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Volume 21, Number 12 637-688 Pages May 2011

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Indian Journal of

Holt-Oram Syndrome

From the Desk of Editor in Chief

Padma Shri and Dr BC Roy National AwardeeDr 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

emedinews is now available online on www.emedinews.in or www.emedinews.orgHead Office: E - 219, Greater Kailash, Part - 1, New Delhi - 48, India. e-Mail: [email protected], Website: www.ijcpgroup.com

Breaking News: Person Revived after 96 Minutes of CPRCA 54-year-old man with post MI ventricular fibrillation regained spontaneous circulation after a dozen defibrillator shocks and continuous CPR for 96 minutes with full physical and neurological recovery reports Dr Roger D. White at the Mayo Clinic in Rochester, Minn in a case report published online April 20 in the Mayo Clinic Proceedings. The patient was resuscitated for initial 31 minutes by the emergency staff along with DC shocks. At the 31st minute a helicopter transport crew arrived and continued applying defibrillator shocks to the man who did not have a pulse, yet showed signs of systemic blood flow as measured by an end-tidal carbon dioxide sensor. The team administered a total of 12 defibrillator shocks and kept the patient’s blood flowing with continuous chest compressions. A key piece of technology on the scene was capnography, which measures how much blood is flowing through the lungs and subsequently to other organs. Capnography has been used to monitor patients in operating rooms but is not often used by ER when treating cardiac arrest. As the measurement remained sufficiently high, the rescuers were encouraged to continue resuscitation efforts.At the hospital, he was stabilized and taken to the cath lab and was stented for 100% occlusion in the mid-left anterior descending coronary artery. The persistent low blood pressure was stabilized with an intra-aortic balloon pump. The patient was discharged after 10 days with no neuro damage.Lessons learned• It’s the only case where a person has been revived after 96 minutes

of clinical death• We had a similar case where CPR was continued for 45 minutes• GB Pant reports a similar case with revival after an hour and with

stenting (Dr Vijay Trehan)• Medicolegal implications: Do not stop resuscitation for up to 100

minutes and make sure you measure E tube CO2 levels• Transport the patient to nearest cardiac hospital for possible

angiography and IABP (intra aortic balloon pump), if required.

Dr KK AggarwalEditor in Chief————————————————————————————

NDM-1 in Pune: ResearchersSuperbug gene detected in 20 patientsResearchers from the government-run B J Medical College (BJMC) and the National Centre for Cell Science (NCCS), in preliminary findings of a study to find the New Delhi metallobeta lactamase-1 (NDM-1) incidence in Pune, reported the strain in the city in 20 cases.In Pune, clinical microbiologists at the government-run BJMC and Sassoon General Hospital and the NCCS collected samples of blood, urine and pus from 3,172 patients at Sassoon General Hospital in the last two months and found that 885 had gram negative bacilli (bacteria which causes a majority of infections). Of these 885 as many as 181 patients were resistant to the carbapenem family of drugs while 20 were detected with the NDM-1 gene.NDM-1 is an enzyme that makes bacteria resistant to a broad range of beta-lactam antibiotics including antibiotics of the carbapenem family, a mainstay for treatment of antibiotic-resistant bacteria. The gene for NDM-1 is a member of a large gene family that encodes beta-lactamase enzymes called carbapenemases. Infections with these bacteria are hard to treat successfully, say microbiologists.

Data from well-known medical journals across the world document emergence of similar metallo-b-lactamases bacteria from at least 28 countries including South Korea, Japan, China, Greece, Brazil, Australia, Italy, Portugal and Spain.Detection of NDM-1 is important as it shows an increasing presence of drug-resistant bacteria.

—Indian Express

WHO Warns of Enormous Burden of Chronic DiseaseChronic illnesses like cancer, heart disease and diabetes have reached global epidemic proportions and now cause more deaths than all other diseases combined, the World Health Organization (WHO) said on Wednesday. In its first worldwide report on so-called non-communicable diseases, or NCDs, the United Nations health body said the conditions caused more than half of all deaths in 2008 and pose a greater threat than infectious diseases such as malaria, HIV and tuberculosis (TB) – even in many poorer countries. NCDs, which include heart disease, lung diseases, cancer and diabetes, accounted for 36 million, or 63 percent, of the 57 million deaths worldwide in 2008. Millions of lives could be saved and much suffering avoided if people did more to avoid risk factors like smoking, drinking and being overweight, the WHO said.

Pediatric UpdateWhat is Candida Score?In non–neutropenic critically ill patientMultifocal colonization 1 pointSurgery 1 pointTPN 1 pointSevere sepsis 2 pointsCut off value 2.5Sensitivity 81%, specificity 74%Score >2.5 - sensitive indication of proven infection (7.75 times more likely to have infection).

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

Obesity UpdateLife after Bariatric Surgery Post operative (Stage I) Full liquids: Once clear liquids are tolerated, a full liquid diet is started. This will last for one week. Foods in this stage should be smooth (no lumps or seeds). Thicker foods such as plain or ‘lite’ yogurt, sugar free pudding, or baby food in small frequent meals (i.e., 1/4 cup of low fat milk). are usually tolerated. Protein supplement is crucial at this point.

—Dr Parveen Bhatia and Dr Pulkit Nandwani

Medi Finance UpdateInvestment tipsAn investment in bank’s fixed deposits (FDs) has low risk but minimum gain. A bank gives 6% interest with inflation of 5%; the yield is only 1%. Company FDs can be invested in only after thorough analysis of the company.

Lab UpdateComplete Blood Count (CBC)CBC measures the amount of various types of blood cells in a sample of your blood. Blood cancers like AML, ALL, CML, CLL may be detected using this test if too many or too few of a type of blood cell or abnormal cells are found.

—Dr Arpan Gandhi and Dr Navin Dang

7th May 2011, Saturday

An IJCP Group Publication

Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean

Harvard Medical SchoolGroup Consultant Editor

Dr Deepak ChopraChief Editorial Advisor

Dr KK AggarwalCMD, Publisher and Group Editor-in-Chief

Dr Veena AggarwalJoint MD & Group Executive Editor

Anand Gopal BhatnagarEditorial Anchor

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

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Volume 21, Number 12, May 2011

Online SubmissionIndian Journal of

Clinical PracticeContentS

Advisory BodiesHeart Care Foundation of India

Non-Resident Indians Chamber of Commerce & IndustryWorld Fellowship of Religions

FROM THE DESK OF GROUP EDITOR-IN-CHIEF

Broccoli Compound may Combat COPD 643

ORIGINAL STUDy

Liv.52 DS Syrup in the Management of Alcoholic Hepatitis: An Open Label Study 645

S Ganesh, D Palaniyamma, Suprabha Hegde

REVIEW ARTICLE

Differentiation and Diagnosis of Tremor 651

Paul Crawford, Ethan E. Zimmerman

Drugs and Dreams 658

Sarita Goyal, Jyoti Kaushal, MC Gupta, Savita Verma

CASE REPORT

Mucormycosis 662

SA Kareem, Valluvan

Holt-Oram Syndrome 666

Sunil Mhaske, Sandeep Mhaske

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.

Note: Indian Journal of Clinical Practice does not guaran-tee, 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.

Published, Printed and Edited byDr KK Aggarwal, on behalf of

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the prior written permission of the publisher.

Volume 21, Number 12, May 2011

Indian Journal of

Clinical PracticeContentS

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CLINICAL STUDy

Biopsy of Skin Diseases in Urban and Suburban Population 669

Amar Ranjan

PRACTICE GUIDELINES

AAP Reports on Use of Probiotics and Prebiotics in Children 676

RESEARCH REVIEW

From the Journals ... 678

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A T T E N T I O N

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643Indian Journal of Clinical Practice, Vol. 21, No. 12, May 2011

In chronic obstructive pulmonary disease (COPD), damage to immune cells limits the lungs’ ability to fight off bacterial infections. According to a new study, boosting the activity

of a specific molecule in these cells can restore their defensive powers. In patients with COPD, immune cells called macrophages lose their ability to engulf and remove bacteria, making the lungs more vulnerable to infection. Until now, no one knew how to reverse this damage to the macrophages.

A team of scientists at Johns Hopkins University, led by Drs Shyam Biswal and Robert Wise, investigated why macrophages don’t work properly in COPD patients. Previous research suggested that a process called oxidative stress might be to blame. Oxidative stress occurs when the body can’t effectively neutralize damaging compounds called peroxides and free radicals.

A molecule called Nrf2 can cause cells to make more antioxidants, which neutralize these harmful compounds. Previous studies found reduced Nrf2 activity in severe COPD. The scientists suspected that increasing Nrf2 activity might restore the ability of macrophages to remove bacteria. To test their theory, the team used a chemical called sulforaphane, which is known to activate Nrf2. A precursor of sulforaphane is found in broccoli. The research was cosponsored by NIH’s National Heart, Lung and Blood Institute (NHLBI) and National Institute of Environmental Health Sciences (NIEHS). The results appeared in the April 13, 2011, issue of Science Translational Medicine.

The researchers first took macrophages from the lungs of patients with moderate COPD. When they treated these macrophages with sulforaphane, they saw higher Nrf2 levels in the cells. Sulforaphane treatment also boosted the ability of cultured macrophages to clear 2 of the major types of bacteria that infect COPD patients. Macrophage uptake of bacteria rose 300% after treatment, whether the cells came from smokers or nonsmokers. Experiments in mouse and human cells revealed that sulforaphane, through Nrf2, increases levels of a receptor called MARCO on macrophages. MARCO activity was necessary for macrophages to engulf bacteria after sulforaphane treatment. Mice exposed to smoke had lower levels of MARCO. Furthermore, smoke-exposed mice genetically engineered to lack Nrf2 had more lung inflammation and higher levels of bacteria.

