diseases. Experimental studies have shown their Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

Review ARticle use as bifidogenic agents by relieving constipation along with other useful pharmacologic activities. Inulin ingestion improved constipation along with increase in stool mass as observed in a clinical trial.23 Cassia occidentalis: Sennosoids, anthraquinone from C. occidentalis act mainly on rectum and colon, and also have hepatoprotective activity.24 Its use is widely accepted as laxative and anthelmintic.25 Studies show its definite laxative activity and use in constipation.26,27 Solanum nigrum: Alkaloids like solanine, and other saponins provide laxative activities and also benefit in hepatic health.28 It is well known for its wide therapeutic activity that includes laxative activity.29 Glycyrrhiza glabra: The major alkaloids are glycyrrhizin, glycyrrhizic acid that provide tonic, laxative, demulcent activities.30 The British Herbal Compendium also indicates its use in chronic gastritis and provides GI support. It has spasmolytic, mild laxative activities.31 GI prokinetics promote coordination of the gut wall contractions, enhancing propulsive motility and consequently caudal displacement of luminal contents.

Research shows that G. glabra has definite prokinetic activity and helps relieve constipation.32 Zingiber officinale: The rhizome contains essential oils which have monoterpenes, mainly geranial and neral, and sesquiterpenes. It is an antiflatulent, antispasmodic and is used in irritable bowel syndrome. It also enhances bioavailability of the other actives.33 [6]-gingerol from Z. officinale modulates small intestinal motility by either enhancing or inhibiting intestinal muscle tone; contributes to peristaltic activity via a direct action on the muscle cells and stimulating nerves.34 Embelia ribes: The dried fruit contains embelic acid, embedin and volatile oil. It has anthelmintic and gastrosupportive effects.35 Studies have been shown that it also has anthelmintic efficacy upto 93%, relative to pyrantel tartate.36

Patients and Methods

Inclusion Criteria: Patients in the age group of 30-65 years suffering from chronic constipation and willing to sign informed consent document.

Exclusion Criteria: Patients with suspected carcinoma, rectal prolapse, perianal abscess and not willing to sign informed consent.

Study Procedure: Forty-five patients (24 female and 21 male) suffering from chronic constipation were included in the study. All the subjects were given Herbolax tablet at a dose of two tablets at bedtime.

Patients were asked to report if they had a sense of griping pain, purging, colic or excessive watery stools or a sense of thirst and weakness to rule out electrolyte imbalances. Treatment was stopped once the patient was relieved of constipation and all the subjects were followed up for two weeks.

Results

All the patients responded to Herbolax from the first dose onwards. Seven subjects with chronic constipation responded after 4-5 days. In 18 cases, Herbolax was stopped from the 3rd day onwards, whereas it was continued in the rest for one week. All patients reported smooth evacuation without any strain. No subject reported purging, griping or abdominal pain and watery stools, weakness, lethargy or cramps.

Efficacy was evaluated based on the subjective description of the grade in relief from constipation as excellent (n = 13), good (n = 18), fair (n = 14) or no response (n = 00).

Conclusion

Several clinical trials have been conducted to evaluate the safety and efficacy of Herbolax.

The response of the patients to Herbolax indicates that it contains optimal amount of ingredients, which do not induce side effects, nor overactivity of the GIT. The absence of the symptoms of electrolyte disturbance indicates that Herbolax does not tamper with the vital internal milieu of the body. Thus, it may be stated that Herbolax is free from side effects and dependency.

Clinical Trial 1

Clinical Trial 2

A clinical trial of Herbolax in constipation during postoperative period.37

Experiences in the treatment of constipation in pregnancy with a herbal drug - Herbolax.38

Aim

Aim

To evaluate the efficacy and safety of Herbolax in patients with acute and chronic constipation.

To establish use of Herbolax as safe and effective remedy in constipation in obstetric and gynecological cases.

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Review ARticle Patients and Methods

Inclusion Criteria: Women who complained of constipation in obstetric and gynecological cases and willing to sign informed consent.

Exclusion Criteria: Patients with history of alcohol or smoking abuse and not willing to sign informed consent.

Study Procedure: Two hundred cases (drawn both from obstetric and gynecological units) were selected for this open clinical trial. They had not had bowel movement for 2-3 days. The obstetric cases were taken from all three trimesters and also from postnatal cases; the gynecological cases were mainly postoperative. All the patients were given Herbolax two tablets at bedtime and the time of evacuation of bowels was noted.

Results

One hundred forty patients (70%) had bowel movements on the very next day after the first dose, 55 patients (27.5%) required a second dose (moderate response). Five patients did not have bowel movements even after the second dose. No adverse effects were reported or observed during the entire study period.

Conclusion

Results showed that Herbolax can be safely recommended for simple nonorganic constipation during pregnancy, in postpartum and postoperative cases.

Clinical Trial 3 Trial with Gasex and Herbolax for abdominal preparation before radiological examination.39 Aim

To assess the effectiveness of Gasex and Herbolax for preparation of patients who were referred for X-rays of the abdomen, excretory system and lumbosacral spine, urography and oral cholecystograms.

Patients and Methods

Inclusion Criteria: Patients scheduled for X-rays of the abdomen, excretory system and lumbosacral spine, urography and oral cholecystograms and willing to sign informed consent.

Exclusion Criteria: Patients with history of alcohol and smoking abuse and unwilling to sign informed consent.

496

Study Procedure: Five hundred seventy patients (393 males and 177 females) with age ranging from nine to 85 years were included in the study. Two tablets of Herbolax at bedtime were given to only those patients who were either below the age of 12 years (4 cases), or gave a history of undue sensitivity to laxatives (26 cases). The remaining 540 cases were advised four tablets at bedtime for 2 days. Gasex was administered as two tablets thrice-daily, irrespective of the age and bowel habits of the individuals.

Results

Most cases (63%) in Group I (normal bowel habits) had more than one motion the next morning. In Group II (sometimes constipated), 55% had more than one motion, while in Group III (often constipated) the number of such cases was reduced to 33.3% only.

X-ray examination in 92% cases showed satisfactory preparation; the X-rays obtained were of adequate diagnostic quality. Only 8% showed poor preparation.

There were absolutely no side effects.

Conclusion

The combination of Gasex and Herbolax can be recommended for preparation of abdomen before radiological examinations.

Clinical Trial 4 Role of Herbolax in radio-diagnosis.40 Aim

To assess effectiveness of Herbolax for preparation of patients who were referred for plain X-ray of abdomen, KUB (kidney, ureter and bladder), gallbladder region and lumbosacral spine.

Patients and Methods

Inclusion Criteria: Patients scheduled for plain X-ray of abdomen, KUB, gallbladder region and lumbosacral spine and willing to sign informed consent.

Exclusion Criteria: Patients with history of alcohol and smoking abuse and unwilling to sign informed consent.

Study Procedure: On the night before the X-ray examination, 40 patients were advised to take light diet at bedtime; Herbolax (4-6 tablets at bedtime with cold water); nil orally in the morning and to report for X-ray examination at 9 a.m.

Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

Review ARticle Results

There were no gas shadows or fecal matter to obstruct the view. Kidney shadows, gallbladder or spinal vertebrae were well-outlined and visualized. Radioopaque shadows were clear and measurement of the kidney size was possible.

Conclusion

Results showed that Herbolax is safe and effective in the preradiographic preparation of abdomen. There were absolutely no side effects.

Summary of the Review Herbolax, a polyherbal formulation, acts gently and assures smooth evacuation of fecal matter without disturbing the fluid-electrolyte balance. It does not cause physiological dependence, and hence, is safe for long-term use. The response of the patients to Herbolax indicates that it contains optimal amount of ingredients, which do not induce side effects, or overactivity of the GIT. Absence of symptoms of electrolyte disturbance indicates that Herbolax does not tamper with the vital internal milieu of the body. Therefore, it could be concluded that Herbolax is a safe and efficacious option for the treatment of constipation and preradiography preparation of the abdomen.

References 1. Talley NJ, et al. Gastroenterology 1993;105(3):781-90.

2. Stewart WF, et al. Am J Gastroenterol 1999;94(12): 3530-40.

3. Swenson WM, et al. Am J Surg 1968;115(3):405-7.

4. Thompson WG, et al. Gastroenterol Int 1992;5:75-91.

5. Badiali D, et al. Dig Dis Sci 1995;40(2):349-56.

6. Burkitt DP, et al. JAMA 1974;229(8):1068-74.

7. Thompson WG, et al. Gut 1999;45(Suppl 2):43-7.

8. Maleki D, et al. Dig Dis Sci 1996;41:1900.

9. Hinton JM, et al. Gut 1969;10(10):842-7.

10. Stivland T, et al. Gastroenterology 1991;101(1):107-15.

11. Fallon M, O’Neil B. BMJ 1997;315(7118):1293-6.

12. Sekas G. Pract Gastroenterol 1987;11:33.

13. Brocklehurst JC. Clin Gastroenterol 1985;14(4):725-47.

14. Prather CM, Ortiz-Camacho CP. Mayo Clin Proc 1998;73(9):881-7.

15. Anonymous. Agro-techniques of selected medicinal plants. National Medicinal Board. Department

of AYUSH. Ministry of Health & Family Welfare 2001;1:131.

16. Chopra RN, et al. Glossary of Indian Medicinal Plants.

National Institute of Science & Communication. 4th Reprint, New Delhi 1996a:181.

17. Chakma TK, et al. Ars Pharma 2006;47(2):211-7.

18. Md. Harun-Ur-Rashid, et al. Pak J Bio Sci 2002;5(9): 968-9.

19. Chopra RN, et al. Glossary of Indian Medicinal Plants.

National Institute of Science & Communication. 4th Reprint, New Delhi 1996b:242.

20. Chattopadhyay RR, Bhattacharya SK. Pharmacog Rev 2007;1(1):151-6.

21. Asolkar LV, et al. Second supplement to glossary of Indian Medicinal Plants with active principles. CSIR. Govt. of India, New Delhi 1992a:201.

22. Tiwari S. J Natural Products 2008;1:27-35.

23. Kaur N, Gupta KK. J Biosci 2002;27(7):703-14.

24. Asolkar LV, et al. Second supplement to glossary of Indian Medicinal Plants with active principles. CSIR. Govt. of India, New Delhi 1992b:179.

25. Jiofack T, et al. J Med Plant Res 2008;2(8):197-206.

26. Vaghasiya Y, et al. Turk J Biol 2007;31:243-8.

27. Ogunkule ATJ, et al. African J Biotechnol 2006;5(21): 2020-3.

28. Chopra RN, et al. Glossary of Indian Medicinal Plants.

National Institute of Science & Communication. 4th Reprint, New Delhi 1996c:229.

29. Yoganath N, et al. KUJSET 2009;5(1):99-103.

30. Chopra RN, et al. Glossary of Indian Medicinal Plants.

National Institute of Science & Communication. 4th Reprint, New Delhi 1996d:126.

31. Khare CP. Indian Medicinal Plants: an illustrative Dictionary. Springer, New Delhi 2007a:289-90.

32. Srinivasan D, et al. Pharmacog Mag 2009;5(17):37-42.

33. Khare CP. Indian Medicinal Plants: an illustrative Dcitionary. Springer, New Delhi 2007b:733-4.

34. Satoh K, et al. Biol Pharm Bull 2001;24(10):1122-6.

35. Hórdegen P, et al. J Ethnopharmacol 2006;108(1):85-9.

36. Chopra RN, et al. Glossary of Indian Medicinal Plants.

National Institute of Science & Communication. 4th Reprint, New Delhi 1996e:106.

37. Reddy K, Kulkarni KS. The Antiseptic 2001;98(7): 252-3.

38. Gupta SS, et al. Probe 1979;XVIII(2):93-5.

39. Singh I, Singh R. Ind Med J 1986;80(6):87.

40. Gupta P. Capsule 1986;(Feb./Mar.):133-4.

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Clinical review

Role of Prebiotics and Probiotics in Treatment of Irritable Bowel Syndrome (IBS) RT Borse*, RM Barve**

Abstract Irritable bowel syndrome (IBS) is a chronic condition and one of the commonest functional gastrointestinal disorders affecting 3-15% of the general population. It is characterized by abdominal pain or discomfort, and bloating along with altered bowel habits. The pathophysiology of IBS is least understood, but it is believed to be multifactorial. IBS has been associated with several factors such as dysmotility, motor and sensory dysfunction, abnormal fermentation, immune mechanisms, visceral hypersensitivity and alteration in intestinal microflora and psychological factors. Probiotics have been shown to have a beneficial effect in IBS by restoring normal flora in intestine. Probiotics in IBS diminish gas production by changing the colonic flora. In this review, randomized control trials were selected in which patients of IBS were treated either with probiotics or with placebo. Preliminary results are encouraging and show a trend towards the improvement of symptoms of IBS by using probiotics. As evidenced by many studies, probiotics are safe and well-tolerated.