The team gave sulforaphane with a nebulizer to mice exposed to smoke and found that the mice’s lungs showed reduced inflammation and bacterial burden. The researchers also gave human COPD patients broccoli sprout extract enriched with sulforaphane for two weeks. The patients taking the extract had higher levels of MARCO and Nrf2-controlled antioxidants in their blood cells. A NHLBI-sponsored clinical trial is now being conducted to test if sulforaphane can provide relief to patients with COPD.

n n n

From the Desk oF Group eDitor-in-ChieF

Broccoli Compound may Combat COPD

Dr KK AggarwalPadma Shri and Dr BC Roy National Awardee

Sr Physician and Cardiologist, Moolchand MedcityPresident, Heart Care Foundation of India

Group Editor-in-Chief, IJCP Group Editor-in-chief, eMedinewS

Chairman Ethical Committee, Delhi Medical CouncilDirector, IMA AKN Sinha Institute (08-09)

Hony. Finance Secretary, IMA (07-08)Chairman, IMA AMS (06-07)

President, Delhi Medical Association (05-06)[email protected]

http://twitter.com/DrKKAggarwalKrishan Kumar Aggarwal (Facebook)


Liv.52 DS Syrup in the Management of Alcoholic Hepatitis: An Open Label StudyS Ganesh*, D Palaniyamma**, Suprabha Hegde†

*Consultant Gastroenterologist and Hepatologist, Chennai**Medical Advisor†Research AssociateR&D Center, The Himalaya Drug Company, Makali, BangaloreAddress for correspondenceDr D PalaniyammaMedical Advisor, R&D Center, The Himalaya Drug Company Makali, Bangalore - 562 123E-mail: [email protected]

AbstrAct

The course of alcoholic liver disease is prolonged and variable and hence evaluation of beneficial effects of therapy is essential. The aim of the present study was to evaluate clinical efficacy and safety of Liv.52 DS syrup in patients suffering from alcoholic hepatitis (AH). An open clinical study was carried out in 50 patients with AH; all patients were given orally Liv.52 DS syrup (2 tsp) t.i.d. for two months. Patients were evaluated at monthly intervals. The parameters used were: Jaundice, anorexia, nausea/vomiting, fever, pruritus and liver function tests. Routine hematology was done before and after treatment to assess the safety profile. Treatment with Liv.52 DS syrup significantly improved clinical signs and symptoms as well as biochemical parameters. There were no drop outs in the trial period, indicating excellent patient compliance. There were no adverse drug reactions. No difference in hematological parameters was observed after treatment, which clearly indicates safety of the drug. The overall impression by the investigator showed marked improvement in 50%, moderate improvement in 28%, slight improvement in 10% and no change in 12% cases. Overall impression by the patients showed marked improvement in 56%, moderate improvement in 22%, slight improvement in 6% and no change in 16%. So, it can be concluded that Liv.52 DS syrup is safe and effective in patients suffering from AH.

Key words: Alcoholic hepatitis, Liv.52 DS syrup

Possible factors that affect development of liver injury include the dose, duration and type of alcohol consumption, drinking patterns, ethnicity and associated risk factors including obesity, iron overload, concomitant infection with viral hepatitis, and genetic factors. Geographic variability exists in the patterns of alcohol intake globally.5 The majority drink small or moderate amounts and do so without evidence of clinical disease.6-8

A subgroup, however, drinks excessively, develop physical tolerance and withdrawal, and are diagnosed with alcohol dependence.9 A second subset, alcohol abusers and problem drinkers, includes those who engage in harmful use of alcohol, defined by the development of negative social and health consequences of drinking (e.g., unemployment, loss of family, organ damage, accidental injury or death).10

ALD takes a prolonged and varied course; hence, evaluation of beneficial effects of therapy has been difficult. Multiple stages of the disease may be present simultaneously in a given individual.11,12 These are often grouped into three histological stages of ALD: Fatty liver or simple steatosis, AH and chronic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with several histologic changes (which have varying degrees of specificity for ALD), including the presence of Mallory’s hyaline, megamitochondria or perivenular and perisinusoidal fibrosis.11 Fatty

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Alcoholic liver disease (ALD) encompasses a spectrum of injury, ranging from simple steatosis to frank cirrhosis. It is common

for patients with ALD to share risk factors for simultaneous injury from other liver insults (e.g., coexisting nonalcoholic fatty liver disease, or chronic viral hepatitis).1 The term alcoholic hepatitis (AH) was first used by Beckett et al in 1961.2 Despite this long-standing observational relationship between alcohol consumption and liver disease, significant work has been required to determine quantity of alcohol to be consumed to cause liver disease, and which cohort of patients are at highest risk of developing significant liver injury.2,3 AH is a common and life-threatening cause of liver failure, especially when severe. It is usually subacute and has been developing for weeks to months before it becomes clinically apparent. Patients with AH usually have a history of drinking heavily for many years.4

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646 Indian Journal of Clinical Practice, Vol. 21, No. 12, May 2011

liver develops in about 90% of individuals who drink >60 g/day of alcohol,13 it may also occur in individuals who drink less.14 Uncomplicated fatty liver is usually asymptomatic and self-limited, and may be completely reversible with abstinence after about 4-6 weeks.15 Despite abstinence, progression to fibrosis and cirrhosis occurs in 5-15%. In a study, continued alcohol use (40 g/day) increased the risk of progression to cirrhosis to 30%, and fibrosis or cirrhosis to 37%.16 Fibrosis starts in the perivenular area and is affected by the amount of alcohol ingested.17,18 Perivenular fibrosis and deposition of fibronectin occurs in 40-60% of patients who ingest >40-80 g/day for an average of 25 years.

The diagnosis of ALD is based on a combination of features, including a history of significant alcohol intake, clinical evidence of liver disease and supporting laboratory abnormalities.19 The diagnosis of ALD is made by documentation of alcohol excess and evidence of liver disease.20 Many laboratory abnormalities, including elevated serum aminotransferases, have been found in patients with alcoholic liver injury, and used to diagnose ALD.21 In severe AH, serum aspartate aminotransferase (AST) is typically elevated to a level of 2-6 times the upper limits of normal. AST levels >500 IU/l or an alanine aminotransferase (ALT) >200 IU/l are uncommon in AH (other than alcoholic foamy degeneration, or concomitant acetaminophen overdose),22 and should suggest another etiology. AST/ALT ratio is >2 in about 70% patients, but this may be of greater value in patients without cirrhosis.23-25 Ratios >3 are highly suggestive of ALD.26

Palpation of the liver may be normal in ALD, and does not provide accurate information regarding liver volume.27 Physical findings more commonly observed are: Parotid enlargement, Dupuytren’s contracture and especially those signs associated with feminization.28 Specific features associated with an increased risk of mortality over one year: Hepatic encephalopathy (4.0), presence of visible veins across the anterior abdominal wall (2.2), edema (2.9), ascites (4.0), spider nevi (3.3) and weakness (2.1).29 An hepatic bruit in the setting of AH has been reported.30 ALD does not exist in isolation; other organ dysfunction related to alcohol abuse may coexist, including cardiomyopathy,31,32 skeletal muscle wasting,33 pancreatic dysfunction and alcoholic neurotoxicity.34 These should be looked for during clinical examination for appropriate treatment of the same.35

The diagnosis of fatty change, established cirrhosis and

hepatocellular carcinoma may be suggested by ultrasound, CT scan or magnetic resonance imaging (MRI) and confirmed by other laboratory investigations.36,37

Therapy of ALD is based on the stage of disease and the specific goals of treatment.38,39 Complications of cirrhosis, including evidence of hepatic failure (encephalopathy) as well as portal hypertension are treated as in patients with non-ALD, with additional attention given to other organ dysfunction associated specifically with alcohol.39 Abstinence is the most important therapeutic intervention for patients with ALD.40 It improves outcome and histological features of hepatic injury, reduces portal pressure and decreases disease progression40-43 but over one year, relapse rates range from 67 to 81%.44 Several medications have been used to help sustain abstinence. One of the first agents to be used was disulfiram. Naltrexone is a pure opioid antagonist and controls alcohol craving. However, it can also cause hepatocellular injury. Acamprosate (acetylhomotaurine) is a novel drug with structural similarities to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and is associated with a reduction in withdrawal symptoms.45 Pentoxifylline, a nonselective phosphodiesterase inhibitor, has a moderate anticytokine effect attributed to reduced transcription of the tumor necrosis factor (TNF) gene.46 Anti-TNF antibody infliximab, the chimeric human and mouse monoclonal antibody, binds to TNF and blocks its biological effects.47 Other measures include nutritional supplements, corticosteroids, antioxidants and in severe acute cases, liver transplantation.48-51 Liv.52 DS syrup, a polyherbal formulation, was evaluated in patients with AH. It is a hepatospecific formulation, designed for the management of liver disorders. It restores metabolic efficiency of liver in various forms of hepatocellular jaundice like infective and chronic active hepatitis, drug-induced hepatitis and alcohol-induced hepatic damage.

Aim

To evaluate the clinical efficacy and safety of Liv.52 DS syrup in patients suffering from AH.

Material and Methods

Study Design

An open clinical study in 50 patients with AH and attending the Malar Hospitals, Chennai, Tamil Nadu, India, after obtaining Ethics Committee approval and applicable regulatory authorities.

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Inclusion criteria: Fifty patients with AH aged >18 years with signs and symptoms of hepatitis (jaundice, anorexia, nausea/vomiting, fever, pruritus) and abnormal liver function tests (LFT) provided they could attend on all the specified assessment visits and willing to give the informed consent, and comply with the study procedures.

Exclusion criteria: Severe hepatic cirrhosis, hepatic encephalopathy, esophageal varices, severe systemic illness and those who were not ready to provide informed consent or comply with the study procedures.

Study Procedure

Study subjects were explained the nature of study; written consent was obtained. Detailed history of alcohol consumption including medical history was noted. Clinical examination was done, following which the patients were given orally Liv.52 DS syrup (2 tsp) t.i.d. for two months.

Follow-up and Assessment

Patients were evaluated at monthly intervals for study period. Assessment was done using subjective and objective parameters, which were scored arbitrarily. Parameters evaluated were jaundice, anorexia, nausea/vomiting, fever, pruritus and LFT. Adverse effects (AE), as volunteered by the patients, were recorded. Scoring was done as follows: 0-Nil, 1-Mild, 2-Moderate and 3-Severe.

Primary endpoints: Clinical recovery from the signs and symptoms and normalization of LFTs. Secondary endpoints: Incidence of any AE and the overall compliance to Liv.52 DS syrup.

Statistical Analysis

Results were expressed as number of incidences for clinical signs and symptoms and as mean ± SD for hematological, biochemical and clinical evaluations. Statistical analyzes were carried out using Fisher’s exact

test or paired student’s t-test. The minimum level of significance was fixed at p < 0.05. Statistical analysis was carried out using GraphPad Prism Software (Version 4.01).

Results

Fifty male patients (mean age of 50.36 ± 8.46 years) were included in the study. Duration of alcohol use was 10.85 ± 5.72 years and baseline weight was 75.78 ± 6.40. All patients received Liv.52 DS syrup in recommended doses for two months (Table 1). At entry, 21 patients had jaundice, which improved with treatment; symptoms persisted in only 10 patients at one month (p < 0.03) and seven patients at two months (p < 0.003). All 50 patients had anorexia and nausea, which improved significantly at one month (p < 0.0001) and at two months (p < 0.0001). Four patients had fever that subsided within 3-4 days of treatment as elicited by the subjects at one month. Pruritus, present in eight cases at entry, reduced to three cases at one month and two cases at two months (Table 2). LFT parameters (SGOT, SGPT, serum bilirubin, total protein, albumin and globulin) showed improvement. SGOT, SGPT and serum bilirubin showed a significant reduction (p < 0.0001) at the end of study period versus the baseline values (Table 3).

The overall impression by the investigator showed marked improvement in 50%, moderate improvement in 28%, slight improvement in 10% and no change in 12%. The overall impression by the patients showed marked improvement in 56%, moderate improvement in

Table 1. Demographic DetailsParticulars Liv.52 DS syrup (n = 50)Age years 50.36 ± 8.46 Duration of alcoholism (Years) 10.85 ± 5.72 Weight (Kgs) 75.78 ± 6.40Smoking (no. of patients) 19Diet (Veg:Non-veg) 02:48

Table 2. Effect of Liv.52 DS Syrup on Clinical Signs and Symptoms in Patients with AH (n = 50)Parameters Treatment duration

Day 0 At 1 month At 2 monthsPresent Absent Present Absent Present Absent

Jaundice 21 29 10 40 (p < 0.03) 7 43 (p < 0.003)Anorexia 50 0 28 22 (p < 0.0001) 12 38 (p < 0.0001)Nausea/vomiting 50 0 14 36 (p < 0.0001) 6 44 (p < 0.0001)Fever 4 46 0 50 (NS) 0 50 (NS)Pruritus 8 42 3 47 (NS) 2 48 (NS)

Significance with respect to Day 0; NS: Not significant

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Table 3. Effect of Liv.52 DS Syrup on Hematological and Biochemical Parameters in Patients with AHParameters Treatment duration Probability

At 1 month At 2 monthsHematological parametersHemoglobin (g/dl)

13.62 ± 0.96 13.57 ± 0.88 NS

WBC (/cu mm) 7682 ± 1104 7886 ± 1015 NSNeutrophils (%) 67.34 ± 5.27 67.85 ± 4.11 NSLymphocytes (%)

22.80 ± 4.21 23.70 ± 3.27 NS

Monocytes (%) 3.84± 2.50 3.54 ± 2.22 NSEosinophils (%) 4.04 ± 2.70 3.90 ± 2.00 NSBasophils (%) 1.70 ± 1.72 1.48 ± 1.46 NS

Biochemical parametersSGOT (IU/l) 73.40 ± 13.30 59.10 ±

12.91p < 0.0001

SGPT (IU/l) 94.36 ± 20.91 68.08 ± 22.57

p < 0.0001

Serum bilirubin (mg/dl)

1.97 ± 0.94 1.57 ± 0.81 p < 0.0001

Total protein (g/dl)

7.20 ± 0.33 7.19 ± 0.28 NS

Albumin (g/dl) 3.93 ± 0.31 3.92 ± 0.24 NSGlobulin (g/dl) 3.25 ± 0.18 3.29 ± 0.19 NS

Significance as compared to respective Day 0 values; NS: Not significant

22%, slight improvement in 6% and no change in 16%. On clinical examination, pulse (76.88 ± 4.61), blood pressure (120.96 ± 4.59/80.36 ± 4.83) and other systemic examination were normal in all patients. There were no changes in routine hematological tests (hemoglobin, white cell count). No AE were reported following treatment, which clearly indicates the safety of the drug. No drop out was observed during the trial period indicating excellent patient compliance.

Discussion

In the present study, there were significant improvements in clinical and liver function parameters of AH with Liv.52 DS syrup treatment. Its efficacy is due to the synergistic actions of the potent constituent hepatoprotective herbs, which include: Capparis spinosa, Cichorium intybus, Solanum nigrum, Terminalia arjuna, Cassia occidentalis, Achillea millefolium and Tamarix gallica.

P-Methoxybenzoic acid from C. spinosa has potent hepatoprotective activity against chemically-induced hepatotoxicity and prevents rise of malondialdehyde

(plasma and hepatic) and enzymes (AST and ALT).52-54 It improves functional efficiency of liver; has protective action on liver histology, and a salutary effect on liver glycogen and serum proteins.55 Flavonoids of C. spinosa have significant antioxidant activity.56

C. intybus increases circulating leukocytes, splenic plaque-forming cells, hemagglutination titers, secondary IgG antibody response, phagocytic activity, natural killer cell activity, cell proliferation and interferon-g secretion.57,58 It hepatoprotective activity suppresses oxidative DNA degradation in tissue debris.59 It also has potent antioxidant action.60,61 S. nigrum protects DNA against oxidative damage62 and is also a potent scavenger of hydroxyl and diphenylpicrylhydrazyl radicals.63 Significant inhibition of cytotoxicity, and hydroxyl radical scavenging potential against gentamicin-induced toxicity has been noted.64

T. arjuna reduces cholesterol levels and is also useful in liver disorders.65,66 It has potent antioxidant activity.67 Arjunaphthanoloside inhibits nitric oxide (NO) production, and terminoside A decreases inducible NO synthase levels in lipopolysaccharide-stimulated peritoneal macrophages.68 It has antiviral and antibacterial activities.69,70 C. occidentalis exerts significant hepatoprotective effects in chemically-induced liver damage by modulating hepatic enzymes.71,72 A. millefolium is beneficial in chronic hepatitis73 and has antihepatoma activity.74 T. gallica is a hepatic stimulant, digestive and hepatoprotective, and has a salutary effect on liver glycogen and serum proteins.75

Liv.52 DS syrup restores metabolic efficiency of the liver by protecting the parenchyma and promoting hepatocellular regeneration. The antiperoxidative activity of Liv.52 DS syrup prevents loss of functional integrity of the cell membrane, maintains cytochrome P450 enzyme system, shortens the disease recovery period, and ensures early restoration of hepatic functions in infective hepatitis.76 It protects against alcohol-induced hepatic damage by facilitating rapid elimination of acetaldehyde, the toxic intermediate metabolite of alcohol metabolism.77,78 It decreases lipotropic activity in chronic alcoholism, and prevents fatty infiltration of the liver. As a daily health supplement, it improves appetite, digestion and assimilation processes, and promotes weight gain. As a whole, Liv.52 DS syrup has hepatoprotective, antioxidant, antimicrobial and anti-inflammatory properties.

Conclusion

This clinical study has clearly shown significant improvement in clinical as well as biochemical parameters

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of AH with Liv.52 DS syrup. No differences in hematological parameters and no adverse drug reactions reported following treatment for the study period clearly indicate its safety. There were no drop outs indicating excellent patient compliance. So, it can be concluded that Liv.52 DS syrup is safe and effective in patients suffering from AH.