Key words: Irritable bowel syndrome, probiotics, microflora

I

rritable bowel syndrome (IBS) is a chronic condition and one of the most common functional gastrointestinal disorders that severely hampers the quality-of-life of affected individuals.1 The prevalence of IBS in the general population ranges from 3% to 15% and is more commonly seen in females (2 or 3 times than males).2 IBS is characterized by intermittent abdominal pain or discomfort, altered bowel habits (diarrhea and/or constipation) and other gastrointestinal symptoms such as bloating and flatulence in the absence of structural abnormalities in the intestine. IBS is encountered commonly in clinical practice; still there is a need to understand its pathophysiology.

Several factors such as dysmotility, motor and sensory dysfunction, abnormal fermentation, immune mechanisms, visceral hypersensitivity and psychological factors are believed to be involved.3-5 The characteristic symptom patterns according to the IBS consensus ‘Rome II’ criteria are shown in Table 1.6 As no curative treatments are available, currently the drugs in IBS management are used mainly for alleviating the symptoms. Antispasmodic drugs can be used for pain, laxatives can be used for relieving constipation and *Associate Professor, Dept. of Medicine **Assistant Professor, Dept. of Pharmacology BJ Medical College and Sasoon General Hospitals, Pune Address for correspondence E-mail: rohidas_borse@yahoo.co.in

Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

Table 1. Rome II Consensus Diagnostic Criteria for Irritable Bowel Syndrome (IBS)6 At least 3 months or more, which need not to be consecutive, in the preceding 12 months of abdominal pain that has at least 2 features:  



Relieved with defecation Onset associated with a change in form (appearance) of stool Onset associated with a change in frequency of stool

Symptoms which support the diagnosis of IBS: 



Abnormal stool frequency (‘abnormal’ may be defined as >3 bowel movements per day and <3 bowel movements per week) Abnormal stool passage (straining, urgency or feeling of incomplete evacuation)



Abnormal stool form (hard or watery stool)



Abdominal bloating

antidiarrheal agents can be used for the management of diarrhea. The evidence for efficacy of the most of the drugs in the treatment of IBS is weak.7 Newer drugs, such as different serotonergic receptor modulators like tegaserod (5-HT4 agonist) and alosetron (5-HT3 antagonist), are efficacious but, because of concerns about possible cardiovascular risks8 and enterocolitis,9 respectively, now a days, these newer drugs are either unavailable or have restrictions for general use. Probiotics may be the good alternative for current therapy for IBS because recent studies have observed alteration in intestinal microflora 499

Clinical review in IBS patients10,11 that can be restored by using probiotics.12 Probiotics are living micro-organisms (bacteria or yeasts), which have potential beneficial effects in the prevention or in the treatment of various gastrointestinal and other disorders. Prebiotics are poorly absorbed dietary oligosaccharides, which stimulate gut beneficial microbes.13 This review will discuss brief overview of probiotics and prebiotics, the potential role of probiotics in the treatment of IBS concentrating on how their currently known benefits influence the pathophysiology of IBS. The evidences from randomized, placebo-controlled trials are also reviewed.

Probiotics and Prebiotics The term probiotic was derived from a Greek word, which means ‘for life’. Probiotics are defined as “live microbial food supplements or components of bacteria which have been shown to have beneficial effects on human health”.14 Probiotics consist of either yeasts or bacteria. The micro-organisms most commonly used as probiotics are lactobacilli and bifidobacteria. Prebiotic is also described as “nonabsorbable food components that beneficially stimulate one or more of the gutbeneficial microbe groups and thus have a positive effect on human health”.15 The most commonly used prebiotic is fructo-oligosaccharides.

For an organism to be considered as probiotic, the following criteria need to be fulfilled:  It should be isolated from the same species as its intended host.  It should be nonpathogenic.  It should have a demonstrable beneficial effect on the host.  It should be able to survive transit through the gastrointestinal tract.  On storage, large number of viable bacteria must be able to survive over a prolonged period.

Single or mixed cultures of live micro-organisms are used in probiotic preparations (Table 2).16 These probiotics may be useful in various conditions. Indications, where probiotics can be used are shown in Table 3.

Since, probiotics contain live micro-organisms which are beneficial, concurrent administration of antibiotics can kill a large number of the organisms, reducing the efficacy of the Lactobacillus and Bifidobacterium species. Patients should be strictly instructed to separate administration of antibiotics from these 500

Table 2. Micro-organisms Used as Probiotics Bacteria

Yeast and moulds

Lactobacillus: acidophilus, rhamnosus, sporogenes, plantarum, delbrueckii, reuteri, fermentum, lactis, cellobiosus, brevis

Saccharomyces boulardii

Bifidobacterium: bifidum, infantis, longum, animalis

Aspergillus niger

Streptococcus: thermophilus, lactis, cremoris, salivarius, intermedius

Saccharomyces cerevisiae Aspergillus oryzue Candida pintolopesii

Propionibacterium Pediococcus Bacillus

Table 3. Indications for Use of Probiotics17 Rotavirus diarrhea

Inflammatory bowel disease

Irritable bowel syndrome

Helicobacter pylori infection

Diarrhea (antibioticassociated or in travelers)

Various cancers

Prevention of vaginitis

Dental caries

Urogenital infections

Atopic eczema

Cystic fibrosis

bacteria-derived probiotics by at least two hours.18 Probiotics should be used cautiously in patients taking immunosuppressants such as cyclosporine, azathioprine and chemotherapeutic agents, since probiotics could cause an infection in immunocompromised patients.19 Probiotics are generally considered safe and well-tolerated. As evidenced by epidemiologic studies, bacteremia or sepsis from lactobacilli is extremely rare.

Numerous probiotics have a long history of safe use and no health hazards have been observed.20 Proposed Mechanism of Action of Probiotics in IBS

There is evidence for a pro-inflammatory state in IBS patient. A recent study reported increased number of activated mast cells in the proximity of colonic nerves in the lamina propria, where mast cell secreted mediators such as histamine and tryptase may play role in the development of abdominal pain.21 Another evidence for a pro-inflammatory state in IBS patients comes from a recent study reporting decreased interleukin (IL)-10/IL-12 ratios in IBS patients. O’Mahony et al reported that treatment of IBS with Bifidobacterium infantis normalized pro-inflammatory IL-10/IL-12 ratios towards an anti-inflammatory state, which was associated with significant improvement in IBS symptoms.22 Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

Clinical review Pain is one of the important symptoms in IBS and visceral hypersensitivity is believed to be responsible for this symptom.23 Beneficial probiotic effects on sensory mechanisms are proposed by two clinical trials that demonstrated significant improvement of abdominal pain in IBS patients after treatment with different Lactobacilli or Bifidobacteria.22,33 Altered bowel habits such as diarrhea or constipation are main characteristics of IBS for which altered gut motility is considered to be an important underlying factor. One recent study indicates a potential beneficial influence of probiotics in improving gut motility.24 The resident flora play very important role in enhancing the intestinal barrier function, i.e., preventing adhesion and thereby inhibiting the invasion of pathogenic agents into the body.25 There is evidence that postinfectious IBS patients may experience increased gut permeability.26 A recent study

by Lamine et al showed an improvement of barrier functions by probiotics.27 Bloating and abdominal distension are commonly seen in patients with IBS. Dysmotility and consequent difficulty in propelling gas may be responsible for these symptoms. King et al observed a greater gas production in IBS patients than in control individuals, which suggests that abnormal fermentation may be responsible for bloating in some IBS patients.4 Probiotics, which are aimed at reducing abnormal fermentation, may be useful only in those patients in whom abnormal fermentation is due to altered flora.28 Alteration of the colonic flora with administration of probiotics may modify fermentation processes and hence gas production, colonic transit and fluid fluxes.

In fact, abdominal bloating, distension or flatulence, which are dominant symptoms in many IBS patients, have been shown to improve significantly by probiotic treatment in several placebo-controlled trials.22,29 Current Evidence from Randomized Placebocontrolled Clinical Studies

To evaluate the evidence for usefulness of probiotics in IBS, we chose to focus only on data from randomized placebo-controlled clinical trials. In such trials, patient of IBS were taken who were either treated with placebo or with probiotics. Summary of these trials is shown in Table 4.22,29-38 Nobaek et al observed a significant improvement in flatulence in Lactobacillus plantarum-treated group Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

as compared with placebo-treated group. In both the probiotic and the placebo-treated groups, pain parameter was improved. In this study, there was a 12-month follow-up questionnaire, in which the probiotic-treated patients maintained better overall gastrointestinal functions than the placebotreated patients. This might suggest a possible longterm beneficial alteration in colonic flora due to probiotics.29 In another study (Niedzielin et al), there was a significant improvement of pain in L. plantarumtreated IBS patients and had a responder rate for overall IBS symptom improvement of 95% as compared with only 15% in the placebo group.30 In another study conducted by Kim et al, 25 patients of diarrhea-predominant IBS were either treated with placebo or PROBIOTIC-MIX*. There was borderline significant improvement in abdominal bloating, but no effects were seen on other IBS symptoms in PROBIOTIC-MIX* treated group.32 In his study, Saggioro A administered a combination of L. plantarum with Lactobacillus acidophilus. There was a significant improvement in pain and overall IBS symptom score by probiotic combination as compared to placebo-treated group.33 Kim et al (2005) observed a significant improvement of flatulence in the PROBIOTIC-MIX* group as compared with placebo group, but there were no statistical differences in relation with the improvement of bloating, pain and urgency scores in both groups.34 Oâ&#x20AC;&#x2122;Mahony examined the effects of two different probiotics, Lactobacillus salivarius and B. infantis, on IBS symptoms. Patients were randomized to receive either one of the two different probiotics or placebo.

The patients were assessed weekly for the symptoms of IBS over a period of eight weeks and also during the washout period of four weeks. This study included the assessment of quality-of-life, cytokine profiles i.e., the ratio between IL-10 and IL-12 in peripheral blood mononuclear cells, before and after treatment.

B. infantis was superior to placebo in alleviating all symptom scores except for stool frequency and stool consistency. Beneficial effects on the weekly symptom scores were significant in all eight treatment-weeks and 4 washout-weeks. In contrast, L. salivarius showed a significant symptom improvement over placebo only in the second treatment week. The most important finding of this study was the observation of a decreased baseline IL-10/IL-12 ratio in IBS patients that was normalized after treatment with B. infantis.

501

Clinical review Table 4. Summary of Randomized Placebo-controlled Clinical Trials Study

Probiotic

Patients (n)

O’Mahony 200522

B. infantis

75

Nobaek 200029

L. plantarum

60

Niedzielin 200130 Sen 200231 Kim 200332 Saggioro 200433

L. plantarum L. plantarum PROBIOTIC-MIX* L. plantarum

Kim, Vazquez 200534 Niv 200535 Kajander 200836 Hun 200937 Guandalini 201038

L. acidophilus PROBIOTIC-MIX* L. reuteri L. rhamnosus, P. freudenreichi, B. animalis B. coagulans GBI-30 PROBIOTIC-MIX*

40 12 25 70

Study design (all placebo-controlled) 8 weeks parallel group; 4 weeks washout 4 weeks parallel group; 12 months follow-up 4 weeks parallel group (2x) 4 weeks (crossover) 8 weeks parallel group 4 weeks parallel group

Significant symptomatic improvement in Pain, abdominal bloating

Pain None Abdominal bloating Pain, overall symptom score

48 54 86

4 or 8 weeks parallel group 6 months parallel group 5 months

Flatulence None Pain, distention

44 59

8 weeks 6 weeks parallel group 2 weeks washout (crossover)

Pain, abdominal bloating Individual symptom score for pain/ discomfort, bloating/distension

Flatulence

PROBIOTIC-MIX* = Probiotic cocktail containing Bifidobacteria (B. longum, B. infantis, B. breve), lactobacilli (L. acidophilus, L. casei, L. bulgaricus L. plantarum), and Streptococcus salivarius subspecies thermophilus.

The reduced baseline IL-10/IL-12 ratio shows a pro-inflammatory state providing further evidence for an immune-mediated pathophysiology of IBS. Moreover, the probiotic-induced normalization of the IL-10/IL-12 ratio towards an anti-inflammatory state suggests the beneficial effect of the probiotic on IBS symptoms. This gives an idea of involvement of immunomodulatory mechanisms in IBS symptom generation. Surprisingly, and despite improvement in composite symptom scores, quality-of-life was not improved in patients treated with probiotics.22 Kajander conducted a 5-month treatment trial in 86 patients with IBS either receiving multispecies probiotic supplementation (Lactobacillus rhamnosus GG, L. rhamnosus Lc705, Propionibacterium reudenreichii ssp. shermanii JS and Bifidobacterium animalis ssp. lactis Bb12) or placebo. Over the period of five months, probiotic-treated group showed improvement in the parameters like abdominal pain and distention. In this study, microarray-based intestinal microbiota stability was done. Probiotictreated group showed stabilization of the microbiota, as the microbiota similarity index increased with the probiotic supplementation while it decreased with placebo.36 The study conducted by Hun L, involved 44 subjects who received either placebo or Bacillus coagulans GBI-30, 6086 once a day for eight weeks.

Self-assessments of the severity of IBS symptoms 502

(abdominal pain and bloating) were recorded every day for eight weeks. Because baseline values were significantly different between the two study groups, within group analysis was conducted. Improvements from baseline, abdominal pain and bloating scores in the B. coagulans GBI-30, 6086 group were statistically significant for all weekly comparisons (p < 0.01). In the placebo group, only changes in abdominal pain scores at Weeks 6 and 8 achieved statistical significance (p < 0.05).37 In another study conducted by Guandalini S et al, children aged 4-18 years and diagnosed to have IBS were randomized to receive either PROBIOTICMIX* or a placebo for six weeks. At the end, after a ‘washout’ period of two weeks, each patient was switched to the other group and followed for a further six weeks. PROBIOTIC-MIX* was significantly superior to placebo in the primary endpoint i.e. the subjective assessment of relief of symptoms. No significant difference was found in the stool pattern. No untoward adverse effect was recorded in any of the patients.38 The study conducted by Niv et al in 54 patients with IBS who received either Lactobacillus reuteri ATCC 55730 or placebo for six months. Over the six months, the entire study population improved in all symptoms but there were no significant differences between the probiotic and the placebo group.

However, in the probiotic-treated patients, a trend towards better improvement in relieving constipation Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

Clinical review Table 5. Benefits of Using Probiotics in IBS 

Improvement in symptoms like predominant diarrhea/ constipation



Reduces abdominal pain



Reduces abdominal bloating/distension



Stabilizes intestinal microflora

7.

8.

9.

observed.35

and gas was Sen administered L. plantarum 299V or placebo to IBS patients in a crossover fashion.

No beneficial effect was seen on symptoms after administration of the probiotic.31 All clinical trials performed to date have low numbers of patients. Moreover, comparison between trials is difficult because of the different inclusion criteria, the different probiotic preparations and the treatment protocols used; however, it is the opinion of the authors of this review that probiotics may be beneficial in the treatment of IBS. As evidenced in most of the above studies, the use of probiotics is generally safe and well-tolerated by patients. The beneficial effects that a probiotic preparation can offer to the patient of IBS, as confirmed by the above studies, are enumerated in Table 5.

Conclusion In summary, data from basic and clinical research suggest that probiotics have effect on different IBS disease mechanisms by modulating immune responses, visceral sensory and motor functions. Current evidence from the above clinical trials confirm that probiotics have beneficial effects in improving the symptoms of IBS like abdominal pain, flatulence, diarrhea/ constipation. Probiotics are generally safe and welltolerated, as experienced in these studies. Most of the randomized placebo-controlled clinical trials showed promising results of probiotics in the management of IBS. This review suggests that probiotic therapy is a definitive promising strategy to treat the patients with IBS. References 1.

2.

3.

4.

5.

6.

Cain KC, et al. Am J Gastroenterol 2006;101(1):124‑32.

Cremonini F, Talley NJ. Gastroenterol Clin North Am 2005;34(2):189-204.

Cann PA, et al. Gut 1983;24(5):405-11.

King TS, et al. Lancet 1998;352:1187-9.

Camilleri M. Neurogastroenterol Motil 2005;17(3):311‑6.

Thompson WG, et al. Gut 1999;45(Suppl 2):II43-7.

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Quartero AO, et al. Cochrane Database Syst Rev 2005;18 (2):CD003460. h t t p : / / w w w. f d a . g ov / Dr u g s / Dr u g Sa f e t y / t m a r k e t Dr ugSafetyInformationforPatientsandProviders/ DrugSafetyInformationforHeathcareProfessionals/Public HealthAdvisories/UCM051284. Accessed on 30th December 2010. http://www.accessdata.fda.gov/drugsatfda_docs/label/ 2008/021107s013lbl.pdf. Accessed on 30th December 2010.

Quigley EM, Flourie B. Neurogastroenterol Motil 2007; 19(3):166-72.

Malinen E, et al. Am J Gastroenterol 2005;100(2):373‑82.

Andresen V, Baumgart DC. Inter J Probiotics Prebiotics 2006;1:11-8.

Sartor RB. Gastroenterology 2004;126(6):1620-33.

Salminen S, et al. Br J Nutr 1998;80(Suppl 1):S147‑71.

Gibson GR, Roberfroid MB. J Nutr 1995;125(6):1401‑2.

D’Souza AL, et al. BMJ 2002;324:1361.

Gorbach SL. Dig Liver Dis 2002;34(Suppl 2):S2-7.

Natural Medicines Comprehensive Database Lactobacillus monograph. www.naturaldatabase.com. Accessed 2010 December 30.

Marteau P, Shanahan F. Best Pract Res Clin Gastroenterol 2003;17(5):725-40.

Reid G. Clin Infect Dis 2002;35(3):349-50.

Barbara G, et al. Gastroenterology 2004;126(3):693‑702.

O’Mahony L, et al. Gastroenterology 2005;128(3):541‑51.

Delvaux M. Best Pract Res Clin Gastroenterol 2004;18(4): 747‑71.

Bazzocchi G, Dig Liver Dis 2002;34(Suppl 2):S48-53.

Baumgart DC. Curr Opin Clin Nutr Metab Care 2002; 5(6):685-94.

Spiller RC, et al. Gut 2000;47(4):804-11.

Lamine F, et al. Scand J Gastroenterol Hepatol 2004;39 (12):1250-8.

Balsari A, et al. Microbiologica 1982;5(3):185-94.

Nobaek S, et al. Am J Gastroenterol 2000;95(5):1231-8.

Niedzielin K, et al. Eur J Gastroenterol Hepatol 2001; 13(10):1143-7.

Sen S, et al. Dig Dis Sci 2002;47(11):2615-20.

Kim HJ, et al. Aliment Pharmacol Ther 2003;17:895‑904.

Saggioro A. J Clin Gastroenterol 2004;38(6 Suppl): S104‑6.

Kim HJ, et al. Neurogastroenterol Motil 2005;17(5): 687‑96.

Niv E, et al. Clin Nutr 2005;24(6):925-31.

Kajander K, et al. Aliment Pharmacol Ther 2008; 27(1):48‑57.

Hun L. Postgrad Med 2009;121(2):119-24.

Guandalini S, et al. J Pediatr Gastroenterol Nutr 2010; 51(1):24‑30.

n Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

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clinical diagnosis

A Study of Arginase Activity in Hepatocellular Damage as a Diagnostic Index NR Malukar*, Ajay S Dabhi**, M Vadivelan**, HB Sirajwalaâ&#x20AC;

Abstract Aims: To study arginase activity in hepatocellular damage as a diagnostic index by comparing it with other enzyme markers of hepatocellular damage like serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and alkaline phosphatase (ALP). Material and methods: The study was conducted at Shree Sayaji General Hospital, Vadodara. Fifty patients at hepatocellular damage with abnormal liver function tests were selected as study group. In control group, 50 normal subjects were taken without any hepatocellular damage for comparison. Among the study group, arginase activity was compared with other enzymes activity like SGOT, SGPT and ALP. Serum arginase was estimated by indirect urease method of Berthlot. Results: In this study, statistical analysis showed that arginase activity is more specific and highly sensitive for diagnosis of hepatocellular damage (jaundice) as an alternative to SGOT, SGPT and ALP, due to low value of coefficient of variation for arginase and organ specificity than other enzymes. Coefficient variation was lowest for arginase which concluded that it is most stable; its value does not change suddenly and gives similar values for similar levels of serum bilirubin of different patients. Its level rises with severity of damage unlike other enzymes. Conclusion: Serum arginase is simple less expensive, more stable, more sensitive and more specific as an alternative to SGOT, SGPT and ALP as a diagnostic index in hepatocellular damage.

Key words: Arginase, jaundice, liver function tests

H

epatocellular damage is manifested as jaundice. Increase in plasma bilirubin level and serum enzymes namely serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and alkaline phosphatase (ALP), etc. vary markedly throughout the clinical course of the disease. With passage of time, various new tests have been introduced such as lactate dehydrogenase (LDH), cholinesterase, gamma glutamyl transferase, arginase, etc. to know the severity of hepatocellular damage.

Due to diversity of normal liver function and diverse manifestations of hepatic disease, no single test is available to assess overall liver function and its correlation with severity of liver damage.

*Assistant Professor, Dept. of Biochemistry **Assistant Professor, Dept. of Medicine â&#x20AC; Professor and Head, Dept. of Biochemistry Medical College and Shree Sayaji General Hospital, Vadodara Address for correspondence Dr Ajay S Dabhi 38, Alkanagar, Near Priyalaxmi Mill, Old Alembic Road Vadodara - 390 003, Gujarat E-mail: dr_ajay_44@yahoo.co.in

504

Liver enzymes like SGOT, SGPT, ALP and their levels are affected not only in liver disease but in other diseases also, suggesting their nonorgan specificity. This is evident from Table 1, which shows a comparison of different enzymes in diagnosis of hepatocellular damage. So the present study was undertaken to find out an alternate enzyme which has organ specificity. The enzyme studied here is arginase.

Arginase Arginase (EC 3.5.3.1, L-arginine aminohydrolase) is the terminal enzyme of the urea cycle. It catalyzes the cleavage of L-arginine to L-ornithine and urea (Greenberg 1960). Normal range of arginase activity is 2.5-7.2 IU/l. The enzyme is present in significant concentration only in the liver of ureotelic (urea excreting) animals.2 G Ugarte, M.E. Pino (1960, 1961) found that serum arginase was increased in patients with hepatitis, cirrhosis of liver or hepatic coma, but not in other liver diseases including metastatic cancer.3 The serum arginase level increases 6-12 hours after liver damage, reaches peak value in 48 hours and returns to normal after recovery. Thus, determination of serum arginase in conjugation with SGOT or SGPT Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

clinical diagnosis Table 1. Comparison of Different Enzymes in Diagnosis of Hepatocellular Damage Enzymes

Occurrence

Serum glutamate Liver, kidney, oxaloacetic heart, skeletal transaminase muscle (SGOT)

Serum glutamate Richly found in pyruvic liver. In traces in transaminases other organs (SGPT)

Functions of Human Arginase6 

Comments Increases in acute hepatitis, major crush injuries, severe tissue hypoxemia, myocardial infarction, following surgery or trauma, skeletal muscle disease, cholestasis, chronic hepatitis, chronic pancreatitis and physiological in neonates.

Specific for liver disease. Level rises significantly in progressive muscular dystrophy and dermatomyositis.

Increase in liver cell damage, heart disease, cholestasis and cholecystitis.

Alkaline phosphatase (ALP)

Widespread in many organs.

Increases in liver disease, bone disease, Paget’s disease, rickets and hyperparathyroidism.

Serum arginase

Highest concentration is found in the liver (in cytosol of hepatocytes) and erythrocytes.

Trace amount in kidney, brain, mammary glands, skin and testes.

Increases in hepatocellular damage and chronic mammary carcinoma.

assays could be of value in assessing the stage of liver cell damage.4 Arginase has a molecular weight of 1,07,000.3,4 It has a smaller molecular size (35,000) and seems to leak out of liver cells more easily compared to SGPT (MW-14,000) and SGOT (MW-94,000).1 Half-life of arginase is apparently shorter in circulation.