ReferencesPatrick CH. Alcohol, Culture, and Society. Durham, NC: Duke University Press; 1952.Beckett AG, et al. Br Med J 1961;2(5260):1113-9.Jensen K, et al. Hepatology 1994;20(4 Pt 1):1061-77.Amini M, et al. World J Gastroenterol 2010;16(39):4905-12.Mandayam S, et al. Semin Liver Dis 2004;24:217-32.Caetano R, et al. Ann Epidemiol 1997;7(8):542-9.Tam TW, et al. J Stud Alcohol 2000;61(4):617-21.Greenfield TK, et al. Am J Public Health 2000;90(1):47-52.Hasin D, et al. J Stud Alcohol 2000;61(3):431-8.American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th edition, American Psychiatric Association: Washington, DC, 1994.Lefkowitch JH. Clin Liver Dis 2005;9(1):37-53.Méndez-Sànchez N, et al. Ann Hepatol 2005;4(1):32-42.Crabb DW. Keio J Med 1999;48(4):184-8.Lieber CS, et al. J Clin Invest 1965;44:1009-21.Mendenhall CL. Am J Dig Dis 1968;13(9):783-91.Teli MR, et al. Lancet 1995;346(8981):987-90.Worner TM, et al. JAMA 1985;254(5):627-30.Savolainen V, et al. J Hepatol 1995;23(5):524-31.Levitsky J, et al. Semin Liver Dis 2004;24(3):233-47.Menon KV, et al. Mayo Clin Proc 2001;76(10):1021-9.Nalpas B, et al. Hepatology 1986;6(4):608-14.Uchida T, et al. Gastroenterology 1983;84(4):683-92.Nanji AA, et al. Enzyme 1989;41(2):112-5.Cohen JA, et al. Dig Dis Sci 1979;24(11):835-8.Niemelä O. Clin Chim Acta 2007;377(1-2):39-49.Nyblom H, et al. Alcohol Alcohol 2004;39(4):336-9.Leung NW, et al. J Hepatol 1986;2(2):157-64.Cozzolino G, et al. Minerva Med 1985;76(16):753-60.Orrego H, et al. Hepatology 1983;3(6):896-905.Goldstein LI. JAMA 1968;206(11):2518-20.Klatsky AL, et al. Am J Cardiol 2005;96(3):346-51.Lazarević AM, et al. J Am Coll Cardiol 2000;35(6):1599-606.Preedy VR, et al. Eur J Neurol 2001;8(6):677-87.Estruch R, et al. Alcohol Alcohol 1993;28(5):543-50.Anderson P, et al. Addiction 1993;88(11):1493-508.Schiano TD, et al. Transplantation 2000;69(4):545-50.

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11.12.13.14.15.16.17.18.19.20.21.22.23.24.25.26.27.28.29.30.31.32.33.34.35.36.

Bird GL. Baillieres Clin Gastroenterol 1993;7(3):663-82.Sougioultzis S, et al. Curr Med Res Opin 2005;21(9): 1337-46.Lieber CS. Curr Gastroenterol Rep 2004;6(1):60-5.Pessione F, et al. Liver Int 2003;23(1):45-53.Borowsky SA, et al. Gastroenterology 1981;80(6):1405-9.Brunt PW, et al. Gut 1974;15(1):52-8. Luca A, et al. Gastroenterology 1997;112(4):1284-9.Miller WR, et al. J Stud Alcohol 2001;62(2):211-20.Palmer AJ, et al. Alcohol Alcohol 2000;35(5):478-92.Akriviadis E, et al. Gastroenterology 2000;119(6):1637-48.Spahr L, et al. J Hepatol 2000;37(4):448-55.Cabré E, et al. Hepatology 2000;32(1):36-42.Mathurin P, et al. J Hepatol 2002;36(4):480-7.Phillips M, et al. J Hepatol 2006;44(4):784-90.Tomé S, et al. J Hepatol 2002;36(6):793-8. Gadgoli C, et al. J Ethnopharmacol 1999;66(2):187-92.Mantawy MM, et al. J Egypt Soc Parasitol 2004;34(2): 659-77.Asolkar LV, et al. (Capparis spinosa). Glossary of Indian Medicinal Plants with active principles. Second supplement, Part I (A-K), (1965-1981), Publications & Information Directorate (CSIR), New Delhi 1992:167.Huseini HF, et al. Phytomedicine 2005;12(9):619-24.Germanò MP, et al. J Agric Food Chem 2002;50(5):1168-71.Amirghofran Z, et al. J Ethnopharmacol 2000;72(1-2): 167-72.Kim JH, et al. Int Immunopharmacol 2002;2(6):733-44.Gazzani G, et al. J Pharm Biomed Anal 2000;23(1):127-33.Llorach R, et al. J Agric Food Chem 2004;52(16):5109-16.El SN, et al. Int J Food Sci Nutr 2004;55(1):67-74.Son YO, et al. Food Chem Toxicol 2003;41(10):1421-8.Heo KS, et al. J Med Food 2004;7(3):349-57.Prashanth Kumar V, et al. Fitoterapia 2001;72(5):481-6.Ram A, et al. J Ethnopharmacol 1997;55(3):165-9.Manna P, et al. BMC Complement Altern Med 2006;6:33.J Munasinghe TC, et al. Phytother Res 2001;15(6):519-23.Ali A, et al. Pharmazie 2003;58(12):932-4.Cheng HY, et al. Antiviral Res 2002;55(3):447-55.Perumal Samy R, et al. J Ethnopharmacol 1998;62(2):173-82.Bin-Hafeez B, et al. J Ethnopharmacol 2001;75(1):13-8. Jafri MA, et al. J Ethnopharmacol 1999;66(3):355-61.Yaeesh S, et al. Phytother Res 2006;20(7):546-51.Lin LT, et al. Phytother Res 2002;16(5):440-4.Sehrawat A, et al. J Enzyme Inhib Med Chem 2006;21(2): 215-23.Goel A, et al. Med Sci Res 1991;19:113.Subbarao VV. Probe 1976;XV(4):235-9. Singh B, et al. Indian J Nuclear Med 2000;15(1):27-9.

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Differentiation and Diagnosis of Tremor

Paul Crawford, Ethan E. Zimmerman

PAUL CRAWFORD, MD, is an associate program director of the Nellis Family Medicine Residency, Nellis Air Force Base, Nev., and an assistant professor in the Department of Family Medicine at the Uniformed Services University of the Health Sciences, Bethesda, Md.ETHAN E. ZIMMERMAN, MD, is a faculty member at the Nellis Family Medicine Residency, and an assistant professor in the Department of Family Medicine at the Uniformed Services University of the Health Sciences.

Source: Adapted from Am Fam Physician. 2011;83(6):697-702.

AbstrAct

Tremor, an involuntary, rhythmic, oscillatory movement of a body part, is the most common movement disorder encountered in clinical practice. Rest tremors occur in a body part that is relaxed and completely supported against gravity. Action tremors occur with voluntary contraction of a muscle and can be further subdivided into postural, isometric, and kinetic tremors. All persons have low-amplitude, high-frequency physiologic tremors at rest and during action that are not reported as symptomatic. The most common pathologic tremor is essential tremor. In one-half of cases, it is transmitted in an autosomal dominant fashion, and it affects 0.4 to 6 percent of the population. More than 70 percent of patients with Parkinson disease have tremor as the presenting feature. This tremor is typically asymmetric, occurs at rest, and becomes less prominent with voluntary movement. Features consistent with psychogenic tremor are abrupt onset, spontaneous remission, changing tremor characteristics, and extinction with distraction. Other types of tremor are cerebellar, dystonic, drug- or metabolic-induced, and orthostatic. The first step in the evaluation of a patient with tremor is to categorize the tremor based on its activation condition, topographic distribution, and frequency. The diagnosis of tremor is based on clinical information obtained from a thorough history and physical examination. For particularly difficult cases, single-photon emission computed tomography to visualize the integrity of the dopaminergic pathways in the brain may be useful to diagnose Parkinson disease.

Key words: Tremor, Parkinson disease, single-photon emission computed tomography

Tremor is an involuntary, rhythmic, oscillatory movement of a body part. It is the most common movement disorder encountered in clinical

practice.1-3 There is no diagnostic standard to distinguish among common types of tremor, which can make the evaluation challenging. However, establishing the underlying cause is important because prognosis and specific treatment plans vary considerably. History and physical examination can provide a great deal of certainty in diagnosis. The most common tremor in patients presenting to primary care physicians is enhanced physiologic tremor, followed by essential tremor and parkinsonian tremor.1,3-6 All tremors are more common in older age.7

Classification

Tremors are classified as either resting or action.8 A rest tremor occurs in a body part that is relaxed and

completely supported against gravity (e.g., when resting an arm on a chair). It is typically enhanced by mental stress (e.g., counting backward) or movement of another body part (e.g., walking), and diminished by voluntary movement of the affected body part.3,9,10 Most tremors are action tremors, which occur with voluntary contraction of a muscle. Action tremors can be further subdivided into postural, isometric, and kinetic tremors.8,9 A postural tremor is present while maintaining a position against gravity. An isometric tremor occurs with muscle contraction against a rigid stationary object (e.g., when making a fist). A kinetic tremor is associated with any voluntary movement and includes intention tremor, which is produced with target-directed movement.2

Essential Tremor

The most common pathologic tremor is essential tremor. In one-half of cases, it is transmitted in an autosomal dominant fashion, and it affects 0.4 to 6 percent of the population.4,8 Careful history reveals that patients with essential tremor have it in early adulthood (or sooner), but most patients do not seek help for it until 70 years of age because of its progressive nature. Despite being sometimes called “benign essential tremor,”

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essential tremor often causes severe social embarrassment, and up to 25 percent of those afflicted retire early or modify their career path.8

Essential tremor is an action tremor, usually postural, but kinetic and even sporadic rest tremors have also been described.3,11 It is most obvious in the wrists and hands when patients hold their arms in front of themselves (resisting gravity); however, essential tremor can also affect the head, lower extremities, and voice.12 It is generally bilateral, is present with a variety of tasks, and interferes with activities of daily living.1,5 In a series of 200 Italian patients referred to a neurologist for evaluation of tremor, 15 percent had uncommon clinical features that included postural, action, rest, orthostatic, and writing tremors, and 10 percent had tongue or facial dyskinesia.13

Diagnostic criteria have been proposed, but none have been accepted universally. Persons with essential tremor typically have no other neurologic findings; therefore, it is often considered a diagnosis of exclusion.12 If the tremor responds to a therapeutic trial of alcohol consumption (two drinks per day), the diagnosis of essential tremor is assured.

Parkinsonism

Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia, rigidity, and postural instability. Many patients will also have micrographia, shuffling gait, masked facies, and an abnormal heel-to-toe test.10,14-16 Causes of parkinsonism include brainstem infarction, multiple system atrophy, and medications that block or deplete dopamine, such as methyldopa, metoclopramide, haloperidol, and risperidone.9,10 Idiopathic Parkinson disease is a chronic neurodegenerative disorder; its prevalence increases with age. It is the most common cause of parkinsonism.17

More than 70 percent of patients with Parkinson disease have tremor as the presenting feature. The classic parkinsonian tremor begins as a low-frequency, pill-rolling motion of the fingers, progressing to forearm pronation/supination and elbow flexion/extension. It is typically asymmetric, occurs at rest, and becomes less prominent with voluntary movement. Although rest tremor is one of the diagnostic criteria for Parkinson disease, most patients exhibit a combination of action and rest tremors.3,11

Enhanced Physiologic Tremor

A physiologic tremor is present in all persons. It is a low-amplitude, high-frequency tremor at rest and during action that is not reported as symptomatic. This tremor can be enhanced by anxiety, stress, and certain medications and metabolic conditions. Patients with a tremor that comes and goes with anxiety, medication use, caffeine intake, or fatigue do not need further testing.1,8

Drug- and Metabolic-induced Tremors

Dozens of medications can cause or exacerbate tremor (Table 1).1,3,8 Patients with new-onset tremor should have a comprehensive medication review with specific attention to medications (prescribed and over-the-counter) started proximal to the onset of tremor.8 Medications particularly prone to inducing or exacerbating tremor are those that stimulate the sympathetic nervous system (e.g., amphetamines, terbutaline, pseudoephedrine) and psychoactive medications (e.g., tricyclic antidepressants, haloperidol, fluoxetine).1,8,12 When medication review reveals a likely culprit, a trial off of this medication should be attempted.

Metabolic causes of tremor are varied.8 Initial workup of tremor may include blood testing for hepatic encephalopathy, hypocalcemia, hypoglycemia, hyponatremia, hypomagnesemia, hyperthyroidism, hyperparathyroidism, and vitamin B12 deficiency.8

Table 1. Selected Medications and Substances that may Exacerbate TremorAmiodarone Hypoglycemic agents

Amphetamines Lithium

Atorvastatin Metoclopramide

b-adrenergic agonists (e.g., albuterol) Methylphenidate

Caffeine Pseudoephedrine

Carbamazepine Terbutaline

Corticosteroids Theophylline

Cyclosporine Thyroid hormones

Epinephrine Tricyclic antidepressants

Fluoxetine Valproic acid

Haloperidol Verapamil

Information from references 1,3, and 8.

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Cerebellar Tremor

The classic cerebellar tremor presents as a disabling, low-frequency, slow intention or postural tremor, and is typically caused by multiple sclerosis with cerebellar plaques, stroke, or brainstem tumors. Other neurologic signs include dysmetria (overshoot on finger-to-nose testing), dyssynergia (abnormal heel-to-shin testing and/or atraxia), and hypotonia.8,18

Psychogenic Tremor

Differentiation of organic from psychogenic tremor can be difficult. Features consistent with psychogenic tremor are abrupt onset, spontaneous remission, changing tremor characteristics, and extinction with distraction8,19 (Table 28,18). Often, there is an associated stressful life event.3 Based on clinical experience, the prevalence of psychogenic tremor is thought to be high, but there are no precise estimates.10

Dystonic Tremor

Dystonic tremor is a rare tremor found in 0.03 percent of the population.20 It typically occurs in patients younger than 50 years. The tremor is usually irregular and jerky, and certain hand or arm positions will extinguish the tremor. Other signs of dystonia (e.g., abnormal flexion of the wrists) are usually present.8,20

Wilson Disease

Wilson disease is a rare, autosomal recessive disorder that manifests in persons five to 40 years of age, sometimes with a “wing-beating” tremor (see http://

www.youtube.com/watch?v=JgDvQUwUOo0 for an example of this tremor). Serum ceruloplasmin level and 24-hour urinary copper excretion should be considered in young patients presenting with tremor to exclude this potentially life-threatening disease.17,21

Diagnostic Approach

The diagnosis of tremor is based on clinical information obtained from a thorough history and physical examination.2,17 Although there is overlap and variability among the individual tremor syndromes, the intrinsic features of the tremor usually provide key diagnostic clues (Figure 12,8,10,17,19; Table 3)1,3,8,10. The first step in the evaluation of a patient with tremor is to categorize the tremor based on its activation condition, topographic distribution, and frequency. The activation condition should be described as rest, kinetic (or intention), postural, or isometric. The examiner can have the patients sit with their hands in their laps to check for rest tremor. A sequential test for postural and kinetic tremors can be done by having the patient stretch his or her arms and hands out, followed by a simple finger-to-nose test.2,3 A rest tremor is virtually synonymous with parkinsonism, whereas an intention tremor often indicates a cerebellar lesion.1,10 Frequency is generally classified as low (less than 4 Hz), medium (4 to 7 Hz), or high (more than 7 Hz). The topographic distribution of the tremor (e.g., limbs, head, voice) can also provide useful information. For example, a high-frequency tremor that involves the head is much more likely to be essential tremor than parkinsonian tremor.2,3 Several historical clues

Table 2. Characteristics of Psychogenic Tremor

Abrupt onset Presence of psychiatric disease

Absence of other neurologic signs Presence of secondary gain

Changing tremor characteristics Reported functional disturbances in the past

Clinical inconsistencies Responsive to placebo

Employed in allied health professions Spontaneous remission

Litigation or compensation pending Static course

Multiple somatizations Tremor increases with attention, and lessens with distractibility

Multiple undiagnosed conditions Unclassified tremor (complex tremors)

No evidence of disease by laboratory or radiologic investigations Unresponsive to antitremor medications

Information from references 8 and 18.

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Table 3. Features of Common Tremor SyndromesTremor syndrome Clinical features Diagnostic tests TreatmentCerebellar tremor Intention or postural tremor; ipsilateral

involvement to lesion; abnormal finger-to-nose test; imbalance; abnormal heel-to-shin test; hypotonia

Head computed tomography or magnetic resonance imaging

Treat underlying cause, deep brain stimulation

Enhanced physiologic tremor

Postural tremor; low amplitude; use of exacerbating medication

Serum glucose level, thyroid-stimulating hormone level, liver function testing, patient history to evaluate for anxiety and caffeine use

Treat underlying cause, reassurance

Essential tremor Postural tremor; symmetric; involves hands, wrists, lower extremities, head, or voice; family history; improvement with alcohol

No specific test; complete blood count, thyroid-stimulating hormone level, serum chemistry profile may rule out other disease

Propranolol, primidone

Parkinsonian tremor Rest tremor; asymmetric; involves distal extremities; decreases with voluntary movement; bradykinesia, postural instability, and rigidity

No specific test; positron emission tomography or single-photon emission computed tomography for atypical presentation

Dopamine agonists, anticholinergics

Psychogenic tremor Abrupt onset; spontaneous remission; extinction with distraction; changing tremor characteristics

Careful history Mental health counseling

Figure 1. Diagnostic algorithm for tremor.Information from references 2, 8, 10, 17, and 19.

Enhanced physiologic tremor Taking medication associated with tremor?

NoYes

Drug-induced tremor Relieved with distraction?

Trial off medication

Psychogenic tremor Organic cause

Go to Figure 2Mental health evaluation

Evaluate for anxiety, caffeine use; serum glucose level; liver function testing; thyroid-stimulating hormone level

NoYes

Yes No

Diagnosis TremorPatient with tremor

Is tremor physiologic?

can play important roles in the differentiation of tremors (Figure 22,8,10,17,19). Tremor in older patients is more likely to be parkinsonian or essential tremor. Patients with sudden onset of tremor should be evaluated to determine if the tremor is caused by

Information from references 1, 3, 8, and 10.

medications, toxins, a brain tumor, or a psychogenic cause. Patients with a gradual onset of tremor should prompt questions about Parkinson disease.