Human liver arginase has two isoenzymes.5 Arginase is present in highest quantity in the liver and less abundantly in erythrocytes and leukocytes. It is present in trace amounts in kidney, intestine, mammary gland, brain, skin and testicular tissue.

Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011













Production of urea to eliminate ammonia from the body.

Arginase is able to inhibit lymphocyte proliferation.

It is also able to inhibit liver cell growth and may act as an antimitotic agent in tissue culture.

Arginase is secreted by macrophages to kill malignant cells in vitro.

Arginase is beneficial for immunity and wound healing.

Arginase is important in maintaining homeostasis of amino acids in the body.7 Inhibitors of arginase are mainly basic amino acids like ornithine and lysine.

Clinical Aspects of Arginase

Deficiency of arginase causes a state of hyperargininemia and finally causes growth retardation, neurological and intellectual impairment. Arginase deficiency may be hereditary or caused by hepatic function impairment. It is a rare autosomal recessive disorder.8 Arginase deficiency leads to elevated blood levels of arginase and ammonia. High ammonia levels are toxic.

Plasma urea levels are lower than normal. Urinary arginase, ornithine and arginosuccinic acid levels are elevated.9 A patient with hyperargininemia may present with:  Severe growth retardation  Microcephaly  Mental retardation  Inability to walk  Spasticity  Epileptiform EEG All these symptoms are because of arginase deficiency in liver and stratum corneum. Hyperargininemia is a rare autosomal recessive disorder.

Elevation in arginase level can be seen in  Blood  Cerebrospinal fluid  Urine 505

clinical diagnosis Aims of Study  To evaluate the incidence of hepatocellular damage in study and control group cases, its distribution among age and gender and clinical and diagnostic profile.  To observe the rise of serum levels of the enzyme arginase along with serum levels of bilirubin, transaminases (SGOT and SGPT) and ALP in patients with hepatocellular damage.  To study serum arginase activity in hepatocellular damage as a diagnostic aid and whether it offers any alternative to serum transaminases and ALP in terms of sensitivity and also specifically to hepatocellular damage.  To evaluate the importance of arginase level as a criteria for hepatocellular damage and determine the collective value of this with other liver function parameters.

Material and Methods Study Group

In this prospective study, 50 patients who were admitted in different medical and surgical wards at Shree Sayaji General Hospital, Vadodara, Gujarat formed the study group.

Control Group

For comparison, 50 normal subjects were taken with identical age, sex and other parameters without any hepatocellular damage, renal failure and CCF. It was also confirmed that they all were nonalcoholic.

Methods

A detailed history and clinical examination was done in each case. Blood samples were collected from all cases and analyzed for serum bilirubin (total, direct and indirect) SGOT, SGPT and ALP and arginase. Urine was tested for the presence of albumin, sugar, bile salts and bile pigments. Serum arginase estimation was done

by Berthlot method of indirect urease enzyme.

Statistical Analysis

All observations were tabulated with respect to the groups. Results were expressed as percentage and mean SD (standard deviation). As number of samples was more than 30, instead of ‘t’ test, ‘z’ test was applied.

P < 0.001 was taken as highly significant. Stability of an 506

enzyme is measured by its lowest coefficient variation as compared to other parameters.

Results General Features Sex Incidence

In the study group, out of 50 patients, 37 (74%) were male and 13 (26%) were female. In the control group, 29 (58%) were male and 21 (42%) were female.

Age Incidence

The age in years ranged from 20 to 75 years in male and 14 to 75 years in female in the study group. The mean age of all patients was 41.22 years. Mean age in male patients was 40.95 years and in female patients, it was 42 years. Thus, the largest numbers of patients belong to the age group 31-40 years who constituted 30% of all cases. Sex ratio of 1.5:1 (male:female) suggests male predominance (Table 2).

Symptomatology

Commonest symptoms are anorexia (100%) yellow discoloration of sclera and urine (90%), fever (72%) and pain in right hypochondrial region (68%). Less common symptoms are nausea and vomiting (60%), distension of abdomen (28%). Itching and passing clay colored stool (18%) are infrequent complains.

Type of Hepatocellular Damage

In study patients, the final of diagnosis of hepatocellular damage was established after the careful review and investigations. There are 39 (78%) cases of hepatitis and cirrhosis and 11 (22%) cases Table 2. Age and Sex Distribution in Study Group (Patients with Hepatocellular Damage) Age in years

Number of cases Male

Female

Total

Percentage of total cases

10-20

1

1

2

04%

21-30

10

1

11

22%

31-40

9

6

15

30%

41-50

11

3

14

28%

51-60

3

0

3

06%

61 onwards

3

2

5

10%

37 (74%) 13 (26%) 50 (100%)

100%

Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

clinical diagnosis and control group of serum bilirubin SGOT, SGPT, ALP levels in the present study that p value is <0.001 for all parameters. So, it is highly significant. So, enzymes SGOT, SGPT, ALP can also be taken as parameters for diagnosis of hepatocellular damage (jaundice). The main aim of this study was to study the usefulness of estimation of serum arginase enzyme as a diagnostic index in case of hepatocellular damage (Table 5).

P value <0.001 when comparing study and control group suggests that arginase also is a parameter for diagnosis of hepatocellular damage (jaundice).

Table 3. Types of Hepatocellular Damage Final diagnosis

Male

Number of cases Female

Total

Percentage of total 50 cases

34

05

39

78%

Acute hepatitis

18

05

23

46%

Post necrotic cirrhosis

04

00

04

08%

Alcoholic hepatitis

03

00

03

06%

Alcoholic cirrhosis

3

00

09

18%

Obstructive jaundice

03

08

11

22%

Hepatitis Viral

Alcoholic

Now let us compare the distribution of serum arginase levels in (IU/l) in both sex groups (male and females) of study and control group (Table 6).

100%

of obstructive jaundice. Among 39 hepatitis and cirrhosis patients males are more affected 34 (87.18%) than females five (12.82%). Among obstructive jaundice, patients out of 11 cases, eight (72.73%) females and three (27.28%) males (Table 3).

To find the significance of arginase as a diagnostic index of hepatocellular damage, further statistical analysis required as follows: To measure the stability of an enzyme, itâ&#x20AC;&#x2122;s coefficient of variation which is defined as the percentage of the SD over mean, should be small; smaller the value, more the stability.

Diagnostic Confirmation of a Case of Jaundice by Routine Liver Function Tests

Table 5. Serum Arginase: A Statistical Analysis

After provisional diagnosis with symptoms and examination of patients final diagnosis is done by following biochemical parameters as done routinely.

From Table 4, it is evident from observations of study

Control group

Study group

Range

2.5-7.2

12-74

Mean

4.26

35.48

SD

0.56

18.8

P value

p < 0.001

Table 4. Diagnostic Confirmation of Hepatocellular Damage mg/dl

Karmen units

Serum bilirubin

Karmen units (IU/l)

SGOT

SGPT

Control group

Study group

Control group

Study group

Control group

Range

1.5-22.2

0.3-1

11-32

20-180

Mean

6.5

0.84

19.4

65.46

SD

5.54

0.175

5.29

43.87

P value

p < 0.001

KA units/100 ml ALP

Study group

Control group

12-31

22-250

6-12

9-80

17.98

79.58%

8.84

19.82

5.05

51.42%

1.65

12.57

p < 0.001

p < 0.001

Study group

p < 0.001

Table 6. Distribution of Serum Arginase values in both Sex Groups Sex

Control Number

Range

Mean

Study SD

Number

P value

Range

Mean

SD

Both

50

Female

21

3-7.2

4.61

1.43

13

12-70

41.15

20-10

<0.001

Male

29

2.5-7.1

4.00

1.07

37

12-74

33.49

18.17

<0.001

50

Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

507

clinical diagnosis From Table 7, it is proved that coefficient of variation is lowest in case of arginase compared to bilirubin SGOT, SGPT and ALP. Thus, this enzyme is most stable as an indicator of hepatocellular damage.

Similar observation was also found in a study carried out by Dinesh Puri and Nancy Kaul (1995) (Table 8).

They concluded from their study that scrum arginase qualifies above other liver function tests (SGOT, SGPT, ALP) considered as an indicator of hepatocellular damage as, it is most sensitive, more stable, has least unexplained variations, highest value and is closely related with the severity of jaundice.

All enzymes so far used as hepatic damage markers, including SGOT, SGPT, ALP, LDH, etc. are not actually localized in liver but widely distributed among nonhepatic tissue while liver type arginase is localized in the liver only and has been expected to serve as a more specific marker for liver damage.

Researchers have found out that the serum concentration of arginase may be a reliable indicator of hepatic damage in man and animals (Manning and Crisuli 1981; Ugrate et al 1960, 1961; Pelikan et al 1964; Meller 1967; Cargill and Shields 1971; Mia and Kroger 1978; Sodik 1980).

Though not much work has been done on diagnostic values of arginase as a marker for hepatocellular

damage, it is clear from the results of this study that it is a distinct indicator of hepatocellular damage. The reference mentioned above support the work.

Thus, the result of the present study proves that serum arginase qualifies above other routine liver function tests. SGOT, SGPT, ALP are useful in diagnosis of hepatitis in early stage but fail to satisfy the criterion in close relation with severity of the disease.

Arginase has least coefficient of variation and significant ‘p’ value which make it a better and specific marker of hepatocellular damage compared to SGOT, SGPT, ALP and hence it should be used as a specific and sensitive marker in a case of hepatocellular damage.

Summary A prospective study of 50 cases of hepatocellular damage in the form of jaundice and 50 control subjects is presented in this study. All the cases were studied in detail for their clinical and investigative profile in the light of liver function tests with special reference to the new diagnostic criteria of serum arginase estimation for the diagnosis of hepatocellular damage. Data thus collected was analyzed to derive the conclusions after critical evaluation of the observations in light of focus for arginase in comparison to other parameters in routine clinical practice.

Table 7. Comparisons between all Parameters used in Study Investigation

Healthy subject

Hepatitis patients

Mean

SE

Z test

CV (%)

SGOT (Karmen units)

65.46

6.25

7.37

67.02

SGPT (Karmen units)

79.58

7.31

8.43

64.61

ALP (KA units/100 ml)

19.82

1.79

6.13

63.42

Arginase (IU/l)

35.48

2.67

11.7

52.99

Bilirubin (mg/dl)

6.5

0.78

7.20

85.23

Table 8. Results and Observation of Study by Dinesh Puri Investigation

Hepatitis patients

Mean ± SE

CV

Mean ± SE

CV

0.18 ± 0.1

28.00

9.22 ± 0.62

68.12

SGOT (Karmen units)

11.94 ± 1.10

40.95

254.16 ± 34.81

134.21

SGPT (Karmen units)

12.0 ± 1.34

47.66

230.61 ± 36.13

140.21

ALP (KA units/mm)

7.50 ± 0.60

35.86

33.7 ± 2.48

73.91

Arginase (IU/l)

10.26 ± 0.48

15.10

18.71 ± 1.26

64.11

Bilirubin (mg/dl)

508

Healthy subject

Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

clinical diagnosis The study is concluded with the remark that serum arginase is a simple, less expensive, more sensitive and more specific test that can be used as an alternative to SGOT, SGPT and ALP as a diagnostic index in hepatocellular damage.

Suggested Reading 1. Ikemoto M, Tsunekawa S, Tanaka K, Tanaka A, Yamaoka Y, Ozawa K, et al. Liver-type arginase in serum during and after liver transplantation: a novel index in monitoring conditions of liver graft and its clinical significance. Clin Chem Acta 1998;271(1):11‑23.

2. Aminlari M, Vaseghi T, Sajedianford MJ, Samsami M. Changes in arginase, aminotransferase and rhodanese in domestic animals with experimentally induced liver necrosis. J Comp Pathol 1994:110(1):1-9.

5. Basur L, Cabello J, Véliz M, González A. Molecular forms of human-liver arginase. Biochem Biophys Acta 1966;128(1):149-54.

6. Wang SR, Chen ML, Huang MH, Lin HY, Tasai JJ, Kuo BI. Plasma arginase concentration measured by enzyme-linked immunosorbent assay (ELISA) in normal adult population. Clin Biochem 1993;26(6):455-60.

7. Khangulov SV, Sossong TM Jr, Ash DE, Dismukes GC. L-arginine binding to liver arginase requires proton transfer to gateway residue - His 141 and coordination of the guanidinium group to the dimanganese (II, II) center. Biochemistry 1998;37(23):8539-50.