Most tremors are symmetric, but brain tumors can cause tremors to lateralize to one side. Caffeine and

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fatigue are often exacerbating factors in essential tremor; alleviating factors are difficult to find. A search must be made for associated diseases (e.g., sleep disorders because fatigued muscles may amplify physiologic tremor; polyneuropathy because lack of innervations may cause small involuntary movements that are interpreted as tremor). A family history of neurologic disease or tremor suggests a genetic component, as is often seen in essential tremor. A thorough medication history should be obtained to rule out drug-induced tremor. The patient should also be screened for drugs of abuse and alcohol consumption because alcohol overuse and withdrawal can cause tremor. Conversely, small amounts of alcohol can temporarily relieve essential tremor and can be a clue to the diagnosis.2,3

The assessment of tremor also includes a careful examination for signs associated with tremor syndromes. Bradykinesia and postural abnormalities strongly suggest parkinsonism. Difficulty rising from a seated position, micrographia, reduced arm swing while walking, and masked facies are also features of bradykinesia. Postural

abnormalities can be demonstrated by a positive pull test, which is when the patient stands in a neutral position and the examiner causes him or her to fall by pulling on the upper arms from behind. This can help isolate cerebellar tremor and prompt evaluation for multiple sclerosis or stroke.22 Similarly, the coactivation sign is resistance during passive movement of a tremulous limb, but with disappearance of the tremor, which indicates psychogenic tremor. The examiner should search for dystonia (i.e., sustained muscle contraction), cerebellar signs (e.g., ataxia, uncoordination), pyramidal signs, neuropathic signs, and signs of systemic disease (e.g., thyrotoxicosis). A shuffling gait is consistent with parkinsonism, whereas an unsteady stance with normal gait can indicate orthostatic tremor (a rare lower extremity disorder that produces subjective unsteadiness on standing).2,8

Videos that illustrate different features of tremor are available on the Internet. Some of the more common examples are essential tremor (http://www.youtube.com/watch?v=xVRKO-Sz0x4), parkinsonian tremor (http://www.youtube.com/watch?v=DaIN2zRQn8w),

Figure 2. Diagnostic algorithm for tremor with an organic cause.Information from references 2, 8, 10, 17, and 19.

NoYes

Serum ceruloplasmin level and 24-hour urinary copper secretion

Wilson disease Neurologic signs or symptoms?

NegativePositive

Chelation therapy

Various anatomic, metabolic, and

genetic problems

Appropriate blood or genetic tests with or without head

imaging

Trial of beta blocker

NoYes

Likely essential

tumor

Diagnosis of Tremor with an Organic Cause

Continued from Figure 1 Tremor with organic cause

Age <40 years?

Trial of dopa-minergic agent Monitor

Possible parkinsonism

Parkinsonism

Rigidity, bradykinesia, postural instability?

History of alcoholism?

Action

Withdrawal or alcohol tremor

Postural or intention tremor

IntentionPostural

Trial of beta blocker

Head imaging for stroke, mass multiple

sclerosis

Essential tremor Cerebellar tremor

NoYes

Rest or action tremor?

Rest

NoYes

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and intention tremor (http://www.youtube.com/watch?v=GQm8klm6ub8).

Tremor in Children

The diagnosis of tremor in children is poorly under-stood. A variety of genetic conditions are associated with tremor in children, including spinal muscular atrophy, mitochondrial diseases, Huntington disease, and fragile X syndrome. Brain tumors, hydrocephalus, nutritional deficiencies (e.g., vitamin B12), heavy metal poisoning, prescription medications, pyruvate carboxylase deficiency, and homocystinuria can also cause tremor in children. Tremor in children is potentially serious; patients should be promptly referred to a neurologist.23 Childhood tremor should also prompt an in-depth investigation to elucidate its cause.23

Imaging

A variety of imaging modalities have been studied to help differentiate causes of tremor. Currently, the diagnosis of tremor remains primarily clinical, but for particularly difficult cases, single-photon emission computed tomography (SPECT) to visualize the integrity of the dopaminergic pathways in the brain may be useful to diagnose Parkinson disease. A meta-analysis found that SPECT with presynaptic radiotracers successfully differentiated Parkinson disease in an early phase from normalcy (odds ratio = 60), Parkinson disease from essential tremor (odds ratio = 210), and Parkinson disease from vascular parkinsonism (odds ratio = 105).24 The large odds ratios in this meta-analysis are caused by spectrum bias from the case-control design of the underlying studies.

In a subsequent series of 99 patients with suspected, yet undiagnosed Parkinson disease, baseline scanning with a different type of SPECT ([123I]FP-CIT SPECT) was 78 percent sensitive and 97 percent specific, with a positive likelihood ratio of 26 and negative likelihood ratio of 0.23. Thus, positive SPECT was very good at ruling in a final diagnosis of Parkinson disease three years later.25 Plain computed tomography and magnetic resonance imaging are good choices to rule out secondary causes of tremor (e.g., multiple sclerosis, stroke) when the diagnosis of tremor is not obvious from history and physical examination.26

Data Sources: A PubMed search was completed in Clinical Queries using the key terms tremor, movement disorders, and SPECT. The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. Also searched were the Agency for Healthcare Research and Quality evidence reports, Bandolier, Clinical Evidence, FPIN’s Clinical Inquiry database, the Cochrane database, the Institute for Clinical Systems Improvement, the National Guideline Clearinghouse database, Essential Evidence Plus, EBM Online, and UpToDate. Reference lists of recent review articles were also searched for articles not previously discovered. Search date: May 15, 2010.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official, or as reflecting the views of the U.S. Air Force Medical Service or the U.S. Air Force at large.

ReferencesJankovic J, Fahn S. Physiologic and pathologic tremors. Diagnosis, mechanism, and management. Ann Intern Med. 1980;93(3):460-465.Deuschl G, Bain P, Brin M; Ad Hoc Scientific Committee. Consensus statement of the Movement Disorder Society on Tremor. Mov Disord. 1998;13(suppl 3):2-23.Bhidayasiri R. Differential diagnosis of common tremor syndromes. Postgrad Med J. 2005;81(962):756-762.Louis ED. Clinical practice. Essential tremor. N Engl J Med. 2001;345(12):887-891.Louis ED, Levy G, Côte LJ, Mejia H, Fahn S, Marder K. Clinical correlates of action tremor in Parkinson disease. Arch Neurol. 2001;58(10):1630-1634.Wenning GK, Kiechl S, Seppi K, et al. Prevalence of movement disorders in men and women aged 50-89 years (Bruneck Study cohort): a population-based study. Lancet Neurol. 2005;4(12):815-820.Tse W, Libow LS, Neufeld R, et al. Prevalence of movement disorders in an elderly nursing home population. Arch Gerontol Geriatr. 2008;46(3):359-366.Leehey MA. Tremor: diagnosis and treatment. Primary Care Case Rev. 2001;4:32-39.Habib-ur-Rehman. Diagnosis and management of tremor. Arch Intern Med. 2000;160(16):2438-2444.Chou KL. Diagnosis and management of the patient with tremor. Med Health R I. 2004;87(5):135-138.Cohen O, Pullman S, Jurewicz E, Watner D, Louis ED. Rest tremor in patients with essential tremor: prevalence, clinical correlates, and electrophysiologic characteristics. Arch Neurol. 2003;60(3):405-410.

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Zhang ZX, Román GC. Worldwide occurrence of Parkinson’s disease: an updated review. Neuroepidemiology. 1993;12(4):195-208.Martinelli P, Gabellini AS, Gulli MR, Lugaresi E. Different clinical features of essential tremor: a 200-patient study. Acta Neurol Scand. 1987;75(2):106-111.Rao G, Fisch L, Srinivasan S, et al. Does this patient have Parkinson disease? JAMA. 2003;289(3):347-353.Mason A, Anderson D, Birleson A, et al.; National Collaborating Centre for Chronic Conditions. Parkinson’s disease: diagnosis and management in primary and secondary care. National Institute for Health and Clinical Excellence; 2006. http://www.nice.org.uk/CG035. Accessed June 1, 2010.Bohnen NI, Studenski SA, Constantine GM, Moore RY. Diagnostic performance of clinical motor and non-motor tests of Parkinson disease: a matched case-control study. Eur J Neurol. 2008;15(7):685-691.Pahwa R, Lyons KE. Essential tremor: differential diagnosis and current therapy. Am J Med. 2003;115(2): 134-142.Deuschl G. Differential diagnosis of tremor. J Neural Transm Suppl. 1999;56:211-220.Gupta A, Lang AE. Psychogenic movement disorders. Curr Opin Neurol. 2009;22(4):430-436.

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Kelsberg G, Rubenstein C, St Anna L. FPIN’s clinical inquiries. Differential diagnosis of tremor. Am Fam Physician. 2008;77(9):1305-1306.Chin DK. Clinics in neurology: diagnosis and management of tremors. J Hong Kong Med Assoc. 1988;40(3):223-225.Uitti RJ. Tremor: how to determine if the patient has Parkinson’s disease. Geriatrics. 1998;53(5):30-36.Keller S, Dure LS. Tremor in childhood. Semin Pediatr Neurol. 2009;16(2):60-70.Vlaar AM, van Kroonenburgh MJ, Kessels AG, Weber WE. Meta-analysis of the literature on diagnostic accuracy of SPECT in parkinsonian syndromes. BMC Neurol. 2007;7:27.Marshall VL, Reininger CB, Marquardt M, et al. Parkinson’s disease is overdiagnosed clinically at baseline in diagnostically uncertain cases: a 3-year European multicenter study with repeat [123I]FP-CIT SPECT. Mov Disord. 2009;24(4): 500-508.Dormont D, Seidenwurm DJ, Davis PC, et al. American College of Radiology Appropriateness Criteria: Dementia and movement disorders. 2007. http://www.acr.org/SecondaryMainMenuCategories/quality_safety/app_criteria/pdf/ExpertPanelonNeurologicImaging/NeurodegenerativeDisordersUpdateinProgressDoc9.aspx. Accessed September 22, 2010.