8. Ash DE, Scolnick LR, Kanyo ZF, Vockley JG, Cederbaum SD, Christianson DN. Molecular basis of hyperargininemia: structures-function consequences of mutations in human liver arginase. Mol Genet Metab 1998;64(4):243-9.

3. Chwartz S, MK Clinical aspects of L-arginase, methods in enzymology 1957:857-61.

9. Michels VV, Beaudet AL. Arginase deficiency in multiple tissues in argininemia. Clin Genet 1978; 13(1):61-7.

4. Berüter J, Colombo JP, Bachmann C. Purification and properties of arginase from human liver and erythrocytes.

Biochem J 1978:175(2):449-54.

10. Puri D, Kaul N. Further studies on serum arginase as an indicator of hepatocellular damage. Indian J Clin Biochem 1995;10(1):42-4.

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clinical study

Efficacy and Tolerability of Combination Therapy vs Monotherapy in GERD Patients Manoj Goyal*, Harinder Singh Manesh**, Rani Walia†, MM Gupta‡

Abstract Objective: Proton pump inhibitors (PPIs) and H2 receptor antagonists are used for acid suppression in the treatment of gastroesophageal reflux disease (GERD). Apart from this a PPI and a prokinetic drug are often co-prescribed for the medical treatment of GERD, but there are only a few clinical studies on the efficacy and tolerability of this therapy. This study investigates whether pantoprazole (PPI) plus itopride (prokinetic) lead to an additional benefit in comparison to pantoprazole alone in GERD patients. Methods: It was a randomized, comparative, parallel group, prospective trial involving 50 patients suffering from GERD and having endoscopically confirmed esophagitis. Total patients were randomized into two groups; group A (n = 25) and group B (n = 25), group A received pantoprazole 40 mg twice-daily and itopride 50 mg thrice-daily, whereas group B received pantoprazole 40 mg twice-daily alone for eight weeks. For the assessment of treatment outcome, the primary criterion was healing of esophagitis after eight weeks of therapy as assessed by endoscopy. Relief of symptoms was also studied at four and 8 weeks. Results: After eight weeks of treatment, the endoscopic healing rates were 68% and 56% in group A and B, respectively and the difference in healing rates was not significant statistically (p > 0.05). Symptomatic relief from heart burn and regurgitation was significant statistically (p < 0.05) in both the groups and the difference in symptomatic relief in two groups was also significant statistically at four and eight weeks, where as there was no statistically significant difference (p > 0.05) in relief of other symptoms like retrosternal pain, epigastric pain in two groups. Conclusion: Though the combination of pantoprazole and itopride produces faster and better symptom relief in comparison to pantoprazole alone in patients with GERD, equivalent esophageal healing can be achieved with pantoprazole alone.

Key words: Prokinetic, pantoprazole, itopride, GERD

G

astroesophageal reflux disease (GERD) has evolved from a scarcely reported, little understood disease process just a century ago to now a highly prevalent disease with upto 25% of the population complaining of symptoms of reflux.1 Population based studies show that upto 15% of individuals have heartburn and/or regurgitation at least once a week and 7% have symptoms daily.2 The impact of GERD symptoms on quality-of-life (QOL) is often considerable. Using the psychological general well-being (PGWB) index, Dimenas found

*Assistant Professor, Dept. of Pharmacology MMIMSR, Mullana, Ambala **Professor, Dept. of Pharmacology Govt. Medical College, Patiala (Punjab) †Professor and Head, Dept. of Pharmacology MMIMSR, Mullana, Ambala ‡Professor and Head, Dept. of Medicine Govt. Medical College and Rajindra Hospital, Patiala (Punjab) Address for correspondence Dr Manoj Goyal Dept. of Pharmacology, MMIMSR, Mullana, Ambala, Haryana E-mail: dr_manojgoyal@yahoo.co.in

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that QOL for GERD patients was even lower than the QOL for patients with ischemic heart disease.3 There are three major mechanisms underlying GERD;4 noxious effect exerted by the gastric refluxate (acid, pepsin and bile), a defective clearance of the refluxated contents as a result of impaired esophageal motility, abnormalities of the antireflux mechanisms mainly related to lower esophageal sphincter dysfunction.

Endoscopy is the investigation of choice,5 when despite endoscopy, the diagnosis is unclear or if surgical intervention is under consideration, 24-hour pH monitoring is indicated.6 The goals of treatment are to provide symptom relief, heal erosive esophagitis and prevent complications.7 Treatment includes nonpharmacological measures along with pharmacological approach.

Nonpharmacological approach is suitable for uncomplicated cases and generally includes weight reduction, sleeping with the head of the bed elevated Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

clinical study by about 4-6 inches with blocks and elimination of factors that increase abdominal pressure, dietary modification, like quitting tea, coffee, smoking, alcohol and avoidance of spicy and fatty foods. One should also avoid large quantities of fluids with meals.7 Effective drug groups include antacids, H2-blockers, PPIs8 and prokinetic drugs9-11 and are used at various levels of the disease process alone or in different combinations.

Out of these groups, PPIs are the most effective agents for the treatment of nonerosive and erosive reflux disease,12,13 esophageal complications of reflux disease (peptic stricture or Barrett’s esophagus) and extraesophageal manifestations of reflux disease,14 and for prophylaxis as well.15 PPIs and prokinetics are also often co-prescribed for the medical treatment of GERD but only a few studies have studied the efficacy of combination therapy of a PPI and a prokinetic, none using itopride, so the present study was undertaken to investigate whether pantoprazole plus itopride leads to an additional benefit in comparison to pantoprazole alone in GERD patients.

Material and Methods Patients with symptoms of reflux esophagitis attending the outpatient department or admitted in the Medicine wards of Government Medical College and Rajindra Hospital, Patiala, Punjab, India were the subjects of this trial. In all, the diagnosis was based on history and endoscopic examination. Only endoscopically proven cases irrespective of the grade of esophagitis were considered for the study. Written informed consent was obtained from all patients.



Intake of substituted benzimidazoles (PPIs) with in the last 14 days and H2-blockers or prokinetics during the last 10 days before the start of study.

Total patients were randomized into two groups; one group received pantoprazole 40 mg orally twicedaily16 and itopride 50 mg orally thrice-daily,9 whereas another group received pantoprazole 40 mg twice daily orally alone for eight weeks. The treatment outcome was assessed after four and 8 weeks. The primary criterion was endoscopic healing after eight weeks. Relief of symptoms like heartburn, regurgitation, retrosternal pain and epigastric pain was also studied at four and 8 weeks.

Endoscopy

Endoscopy was performed at the start of study and grading of esophagitis was done according to New Savary-Miller classification.17 Endoscopy was repeated after eight weeks of therapy in all the patients to assess the endoscopic healing.

Therapy

Twenty-five patients (group A) were put on pantoprazole (40 mg) b.i.d. orally and itopride (50 mg t.d.s.) orally for 8 weeks and 25 patients (group B) were put on pantoprazole (40 mg b.i.d.) orally. No other drugs commonly used for treatment of GERD were allowed during the trial.

The patients were instructed to raise head end of the bed and avoid food stuffs which aggravate symptoms of GERD. Patients were also told to avoid smoking, drinking tea, coffee or alcohol.

Follow-up

All those patients who were aged not <18 years and the patients willing to give written consent to be a part of the study were eligible for the study.

The symptoms were evaluated and compliance was checked at four and 8 weeks. Endoscopy was repeated at 8 weeks and findings were again recorded.

Following patients were excluded from the study:  Patients with history of active or inactive gastric or duodenal ulcer disease  Esophageal, gastric surgery or vagotomy  Scleroderma  Long-term use of steroids, aspirin or NSAIDs including cyclooxygenase-2 (COX-2) inhibitors  Medical history of Zollinger-Ellison syndrome

Statistical Formulae and Analysis

Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

The statistical analysis was done within each group at four and 8 weeks in comparison to the baseline and between two groups at four and 8 weeks.

All values were expressed as means ± SD for continuous variables and as frequencies for categorical variables.

The results were analyzed statistically using the following tests.18 511

clinical study Unpaired ‘t’ test: χ2 (chi-square) test with Yate’s correction, p value of <0.05 was taken as significant.

Results Demographic variables are shown in Table 1. In the two treatment groups, the age, duration of symptoms at the baseline were distributed similarly, that means there was no significant difference between the two treatment groups (p > 0.05). At baseline, the symptoms and grades of esophagitis were also distributed similarly and there was no statistically significant difference between two groups (p > 0.05).

Table 2. Comparison of Endoscopic Examination of Group A and Group B Patients at Baseline and after 8 weeks Grade of At baseline esophagitis Group Group P A B value Normal

Table 1. Demographic Data before Inclusion in the Study Group B (n = 25)

No. (% age)

No. (% age)

15 (60)

17 (68)

Female

10 (40)

8 (32)

Smokers

10 (40)

5 (20)

Tea/Coffee

25 (100)

25 (100)

8 (32)

9 (36)

Mean age (years) Mean duration of symptoms (months)

512

Group A (n = 25)

Male

Alcohol

Nil

-

17

14

43 ± 9.80

42 ± 12.20

18.84 ± 12.71

24.44 ± 13.77

P value

3

5

>0.05

5

6

>0.05

Grade II

14

14

>0.05

3

5

>0.05

Grade III

8

6

>0.05

Nil

Nil

-

Total

25

25

25

25

20 No. of patients

The primary criterion to assess the efficacy was endoscopic healing after eight weeks of therapy. At baseline all the patients had endoscopically proven esophagitis and after eight weeks of therapy, complete endoscopic healing was seen in 17 (68%) patients in group A and in 14 (56%) patients in group B. Five (20%) patients in group A and six (24%) patients in group B had Grade I esophagitis as compared to three (12%) and five (20%) patients, respectively at the baseline, that means the patients having higher grades (Grade II and III) of esophagitis were shifted to lower grade (Grade I) after eight weeks, only three (12%) patients in group A and five (20%) patients in group B, had Grade II esophagitis again showing improvement compared to baseline values. No patient was having Grade III esophagitis in either group after eight weeks. The endoscopic healing in each group was significant statistically after eight weeks compared to the baseline, but the difference in healing rates in two groups was not significant statistically (p > 0.05) (Table 2 and Fig. 1).

Group Group A B

Grade I

Endoscopy Healing

Characteristics

Nil

After 8 weeks

14 14

16 12

0

14 8

8 4

Group A Group B

17

3

5

0 0

6

5 6

3

5 0 0

Normal Grade I Grade II Grade III Normal Grade I Grade II Grade III

At baseline

After 8 weeks

Figure 1. Comparison of endoscopic healing between group A and group B at baseline and after eight weeks.

Symptomatic Relief

There was a considerable symptomatic improvement at four weeks and marked symptomatic improvement at 8 weeks in both the treatment groups in comparison to the baseline. The response was better in group A in relief of heartburn after four weeks and the results were significant statistically (p > 0.05) however, no patient had heartburn after eight weeks in either group and the results were clinically significant. Relief from regurgitation was also better and statistically significant in group A patients at four and eight weeks in comparison to group B. The difference in relief of other symptoms like retrosternal pain and epigastric pain was not significant statistically (p > 0.05) in two groups (Figs. 2 and 3).

Discussion The present study was a randomized, comparative, parallel group, prospective trial involving 50 patients suffering from GERD and having endoscopically confirmed esophagitis to see whether combining itopride with pantoprazole leads to any additional benefit in comparison to pantoprazole alone in medical treatment of GERD patients.

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clinical study

30 No. of patients

25

Heartburn Regurgitation Retrosternal pain Epigastric pain

20 15 10 5 0

Baseline

4 weeks

8 weeks

Time (weeks)

Figure 2. Comparison of symptomatic response at four and eight weeks (group A).

30

Heartburn Regurgitation Retrosternal pain Epigastric pain

No. of patients

25 20 15 10 5 0

Baseline 4 weeks

8 weeks

Time (weeks)

Figure 3. Comparison of symptomatic response at four and eight weeks (group B).

The study showed male predominance, male female ratio was 1.77:1. Peak incidence of reflux esophagitis in both the groups was found to be in the age group of 31-50 years. Collective mean age of both the groups (A and B) was 42.36 years. Minimum age was 21 years and maximum 64 years. Duration of symptoms varied from three months to 48 months.

It was found out that there was no statistically significant difference in the endoscopic healing rates in two groups (p > 0.05), however, symptomatic improvement was better with the combination early in the treatment.

Only a few studies have been reported using this therapy, but none using itopride. The results of our study are consistent with two of these studies.

The study done by Madan et al16 concluded that combining mosapride with pantoprazole offers no benefit in endoscopic healing in comparison to pantoprazole alone but was more effective in providing symptomatic relief to patients with erosive GERD. In another study conducted by Van Rensberg et al,19 it was concluded that addition Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

of cisapride to pantoprazole provides no further benefit in comparison to pantoprazole alone in treatment of reflux esophagitis.

From the adverse effects point of view, drugs in both the groups were safe, as none of the adverse effects which occurred led to dropouts.

Though the combination of pantoprazole and itopride produces faster and better symptom relief in patients with GERD, but equivalent esophageal healing can be achieved with pantoprazole alone. Using this treatment the cost of treatment to the patient can be curtailed and compliance can be improved.

References 1. Modlin I, Kidd M. GERD 2003: issues from the past and a consensus for the future. Drugs Today (Barc) 2004;40(Suppl A):3-8.

2. Goyal RK. Diseases of the esophagus. In: Harrison’s Principles of Internal Medicine. 16th edition, Vol. II. Kasper DL, Braunwald E, Fauci AS, (Eds.), The McGrawHill Companies: USA 2005:1739-46.

3. Holtmann G, Maldonado-Lopez E, Haag S. Heartburn in primary care: problems below the surface. J Gastroenterol 2004;39(11):1027-34.

4. Tonini M, DeGiorgio R, DePonti F. Progress with novel pharmacological strategies for gastroesophageal reflux disease. Drugs 2004;64(4):347-61.

5. Lemire S. Assessment of clinical severity and investigation of uncomplicated gastroesophageal reflux disease and noncardiac angina-like chest pain. Can J Gastroenterol 1997;11(Suppl B):37B-40B. 6. Palmer KR, Penman ID, Paterson-Brown S. Alimentary tract and pancreatic disease. In: Davidson’s Principles and Practice of Medicine. 19th edition, Churchill Livingstone: India 2002:747-888.

7. Goyal RK. Diseases of the esophagus. In: Harrison’s Principles of Internal Medicine. 17th edition, Vol. II. Fauci AS, Kasper DL, Longo DL, et al. (Eds.), The McGraw-Hill Companies: USA 2008:1847-55.

8. Richter JE, Bochenek W. Oral pantoprazole for erosive esophagitis: a placebo-controlled, randomized clinical trial. Pantoprazole US GERD Study Group. Am J Gastroenterol 2000;95(11):3071-80.

9. Inoue K, Sanada Y, Fujimura J, Mihara O. Effect of itopride hydrochloride on the digestive symptoms of chronic gastritis with reflux esophagitis. Clin Med 1999;15(11):1803-9.

10. Kim YS, Kim TH, Choi CS, Shon YW, Kim SW, Seo SS, et al. Effect of itopride, a new prokinetic,

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clinical study in patients with mild GERD: a pilot study. World J Gastroenterol 2005;11(27):4210-4.

11. Kakrani AL, Madraki R. Clinical evaluation of itopride hydrochloride in patients with non-ulcer dyspepsia and chronic gastritis. Indian Pract 2002;55(7):441-4.

12. Wurzer H, Schutze K, Bethke T, Fischer R, Luhmann R, Reisenhuber C. Efficacy and safety of pantoprazole in patients with gastroesophageal reflux disease using an intravenous-oral regimen.

Austrian Intravenous Pantoprazole Study Group.

Hepatogastroenterology 1999;46(27):1809-15.

13. Bardhan KD. Pantoprazole: a new proton pump inhibitor in the management of upper gastrointestinal disease. Drugs Today (Barc) 1999;35(10)773-808.

14. Dekel R, Morse C, Fass R. The role of proton pump inhibitors in gastroesophageal reflux disease. Drugs 2004;64(3):277-95.

15. Mőssner J, Koop H, Porst H, Wübbolding H, Schneider A, Maier C. One-year prophylactic efficacy and safety of pantoprazole in controlling

gastroesophageal reflux symptoms in patients with healed reflux oesophagitis. Aliment Pharmacol Ther 1997;11(6):1087‑92.

16. Madan K, Ahuja V, Kashyap PC, Sharma MP. Comparison of efficacy of pantoprazole alone versus pantoprazole plus mosapride in therapy of gastroesophageal reflux disease: a randomized trial. Dis Esophagus 2004;17(4):274-8.

17. Lord RVN, Demeester TR. Reflux disease and hiatus hernia. In: Oxford Textbook of Surgery. 2nd edition, Vol. 2. Morris PJ, Wood WC, (Eds.), Oxford University Press: New York 2000:1239-62.

18. Ghosh MN. Fundamentals of experimental pharmacology. 3rd edition, Hilton and Company: Kolkata 2005:209-29.

19. Van Rensburg CJ, Bardhan KD. No clinical benefit of adding cisapride to pantoprazole for treatment of gastroesophageal reflux disease. Eur J Gastroenterol Hepatol 2001;13(8):909-14.

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Case report

Rosai-Dorfman Disease: A Rare Cause of Chronic Lymphadenopathy in Children 

PN Vinoth*, S Muthamil Selvan*, J Thanka**, Rajendiran**, Vaishanavi Ravi†, J Julius Xavier Scott‡

Abstract Sinus histiocytes with massive lymphadenopathy, also called as Rosai-Dorfman disease, is a rare, pathologic entity characterized by benign proliferation of cervical lymph nodes often being confused with lymphoma. We report here, a child with painless neck swellings of three years duration; relevant literature has been reviewed.

Key words: Rosai-Dorfman, sinus histiocytosis, lymphadenopathy

C

ommon causes of chronic painless lymphadenopathy in children includes infections and malignancies especially lymphomas. Histiocytic necrotizing lymphadenopathy (Kikuchi’s disease), Castleman’s disease, Kimura’s disease, angioimmunoblastic lymphadenopathy are among the rare causes of chronic lymph node enlargement. Sinus histiocytosis with massive lymphadenopathy (SHML) should also be included in the above list. We report here a 10-year-old child, who presented with painless cervical lymph nodes of 3-year duration. A lymph node biopsy showed loss of architecture, dilated sinuses filled with histiocytes that showed lymphophagocytosis highlighted immunohistochemically by S100 and CD68 positivity consistent with the diagnosis of RosaiDorfman disease (SHML).

Case Report A 10-year-old male child, first born to nonconsanguineous parents, presented to us with multiple swellings around the neck of 3-year duration. He was apparently normal three years back, when he first noticed a right neck mass, which was insidious in onset and slowly increasing in size. Similar painless *Assistant Professor, Dept. of Pediatrics **Professor, Dept. of Pathology †CRRI ‡Associate Professor, Dept. of Pediatrics Sri Ramachandra Medical College, Chennai Address for correspondence Dr J Julius Xavier Scott Associate Professor, Dept. of Pediatrics Sri Ramachandra Medical College, Porur, Chennai - 600 116 E-mail: jxscott@hotmail.com

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swellings appeared on the other side of neck. The upper neck swellings progressed to attain the present size of 6 × 5 cm. He had intermittent episodes of high fever which subsided after treatment from local physicians (exact nature of treatment unknown). There has been no accompanying history of weight loss, pruritus or night sweats. There was also no associated history of skin rash, joint pain, bleeding, respiratory distress or difficulty in swallowing. His past, personal and family history were nonsignificant.

Physical examination revealed the presence of multiple large bilateral neck lymph nodes, of which the largest were sized 6 × 5 cm and 5 × 4 cm. The neck nodes were firm, nontender, nonmatted without any skin changes over the surface. There were no other palpable significant lymph nodes in other areas of the body. His chest and abdomen were normal.

He was developmentally, anthropometrically and neurologically normal.

Investigations showed hemoglobin of 12.2 g/dl, WBC 7.5 × 109/l, differential count: Neutrophils (73%), lymphocytes (22%), eosinophils (3%), monocytes (2%) and platelets were 285 × 109/l. Peripheral blood film showed normochromic normocytic red blood cells.

Erythrocyte sedimentation rate (ESR) was 17 mm in the first hour. Biochemical profile revealed normal renal and liver functions including lactate dehydrogenase (LDH). His chest X-ray and ultrasound abdomen was normal. Mantoux test, HIV serology and Epstein-Barr virus (EBV) serology were also negative.

The largest lymph node was excised to find out the cause of this unexplained cervical lymphadenopathy.

Grossly, it was a 5 cm tan lymph node with a solid Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

Case Report

Figure 1. Lymph node with effaced architecture and marked dilatation of sinuses, (H&E x 20).

Figure 4. Histiocytes showing positivity for CD68 (immunohistochemistry x 100).

cut surface and with a firm to rubbery consistency.

The histology of right cervical lymph node on hematoxylin and eosin (H&E) stain showed massive sinus expansion and infiltration of histiocytes, lymphocytes and plasma cells (Figs. 1 and 2). Many of the histiocytes showed predominantly lymphocytes and occasional plasma cells in their cytoplasm suggestive of emperipolesis (Fig. 3). Immunohistochemical stains nicely decorated the histiocytic cells that were markedly positive for S100 and CD68 monoclonal antibody with lymphocytes sitting in their cytoplasm (Fig. 4).

These features were consistent with the diagnosis of SHML (Rosai-Dorfman disease).

Figure 2. The sinuses contain cells predominantly large number of histiocytes, lymphocytes and plasma cells (H&E x 200).

Since, he did not have any systemic symptoms he is being followed-up without any intervention. For the past six months of follow-up, his swellings are of the same size, his weight gain is adequate and he is clinically well. In case of any worsening, we are planning to give a trial of steroids. Presently, he is on regular follow-up at our outpatient department.

Discussion

Figure 3. Histiocytes with vacuolated cytoplasm containing lymphocytes and plasma cells (emperipolesis) (H&E x 200).

Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

Sinus histiocytosis with massive lymphadenopathy (SHML) or Rosai-Dorfman disease is a rare benign idiopathic proliferative disease of the phagocytic histiocytes. This disease was first described by Robb-Smith in 1947 in children and termed this as giant cell sinus reticulosis. But the name SHML was given by Rosai and Dorfman in the year 1969 and 1972, respectively. They reported this distinct histiocytic entity in young black males presenting with 517

Case Report massive, bilateral, painless, cervical lymphadenopathy, often associated with fever, anemia, neutrophilia, elevated ESR and polyclonal gammopathy.1 This most commonly affects young adults, males more commonly than females, with a peak age around 20 years.2 Painless lymphadenopathy is the most frequent symptom and involves the cervical region in upto 90% of patients.2 Other locations such as inguinal (26%), axillary (24%) and mediastinal lymph nodes (15%) are also reported to be involved.2 Foucar et al found 43% of their patients had extranodal involvement of which some didn’t have associated lymphadenopathy.

The most common extranodal sites, in the decreasing order of frequency, are skin, nasal cavity and paranasal sinus, eyelid, orbit, bone, salivary gland and central nervous system.2 Other rare sites include solitary involvement of talus, triquetrum, sclera, conjunctiva, thymus, pleura, pulmonary, liver and genitourinary system.2,3 The etiology is unknown. Sometimes it may be associated with viral infections like EBV, human herpes virus 6 (HHV-6) or it may also be associated with malignancies. But, it is not a true malignant or metastatic lesion. It is a response of lymph nodes to some antigens or irritating material that may leach out from a tumor to a lymph node downstream. The lymph nodes respond by swelling due to extensive expansion of the sinuses that contain large histiocytes with lymphocytes and plasma cells in their cytoplasm (emperipolesis).4-8 Molecular analysis has shown it to be a polyclonal proliferation of histiocytes unlike Langerhan’s cell histiocytosis in which there is a monoclonal activation of CD1a cells.5 Although SHML could be possibly associated with certain infections or malignancies.5,6 Our case was not found to be associated with infection or malignancy. Recent research reveals that defective Fas/FasL signaling leading to altered apoptosis may be an important mechanism whereby uncontrolled histiocytic proliferation is triggered.9 Diagnosis is usually based on the characteristic histopathological and cytological features. The abnormal cells in tissue infiltrates includes activated macrophages that express Leu-M3 and HAM-56 surface antigens as well as receptors for transferrin, interleukin-2, Fc and C3.10,11 Histiocytes with abundant pale cytoplasm and round to oval nuclei with a single nucleolus massively engorge sinuses 518

and interfollicular areas of lymph nodes, usually with evidence of lymphocytophagocytosis.12 Histiocytes also contain large amount of esterases and acid phosphates and show positivity for CD68 and a-1 antitrypsin. They also exhibit some of the phenotypic features of dendritic cells such as S100, cathepsin E, fascin and at times Cd1a.13 In Rosai-Dorfman disease, the clinical course is usually indolent for many years, with spontaneous regression in the majority of patients. Life-threatening complications and organ dysfunction due to SHML is unlikely. However, very rarely the disease may become progressive and require treatment. Involvement of certain extranodal organs such as kidneys and lungs or widespread nodal dissemination is considered as poor prognostic factors.