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Dreams are a series of images, ideas, thoughts, emotions and sensations occurring involuntarily in the mind during certain

stages of sleep.1 The content and purpose of dreams are not fully understood although they have been a topic of interest since ages. The scientific study of dreams is known as oneirology.1

Dreams have a long history. They have been a subject of controversy and disagreement as different indivi-duals have tried to describe in their own manner. They have been described physiologically as a response to a neural process when the person is asleep while the psychological basis proposed is that they are because of reflection of the subconscious mind. The spiritual people ascribe them to as messages from Gods. Pharmacologists are of the view that medications, many hormones, neurotransmitters, herbs and supplements can alter dreams and make them more or less vivid.2

Dreams can be of various forms i.e., pleasant dreams or frightening dreams. Frightening dreams can be either in the form of a nightmare or a night terror. A nightmare is a type of dream that arouses feelings of intense, inescapable fear, terror, distress or extreme anxiety that usually awakens the sleeper. It results in the dreamer

waking with full or partial recall of the dream itself. Recurrent nightmares can be because of post-traumatic stress disorders or due to other psychiatric illnesses. Nightmares are more common in women and are associated with an increase in nocturnal awakenings, sleep onset insomnia and day time memory impairment and anxiety following poor sleep.3 Night terror is an arousal disorder that usually occurs early in the sleep period. It is an episode of extreme fright during sleep without any recollection of a dream. Both nightmares and night terrors strike children much more often than adults.3

Sleep Patterns and Dreams

As indicated by Davidson, Duffy and Osselton, sleep may be divided into two alternative phases: Rapid eye movement (REM) sleep and nonrapid eye movement (NREM) sleep. Although, dreams can occur in both the phases, but they primarily take place in the REM phase which is associated with low-voltage electroencephalogram.4 NREM sleep is further divided into four stages (stage 1 to stage 4). Stage 3 and 4 constitute the deep sleep. It is reported that 80% of persons have dreams during REM sleep and sleep onset (stages 1 and 2) while 20% persons have dreams during deep sleep.5 Patients report that dreams experienced during REM sleep tend to be bizarre and detailed, with storyline plot associations. Unpleasant or frightening dreams usually occur in this period. In contrast, dreams experienced in deep sleep are more diffuse (e.g. dreams about a color or an emotion). Night terrors may occur at this time. The dreams of stages 1 and 2 are simpler, shorter and have fewer associations

*Demonstrator**Professor†Senior Professor and Head‡Associate ProfessorDept. of Pharmacology, Pt. BDS PGIMS, RohtakAddress for correspondenceDr Sarita Goyal Demonstrator, Dept. of Pharmacology 14/9J, Medical Campus, PGIMS, Rohtak - 124 001E-mail: [email protected]

AbstrAct

Dreams are a series of images, ideas, thoughts, emotions and sensations occurring involuntarily in the mind during certain stages of sleep. They have been described physiologically as a response to a neural process when the person is asleep while the psychological basis proposed is that they are because of reflection of the subconscious mind. Pharmacologists are of the view that medications, many hormones, neurotransmitters, herbs and supplements can alter dreams and make them more or less vivid.

Key words: Oneirology, REM sleep, NREM sleep, neurotransmitters

Drugs and Dreams

Sarita Goyal*, Jyoti Kaushal**, MC Gupta†, Savita Verma‡

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than the dreams of REM sleep.5 These phases of sleep, especially REM sleep, can be affected by a variety of drugs and hormones.6

A number of drugs used in various diseases can affect the sleep pattern and can cause dreams. Nightmares including night terrors are also associated with the use of medications which affect the neurotransmitters e.g., adrenergic, cholinergic, dopaminergic, serotonergic and gabaminergic, etc. It has been observed that almost all psychiatric drugs can influence our dreaming but even medications that would not seem suspected, such as blood pressure affecting drugs, may have an effect, some of them reducing nightmares and some increasing them. Individual differences are of course always possible. Not only the drugs used in pharmaco-therapeutics lead to dreams, but even the drugs of abuse can be responsible for change in sleeping pattern and dreams.2

Pharmacotherapeutic Drugs and Dreams

Prescribed drugs used in various disease states can alter the sleeping patterns leading to dreams by affecting one or the other neurotransmitters. Drugs influencing adrenergic, aminergic, dopaminergic and cholinergic neurotransmitters have prominent role on dreams and nightmares.7 These neurotransmitters may function by modulation of the cardinal sleep stages - REM and NREM sleep.8

Antihypertensive Agents

Antihypertensive agents, in general use, affect adrenergic receptors. b-blockers and adrenergic neuron blocking agents are responsible for 34% of clinical trials in which nightmares are reported as an adverse effect.8 b-blockers which cause nightmares or dreams are: Propranolol, atenolol, betaxolol, bisopropolol, labetalol. They are known to be NREM suppressants. Adrenergic neuron blockers-guanethidine, and reserpine have probable association with nightmare reports. These drugs have been shown to affect REM sleep and thus cause dreams. Decrease in dream recall occurs with the use of both adrenergic neuron blockers (REM suppressant) and b-blockers (NREM suppressants).9 Other antihypertensive agents which may cause dreams are angiotensin-converting enzyme inhibitors (captopril, enalapril and quinapril), angiotensin receptor blocker (losartan) and calcium channel blocker (verapamil).8

Hypolipidemic Agents

Nightmares may also be a rare class effect of the statins: Simvastatin, pravastatin, fluvastatin and atorvastatin, which may be linked to REM sleep suppression.8

Drugs used in Alzheimer’s Disease

REM sleep is affected by pharmacological alteration of cholinergic activity in the central nervous system (CNS).8 Many lines of study support the hypothesis that brainstem cholinergic neurons can be excited to induce REM sleep.10 Cholinergic agents (anticholinestrases) such as donepezil, rivastigmine and tacrine are likely to increase the percentage of REM sleep, while cholinergic antagonists have a tendency to decrease REM sleep.11 Anticholinestrases affecting acetylcholine neuroreceptor system thus have a possible association with drug-induced nightmares. Memantine, which is a N-methyl-d-aspartate (NMDA) receptor antagonist, may cause surreal or unpleasant dreams, sometimes nightmares.2

Antidepressants Agents

All drugs that alter serotonin levels may affect sleep and dreaming. This effect is greatest for the monoamine oxidase inhibitors (MAOIs) followed by tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs).12 Intense visual dreaming and nightmares are associated with clomipramine; REM sleep rebound occurring after the withdrawal of these REM sleep suppressant agents.13 Fluoxetine, citalopram, as well as atypical antidepressant mirtazapine can also cause very peculiar, sometimes disturbing dreams.2

Antipsychotics Agents

Antipsychotic (neuroleptic) drugs e.g.; chlorpromazine, thiothixene and clozapine can increase vividness of dream but often decrease dream recall.2

Antiparkinsonian Drugs

Dopamine receptor stimulation may be another common mechanism resulting in drug-induced nightmares. Dopamine agonists - levodopa, bromo-criptine, pergolide, amantadine, selegiline and rasagiline, used to treat Parkinson disease may cause vivid dreams, sometimes of sexual nature.14

Antiepileptic Drugs

Drugs known to affect the gamma-aminobutyric acid

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(GABA) receptor (agonist, modulators and reuptake inhibitors) can cause nightmares and abnormal dreaming. Gabapentin, valproic acid and tiagabine are few examples related to GABA neurotransmitter. Other antiepileptics like lamotrigine and ethosuximide also cause dreams.15

Sedative Hypnotic Drugs

Nightmares and intense dreaming have been associated with the REM sleep rebound associated with withdrawal from REM sleep suppression agents-barbiturates. Benzodiazepines (diazepam, flunitrazepam, nitrazepam) and nonbenzodiazepine hypnotic, zolpidem can also induce dreams and night terrors by increasing REM sleep.16

General Anesthetic Agents

These agents may also induce nightmares. An increased incidence of pleasant dreams is reported with propofol use,17 while thiopental, midazolam, isoflurane and ketamine have been reported to produce disordered dreaming and nightmares.18

Antihistaminic Drugs

Chlorpheniramine has been reported to induce nightmares suggesting a potential role for histamine as a modulator of dreaming.19

Antimicrobial and Immunosuppressant Agents

Viral and bacterial infections can be associated with large increase in NREM sleep. In some studies, several agents like fleroxacin, erythromycin and ciprofloxacin, which are used for the treatment of bacterial infections, are reported to induce nightmares.19 Antiviral agents such as ganciclovir and amantadine may also lead to dreams. Even gusperimus, which is an immunologic response suppressant, is also reported to induce nightmares.7

Analgesic Drugs

People taking opioids as painkillers (morphine, buprenorphine) often report vivid dreams especially in the beginning of their use. Nonopioid pain killer, naproxen may also affect dreams.2

Endocrinal Agents

The hormones dehydroepiandrosterone (DHEA) and testosterone may cause nightmares if the dose is too large.2

Miscellaneous Drugs

Other drugs modulating the various neurotransmitters i.e., orexin, adenosine, histamine, glycine, glutamate, nitric oxide and neuropeptides may also be associated with varied dreams.20 Riluzole and dextromethorphan which are NMDA receptor antagonists may lead to unpleasant dreams, sometimes nightmares. Drug used for smoking cessation i.e., vareniciline which is a nicotine receptor partial agonist may also be responsible for nightmares.2