There are no clear standard guidelines for the treatment of this disease. Most patients with RosaiDorfman disease are asymptomatic and an initial wait and watch approach is a standard option. As spontaneous regression can occur, treatment usually causes more serious side effects than benefit.14 For patients with progressive or symptomatic presentation or for those with cosmetic problems, standard treatment is corticosteroid therapy; usually prednisolone at high doses (initially 2 mg/kg/day) is administered.

Surgery, radiation therapy or chemotherapy (usually with vinca alkaloids or 6-mercaptopurine and oral methotrexate) may be suitable for patients not adequately controlled with steroid treatment.14 Surgical option may be reserved for compressive symptoms. To conclude Rosai-Dorfman disease should be considered as a possible etiology for any child with chronic painless lymphadenopathy.

References 1. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. A newly recognized benign clinicopathological entity. Arch Pathol 1969;87(1): 63-70.

2. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity. Semin Diagn Pathol 1990;7(1):19‑73.

3. Bhatt GM, Kumar S, Sharma A. Rosai-Dorfman disease: a case report with review of literature. Indian J Med Paediatr Oncol 2004;25(4):39-41.

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Case Report 4. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: a pseudolymphomatous benign disorder. Analysis of 34 cases. Cancer 1972;30:1174-88.

5. Mac Lennon KA. Lymph nodes, thymus spleen. In: General and Systemic Pathology. 4th edition, Chap22.

Underwood JCE, (Ed.), Churchill Livingstone 2004:595.

6. Mohan H. The lymphoid system. In: Textbook of Pathology. 5th edition, Mohan H, (Ed.), JP Brothers; New Delhi 2005:444.

7. Guido M, Isabelle J. Tumor aggression in cells, tissues and disease. In: Principles of General Pathology. 2nd edition, Oxford, New York 2004:807-8.

8. Nandi M, Mondal RK, Datta S, Karmakar BC, Mukherjee K, Dhibar DK. Rosai-Dorfman disease.

Indian J Pediatr 2008;75(3):290-4.

9. McClain KL, Natkunam Y, Swerdlow H. Atypical cellular disorders. Hematology Am Soc Hematol Educ Program 2004;1:283-96.

10. Eisen RN, Buckley PJ, Rosai J. Immunophenotypic characterization of sinus histiocytosis with massive lymphadenopathy. Semin Diagn Pathol 1990; 7(1):74-82.

11. Chan JK, Tsang WY. Uncommon syndromes of reactive lymphadenopathy. Semin Oncol 1993; 20(6):648-57.

12. Pritchard J, Malone M. Histiocyte disorders.

In: Oxford Textbook of Oncology. 2nd edition, Peckham M, Pinedo HM, Veronesi U, (Eds.): Oxford University Press: Oxford 2001:1878-94.

13. Jaffe R, DeVaughn D, Langhoff E. Fascin and differential diagnosis of childhood histiocytic lesions. Pediatr Dev Pathol 1998;1(3):216-21.

14. Pulsoni A, Anghel G, Falcucci P, Matera R, Pescarmona E, Ribersani M, et al. Treatment of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): report of a case and literature review. Am J Hematol 2002;69(1):67-71.

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photo quiz

Skin Plaques in a Woman with Renal Disease

A

44-year-old woman was admitted to the hospital for severe pain localized to her lower extremities. She had a history of diabetes mellitus and end-stage renal disease requiring hemodialysis. On the sixth day of hospitalization, she developed tender, flat, hyperpigmented, violaceous plaques with irregular borders on her buttocks and thighs (Figure 1). Laboratory results included the following: ionized calcium level of 4.28 mg per dL (1.07 mmol per L), phosphorus level of 5.9 mg per dL (1.91 mmol per L), parathyroid hormone level of 483 pg per mL (483 ng per L), protein C activity of 41 percent, and protein S activity of 325 percent. The plaques increased in size, followed by blistering and sloughing of the skin (Figure 2). Skin biopsy showed focal necrosis of the deep dermis, microthrombi, and calcification of the vessel walls.

Figure 1.

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

A. Calcific uremic arteriolopathy.

B. Necrotizing vasculitis.

C. Nephrogenic systemic fibrosis.

D. Peripheral arterial disease.

E. Skin necrosis from warfarin therapy.

Discussion The correct answer is A: calcific uremic arteriolopathy.

Calcific uremic arteriolopathy, also known as calciphylaxis, is characterized by small vessel calcification and cutaneous necrosis. The condition occurs primarily in patients with end-stage renal disease who are on dialysis or who have recently received a renal transplant. It has also been reported in patients with primary hyperparathyroidism, alcoholic cirrhosis, or breast carcinoma treated with chemotherapy.1 The Source: Adapted from Am Fam Physician. 2010;82(10):1257-1258.

Figure 2.

prevalence is approximately 4 percent among patients on dialysis.2 The mortality rate can be as high as 80 percent1,3 and is often due to secondary infection of ulcers and sepsis.

The pathogenesis of calcific uremic arteriolopathy is unclear, but hyperparathyroidism, vitamin D supplementation, hyperphosphatemia, hypercalcemia, and abnormalities of coagulation may be related.4 Clinically, calcific uremic arteriolopathy is suggested by painful skin lesions that progress quickly into necrotic, nonhealing ulcers. There are no specific laboratory tests, but laboratory findings, especially increased levels of calcium, phosphorus, and parathyroid hormone, in the presence of suspicious lesions may suggest the diagnosis. Histopathology reveals calcification of the vessel walls and sebaceous gland necrosis. Treatment includes correcting calcium and phosphorus levels,5 hemodialysis, wound debridement, hyperbaric oxygen therapy, and antibiotics. Parathyroidectomy may be required if hyperparathyroidism does not respond to medical management.

Contâ&#x20AC;&#x2122;d on page 522...

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photo quiz ...Contâ&#x20AC;&#x2122;d from page 520 Summary Table Condition

Characteristics

Calcific uremic arteriolopathy

Small vessel calcification and cutaneous necrosis; progressive cutaneous lesions that are painful and ulcerate; usually occurs in patients with end-stage renal disease who are on hemodialysis or have recently received a renal transplant

Necrotizing vasculitis

Pruritic and painful lesions usually preceded by fever, arthralgia, and malaise; occurs in patients with collagen vascular disease, inflammatory bowel disease, or malignancy

Nephrogenic Erythematous papules that coalesce into systemic fibrosis erythematous to brawny plaques; involved skin becomes thickened and woody in texture Peripheral arterial disease

Ulcers typically occur on the toes, heels, and anterior shin; peripheral pulses absent; bilateral necrosis possible

Skin necrosis from warfarin therapy

Necrotic lesions that usually appear in a distinct pattern three to six days after the initiation of therapy and regress after discontinuation; painful rash and petechiae progress to hemorrhagic bullae and necrotic eschar

to brawny plaques. The involved skin becomes thickened and woody in texture. Skin biopsy is essential for diagnosis.

Peripheral arterial disease can cause ulcers and necrosis.

Peripheral pulses are absent, and bilateral necrosis is possible. Ulcers typically occur on the toes, heels, and anterior shin, whereas the trunk and upper extremities usually are not involved.

Skin necrosis from warfarin therapy usually develops in a distinct pattern three to six days after therapy is initiated and regresses after the therapy is discontinued.

Necrosis occurs in areas with significant underlying subcutaneous fat tissue. The rash is painful, and petechiae develop within 24 to 48 hours, progress to hemorrhagic bullae, and quickly change into fullblown necrotic eschar.

References 1. Fine A, et al. Calciphylaxis is usually nonulcerating: risk factors, outcome and therapy. Kidney Int. 2002;61(6):2210-2217.

2. Angelis M, et al. Calciphylaxis in patients on hemodialysis: a prevalence study. Surgery. 1997;122(6):1083-1089.

Necrotizing vasculitis occurs in patients with collagen vascular disease, inflammatory bowel disease, or malignancy. The lesions are usually pruritic and painful and are often preceded by fever, arthralgia, and malaise.

3. Weenig, et al. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol.

2007;56(4):569-579.

Nephrogenic systemic fibrosis occurs in patients with underlying renal disease. The lesions are typically erythematous papules that coalesce into erythematous

5. Moe SM, et al. Management of secondary hyperparathyroidism. Am J Nephrol. 2003;23(6): 369-379.

4. Block GA. Prevalence and clinical consequences of elevated Ca x P product in hemodialysis patients. Clin Nephrol. 2000;54(4):318-324.

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research review

From the Journals...

Do Plasma Injections Improve Chronic Achilles Tendinopathy?

Background: Tendon injuries account for 30 to 50 percent of all sports-related injuries. Achilles tendinopathy can affect sports performance and activities of daily living, and is often recalcitrant to conservative treatments; 25 to 45 percent of patients eventually need surgery. The terms “tendinopathy” and “tendinosis” are more commonly used now instead of “tendinitis,” because the condition characterized by pain, swelling, and decreased activity is not from acute inflammation as much as from abnormal tissue repair and chronic damage to the tendon fibers.

Eccentric exercise (stretching the Achilles tendon while concurrently contracting the calf muscle) has been the mainstay of rehabilitation.

Platelet-rich plasma (PRP) injections into ligaments and tendons have been postulated to stimulate the body’s own healing mechanisms with the release of growth factors that stimulate tissue repair, and there is also evidence that PRP injections are being used more often in clinical practice. The injection is created by centrifuging a sample of the patient’s blood and injecting several milliliters of the platelet-rich portion.

Laboratory-based studies have shown some benefit, but well-designed clinical studies had not been done.

In this trial, de Vos and colleagues studied if PRP injections would improve pain and functional outcome in chronic Achilles tendinopathy when added to the usual care of eccentric exercise.

The Study: This stratified, block-randomized, doubleblind, placebo-controlled trial was performed at a sports medicine center in the Netherlands. Persons 18 to 70 years of age who had chronic midportion Achilles tendinopathy (i.e., symptoms for at least two months, located 2 to 7 cm proximal to the tendon insertion at the calcaneus) were included in the trial.

Those with suspected tendon rupture or other tendon insertion injuries, systemic inflammatory conditions, fluoroquinolone use (which can cause tendinopathy), previous participation in a rehabilitation program, or Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

previous PRP injection were excluded. To adequately power the study, a sample size of 54 participants was randomized into two groups. Under ultrasound guidance, the intervention group received a 4-mL injection of PRP; the control group was injected with the same amount of saline. Both groups had a prescribed rehabilitation program and continued to use eccentric exercises.

The primary outcomes were levels of pain and activity at baseline and at six, 12, and 24 weeks, as measured using the Victorian Institute of Sports AssessmentAchilles (VISA-A) questionnaire. This validated assessment uses a scale ranging from 0 to 100; higher scores indicate less pain and more activity. Secondary outcomes included subjective patient satisfaction, return to sports participation, and adherence to eccentric exercises.

Results: At 24 weeks, the PRP group had improved their VISA-A score by 21.7 points, and the placebo group improved their score by 20.5 points, indicating no significant difference in the primary outcome. There were also no significant differences between groups for the secondary outcomes.

Conclusion: The authors conclude that injection with PRP in addition to traditional eccentric exercise does not significantly improve levels of pain or activity at six, 12, or 24 weeks. They do not recommend adding PRP injections to the treatment of chronic midportion Achilles tendinopathy.

Source: Am Fam Physician. 2010;82(10):1272-1277.

Internal vs. External Monitoring of Uterine Contractions Background: Monitoring uterine contractions by internal tocodynamometry is advised by the American Congress of Obstetricians and Gynecologists in certain situations (e.g., maternal obesity, when oneon-one nursing care is not available, when response to oxytocin is limited). However, this recommendation is based on expert opinion, and several small trials have not shown reductions in adverse neonatal outcomes 523

research review or in operative delivery rates with internal versus external monitoring. Bakker and colleagues conducted a randomized, multicenter clinical trial to determine if using an intrauterine pressure catheter during labor would lead to better outcomes than those associated with external monitoring.

The Study: The authors randomized 1,456 women to receive internal or external monitoring of uterine activity during labor. All participants had a singleton pregnancy in cephalic position with a gestational age of more than 36 weeks and an indication for induction or augmentation of labor. Patients were excluded if they had a uterine scar, were positive for hepatitis B or human immunodeficiency virus infection, or had signs of an intrauterine infection or fetal distress. The use of intrauterine pressure catheters was allowed in the external monitoring group if there were insufficient uterine contractions, if cervical progression had been absent for two hours, or if cesarean delivery was being considered.

Results: No significant difference was noted in operative delivery rates between the groups (31.3 and 29.6 percent in the internal and external monitoring groups, respectively). The groups also were similar in the time to delivery and in antibiotic and analgesic use. Adverse neonatal outcomes (e.g., Apgar scores of less than 7 at five minutes, umbilical artery pH scores of less than 7.05, neonatal admission to the hospital for more than 48 hours) were equivalent between the groups. Post hoc analyses showed no notable interactions between monitoring type and the type of labor (induced versus augmented), body mass index (30 kg per m2 or less versus more than 30 kg per m2), or parity (primiparous versus multiparous) with regard to adverse neonatal outcomes or the need for operative delivery.

Can HSV-2 Suppression Reduce HIV-1 Transmission?

Background: Having symptomatic herpes simplex virus type 2 (HSV-2) infection is thought to increase a patient’s risk of contracting human immunodeficiency virus type 1 (HIV-1) infection. Several trials have shown that daily HSV-2 therapy can reduce plasma HIV-1 levels by 0.25 to 0.50 log10 copies per mL. Celum and colleagues conducted a randomized, double-blind, placebo-controlled trial to evaluate if suppression of HSV-2 infection might prevent transmission of HIV-1 infection.

The Study: The authors recruited 3,408 heterosexual couples with discordant HIV/HSV status (i.e., one partner was seropositive for HIV-1 and HSV-2, and the other partner was HIV-negative but could be positive or negative for HSV-2). Partners with HIV-1 infection were randomized to receive acyclovir, 400 mg twice daily, or a placebo, and both partners were monitored for two years for changes in health status and HIV transmission. The primary end point was a new diagnosis of HIV-1 in the previously negative partner. Exclusion criteria for partners with HIV-1 infection included pregnancy or persistent genital ulcers. These patients were also excluded if they were taking antiretroviral therapy, had a CD4 count of less than 250 cells per mm3 (250 × 109 per L), or had evidence of AIDS. Results: Mean HIV-1 plasma concentration was significantly reduced by 0.25 log10 copies per mL in the acyclovir group compared with the placebo group, as was the risk of symptomatic genital ulcer disease (risk ratio = 0.39). However, HIV-1 transmission rates were equivalent between the groups. No differences in transmission rates were noted with respect to sex, partner’s HIV-1 viral load or symptomatic genital ulcer disease, or to the level of adherence with the assigned treatment.

Conclusion: The authors conclude that compared with external monitoring of uterine activity in women with induced or augmented labor, internal tocodynamometry does not improve the rates of operative delivery or adverse neonatal outcomes.

Conclusion: The authors conclude that daily acyclovir therapy is ineffective in preventing transmission of HIV-1 infection from a partner who is HIV-1– and HSV-2–positive to the partner who is HIV-negative, even with reductions in HIV viral load.

Source: Am Fam Physician. 2010;82(9):1142-1143.

Source: Am Fam Physician. 2010;82(9):1143.

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emedinews section

From eMedinewS Study Finds Strength Training for Seniors Provides Cognitive Function, Economic Benefits A one-year follow-up study on seniors who participated in a strength training exercise program shows sustained cognitive benefits as well as savings for the healthcare system. The research, conducted at the Center for Hip Health and Mobility at Vancouver Coastal Health and the University of British Columbia, is published in the Archives of Internal Medicine. The study is the first to examine whether both cognitive and economic benefits are sustained after formal cessation of a tailored exercise program. It builds on the Brain Power Study, published in the January 2010 issue of Archives of Internal Medicine, which demonstrated that 12 months of onceweekly or twice-weekly progressive strength training improved executive cognitive function in women aged 65-75 years old. Executive cognitive functions are cognitive abilities necessary for independent living.

Measuring Glycated Hemoglobin Levels may Help Identify Prediabetes Specifically, using HbA1C alone - with a range of 5.5-6.5% defining prediabetes - would identify a population with comparable risks for diabetes and heart disease (32.4% and 11.4%, respectively), according to a study in the American Journal of Preventative Medicine.

But using a slightly higher cutoff - beginning at 5.7% - would identify increased risks of 41.3% for diabetes and 13.3% for heart disease.

Three Percent Weight Loss during Marathon Raises Chance of Winning the Race If you are in a marathon running race and lose at least 3% of your body weight during the competition, your chances of getting to the end faster are significantly higher, South African researchers reveal in the British Journal of Sports Medicine. Their findings clash with experts and sporting authorities who say that any weight loss over 2% during a competition undermines athletic performance. The researchers gathered data on 643 competitors, 560 male and 83 female, who Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

When Caring for Central Lines, Appropriate Times for Hand Hygiene Include  Before and after palpating catheter insertion sites (Note: Palpation of the insertion site should not be performed after the application of antiseptic, unless aseptic technique is maintained.)  Before and after inserting, replacing, accessing, repairing or dressing an intravascular catheter  When hands are obviously soiled or if contamination is suspected  Before and after invasive procedures  Between patients  Before donning and after removing gloves  After using the bathroom completed the Mont Saint Michel Marathon race in France in 2009. They ran 42 kilometers (26.0975 miles). They were all weighed moments before the race began and straight after it ended. Their aim was to see what impact weight loss might have on their finishing times.

FDA Launches a New Web Initiative The FDA has launched a new Web-based resource that industry can use to keep abreast of the regulatory status for drugs, devices, food and cosmetics. The Web page: www.fda.gov/ForIndustry/FDABasicsforIndustry -includes the kind of basic information about the regulatory process that is often requested by drug, device and biologic companies.

Walking Speed may Help Clinicians Predict How Long their Older Patients will Live Research by Stephanie Studenski from University of Pittsburg indicates that walking speed may determine how long and how well older people will live. They analyzed data from nine different studies, collectively looking at nearly 35,000 adults aged 65 and older 525

emedinews Section and noted that for a 70-year-old man, the difference between walking 3 minute/hour and 3.5 minute/hour was four years of life on average; for a woman, it’s 6-7 years. According to the paper in the Journal of the American Medical Association, a “70-year-old man who walks at 2.5 minute/hour would expected to live an average of eight years longer than if he walks at 1 minute/hour; for a woman, that difference is about 10 years.

First-in-class Antibiotic has High-risk of Adverse Events and Death Results of a meta-analysis published in the December 20 online issue of the journal Antimicrobial Agents and Chemotherapy say that the usefulness of tigecycline for severe infections comes at a price: A high-risk of adverse events and mortality. The authors recommend that this drug should be used carefully. Tigecycline is an expanded broad-spectrum glycylcycline that is active against pathogens that are susceptible and resistant to other antibiotics.

Insecticidal Nets don’t Reduce Leishmania Risks Results of a paired cluster-randomized trial note that using durable insecticidal nets do not significantly improve on existing measures to control Leishmania donovani infection on the Indian subcontinent. The trial included villages in three Nepalese and one Indian

The results showed no significant reduction in the rate of L. donovani infection in Indian and Nepalese villages receiving long-lasting insecticidal nets versus usual control measures. There is also no effect on the rate of clinical leishmaniasis. The study is published online 29 December 2010 in BMJ. An Inspirational Story Six Principles of Life

1. No point using this limited life to chase unlimited money.

2. No point earning so much money you cannot live to spend it.

3. Money is not yours until you spend it.

4. When you are young, you use your health to chase your wealth; when you are old, you use your wealth to buy back your health. Difference is that, it is too late.

5. How happy a man is, is not how much he has but how little he needs.

6. No point working so hard to provide for the people you have no time to spend with.

Infertility Update

Nutrition Update

What is Intracytoplasmic Sperm Injection?

Breastfeeding or Breast Milk for Procedural Pain in Neonates

Intracytoplasmic sperm injection (ICSI) has revolutionized the treatment and improved the prognosis for fertility of men with very severe oligospermia, asthenospermia (low sperm motility), teratospermia (a higher rate of abnormal sperm morphology), and even azoospermia. This technique involves the direct injection of a single spermatozoon into the cytoplasm of a human oocyte, usually obtained from follicles produced under controlled ovarian hyperstimulation. This technique has also been successful in men with nonmosaic Klinefelter syndrome where spermatozoa are obtained from testicular biopsies.

—Dr Kaberi Banerjee, Infertility and IVF Specialist, Max Hospital; Director Precious Baby Foundation

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district with a high reported incidence of visceral leishmaniasis. Intervention clusters were given durable insecticidal nets, deltamethrin treatment; control clusters continued with existing conventional strategies of irregular insecticide residual spraying and use of untreated nets.

If available, breastfeeding or breast milk should be used to alleviate procedural pain in neonates undergoing a single painful procedure compared to placebo, positioning or no intervention.

Administration of glucose or sucrose had similar effectiveness as breastfeeding for reducing pain.

The effectiveness of breast milk for repeated painful procedures is not established and further research is needed. These studies should include various control interventions including glucose/sucrose and should target preterm neonates.

—Dr. Neelam Mohan, Director Pediatric Gastroenterology, Hepatology and Liver Transplantation, Medanta - The Medicity

Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

Indian Journal of

Clinical Practice

Information for Authors Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767).

Indian Journal of Clinical Practice strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so.

The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript.

Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper.

Covering letter –

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Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.

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

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departments and institutions where the work was performed, name of the corresponding authors, acknowledgment of financial support and abbreviations used.

– The title should be of no more than 80 characters and should represent the major theme of the manuscript.

A subtitle can be added if necessary.

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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.

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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).

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Indian Journal of Clinical Practice, Vol. 21, No. 9, February 2011

Confidence intervals for the measurements should be provided wherever appropriate.

Results These should be concise and include only the tables and figures necessary to enhance the understanding of the text.

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Discussion –

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

References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses).

At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution.

Examples of common forms of references are: Articles

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

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected

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.

2. Total number of pages ________________________

Books

5. Special requests _____________________________

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

6. Suggestions for reviewers (name and postal address)

Articles in Books

2.____________

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

3.____________

3._ _______________

4.____________

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Tables –

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Legends – These should be typed double spaces on a separate sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text.

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

summary, etc.)_______________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________

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VOLUME 12, NUMBER 2

Official Voice of Doctors of India

igh doses or long-term use of PPIs or proton-pump inhibitors can lead to an increased risk of bone fractures. This holds especially true for those over the age of 50, and for people on the high dose. The latest warning is based on a FDA review of several studies of the treatment.

These epidemiologic studies revealed an elevated fracture risk at the hip, wrist and spine. But the studies do not, definitively prove that PPIs are the cause of the fractures.

FDA has instructed the manufacturers of the drugs to change the labels for both the prescription and the over-the-counter versions of the PPIs. The FDA said they should only be taken for 14 days to help ease frequent heartburn and under no circumstances should over-the-counter PPIs be taken for more than three 14-day periods in a year.

Asian Journal of

Ear, Nose Throat

Visceral fat is a hot topic because of metabolic syndrome, which predisposes people to disease.

Intra-abdominal fat, or the fat that wraps around the organs in the abdomen and chest, tends to accumulate at midlife and can contribute to developing diabetes, hypertension and heart disease. The fat around the organs is known to be more related to heart disease and diabetes.

A woman does not need to appear outwardly heavy to have a potentially troublesome extra ‘tire’ around her organs.

Exercise for long has been known to reduce the amount of intra-abdominal fat.

“ Always aim at complete harmony of thought and word and deed. Always aim at purifying your thoughts and everything will be well.

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– Mahatama Gandhi

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Make sure that good nursing care and maintenance of skin hygiene is advised first to patients with bed sores, along with topical antibiotics.

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Most researchers believe that more fractures are due to decreased calcium absorption from the diet because of the reduced stomach acid. But, it’s also possible that these drugs interfere with bone maintenance.

Notably, PPIs have previously been linked to an increased risk of contracting pneumonia and the troublesome bacterium Clostridium difficile, as well as to an increased risk of dementia.

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