Herbal Drugs

Many herbal drugs influence dreaming, especially those with psychotropic effects like Kava-Kava, St. John’s Wort, Valerian, Licorice root, Jasmine, Lavender, Cardamom, Ginkgo biloba, Cinnamon, Marigold, Nutmeg, Peppermint and Passion flower. The Ayurvedic herb Ashwagandha is also well-known for creating surreal dreams.2

Drugs of Abuse and Dreams

There are many drugs, such as opium, cocaine, cannabis, coal tar products and alcohol, which have an abuse potential, may have an influence upon dreams. Dreams caused by such drugs are, however, influenced by the physiological action of the drug taken, the amount used, the idiosyncrasies of the individual and the mentality. Drugs as opium and cocaine, when taken in medicinal doses, produce a sense of well-being and comfort and so tend to promote pleasurable fancies. These drugs, when taken in sufficient doses, cause sleep dreams which are not remembered. Many persons are much distressed by these drugs; and others, in place of awaking refreshed, awake tired and dimly conscious of disturbing dreams.21

CNS stimulant drugs e.g., amphetamines and caffeine may also lead to dreams. Amphetamines are associated with vivid and unpleasant dreams whereas caffeine has been used to induce lucid dreaming, because it makes one sleep lighter.22 Dreams are, thus, reflections of subconscious mind and are caused by a variety of pharmacological agents. These agents act via a variety of neurotransmitters i.e., adrenergic, cholinergic, dopaminergic, serotonergic and gabaminergic, etc. These drugs are either pharmacotherapeutic drugs prescribed for the treatment of various diseases or are the drugs of abuse. These drugs may be responsible

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for causation of dreams which are either pleasant in nature or may be in the form of nightmares.

From the clinician point of view, various strategies can be adopted for the management of varied types of dreams especially nightmares and night terrors. Of foremost importance is the behavioral therapy. Nightmares and night terrors are usually disturbing to family members; therefore, proper diagnosis and education of family members are important components of management. Dreams disorders may respond to medication e.g., fluoxetine for post-traumatic stress disorder, clonazepam for night terrors3 and benzodiazepines for ketamine23 induced dreams but behavioral treatment approaches in the form of reassurance and support have shown excellent results, particularly in patients with post-traumatic stress disorder and recurrent nightmares. This therapy reduces the incidence of nightmares in about 70% of patients. If still the patient is not relieved, changing the suspect agent with a suitable alternative or withdrawal of the drug may help. Inspite of all the above mentioned treatment strategies, still, there is controversy as to what is the best option for the patient and thus research is going on to find the best approach.

Suggested ReadingDreams: The American Heritage Dictionary of the English Language, Fourth Edition 2000. http://www.bartely.com/61/54/D0385400.html. Retrieved on 2009-05-07.Haavisto M. How drugs and herbs affect dreams. Oct. 31, 2008. www.Suite 101.com.Pagel JF. Nightmares and disorders of dreaming. Am Fam Physician 2000;61(7):2037-42.Drugs and dreams. Can Med Assoc J 1970;102(5):524. Foulkes D. Dreaming: a cognitive-psychological analysis. Erlbaum, Hillsdale, NJ 1985.Martin GJ. Drugs and dreams, perspective. Exp Med Surg 1969;27(1-2):1-2.Pagel JF, Helfter P. Drug-induced nightmares: an etiology based review. Hum Psychopharmacol Clin Exp 2003;18(1):59-67.Thompson DF, Pierce DR. Drug-induced nightmares. Ann Pharmacother 1999;33(1):93-8.Brismar K, Motgensen L, Wetterberg L. Depressed melatonin secretion in patients with nightmares due to beta-adrenoceptor blocking drugs. Acta Med Scand 1987;221(2):155-8.Jouvet M. The Paradox of Sleep: The Story of Dreaming. MIT Press: Cambridge 1999.

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Hobson JA, Steriade M. The neuronal basis of behavioral state control: internal regulatory systems of the brain. In: Handbook of Psychology. Bloom F, Mountcastle V, (Eds.), American Physiological Society, Washington 1986:701-823. Gursky J, Krahn LE. The effects of antidepressants on sleep: a review. Harv Rev Psychiatry 2000;8(5): 298-306.Coupland NJ, Bell CJ, Potokar JP. Serotonin reuptake inhibitor withdrawal. J Clin Psychopharmacol 1996;16(5):356-62.Stacy M. Managing late complications of Parkinson’s disease. Med Clin North Am 1999;83(2):469-81.Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30(2):239-45.Pagel JF. Pharmacologic alteration of sleep and dreams: a clinical framework for utilizing the electrop-physiological and sleep stage effects of psychoactive medications. Hum Psychopharmacol Clin Exp 1996;11(3):217-23.Oxorn DC, Ferris LE, Harrington E, Orser BA. The effects of midazolam on propofol-induced anesthesia: propofol dose requirements, mood profiles, and perioperative dreams. Anesth Analg 1997;85(3):553-9.Marsh SC, Schaefer HG, Tschan C, Meier B. Dreaming and anaesthesia: total IV anaesthesia with propofol versus balanced volatile anaesthesia with enflurane. Eur J Anaesthesiol 1992;9(4):331-3.McEvoy GK. Cardiac drugs. In: AHFS Drug Information. American Society of Health Systems Pharmacists, Bethesda 2002:4.Krueger JM, Fang J. Host defence. In: Principles and Practice of Sleep Medicine. Kryger M, Roth T, Dement W, (Eds.), WB Saunders Co: Philadelphia 2003:255-65.Pace-Schott EF. Recent findings on the neurobiology of sleep and dreaming. In: C.U.P. Book Sleep and Dreaming: Scientific Advances and Reconsiderations Based on BBS. Special Issue on Sleep and Dreaming Vol. 23, December 2000.William SW. Book: The Psychology of Dreams. Dodd Mead and Company Inc, NY 1920.Larson M, DO. Clinical Instructor, Department of Child and Adolescent Psychiatry, Harvard University. Updated: 2008.R3 Evers AS, Crowder CM, Balser JR. General anesthetics. In: Goodman and Gilman’s: The Pharmacological Basis of Therapeutics. 11th edition, Brunton LL, Lazo JS, Parker KL, (Eds.), Medical Publishing Division; McGraw Hill: New York 2006:341-68.

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*Professor, Dept. of Ophthalmology**Senior ResidentSri Balaji Medical College and Hospital, Chennai - 600 044

AbstrAct

Mucormycosis is one of the most aggressive fungal infections with very high mortality rate. Mucormycosis, also called ‘zycomycosis’ is a serious and lethal invasive mycoses involving respiratory tract, gastrointestinal tract, skin and spreading to nearby structures like sinuses, orbit and brain. The spores of these fungi are inhaled. In poorly controlled diabetic patients and immunocompromised patients, the spores form hyphae and invade the surrounding tissues and blood vessels, leading to thrombosis and tissue necrosis. The black eschar of the palate is widely described as a hallmark of rhino-orbital mucormycosis. The angioinvasion of the retinal artery results in blindness, cranial nerve involvement, ptosis and later mass lesion resulting in proptosis. Proper management consists of treating the immunocompromised conditions, aggressive surgical debridement and aggressive antifungal therapy. Careful follow-up should continue for at least one year to confirm that there is no evidence of recurrent infection.

Key words: Mucormycosis, apex syndrome, immunocompromised, antifungal treatment

Mucormycosis

SA Kareem*, Valluvan**

Mucormycosis is one of the most aggressive fungal infections with very high mortality rate. The list of immunocompromised

patients is becoming long day-by-day, as they survive longer due to better treatment modalities. The treating doctors should have high degree of suspicion and skill to diagnose and manage these cases or else, in no time, this infection spreads to the brain. These cases may land in any department like Internal Medicine, Eye, ENT and Neurology depending upon the organs involved and extension. We are reporting two cases seen in our department with orbital apex syndrome due to mucormycosis.

Case Reports

First case, a male patient aged 62 years, came with ptosis, diplopia, proptosis and pain left eye for past one week. He was a known diabetic patient for past 12 years, under oral hypoglycemic agents, on irregular treatment and poor glycemic control. On examination, vision right eye, 6/12 with pseudophakia, otherwise NAD, vision left eye no perception of light, ptosis with total ophthalmoplegia, with no corneal sensation and lens mature cataract. Other cranial nerves were normal.

Oral cavity examination showed palatal ulceration, with black eschar, with surrounding hyperemia. Mucormycosis was suspected and urgent CT scan was done. CT showed opacification and destruction of maxillary antrum with extension into the nasal cavity and orbit. ENT and neurosurgical consultations were done and clinical diagnosis of ororhino-orbital mucormycosis was made. The case was admitted and managed by a team of experts from Internal Medicine, ENT, Ophthalmology and Neurology. His diabetes mellitus (DM) was brought under control with insulin and antifungal oral itraconazole 200 mg b.i.d. PO was given. Amphotericin B, the first drug of choice could not be given, because his renal function showed abnormally high values.

Aggressive surgical debridement of the palatal lesion, maxillary antrum and nasal cavity was done by ENT surgeon and histopathological examination showed Rhizomucor. He was under our treatment for 15 days, his proptosis became less and DM was controlled well. As he was showing good improvement, he wanted to go home because of some urgent personal problem and promised to come back after his family problem was over. But he did not come back.

The second case was a female patient aged 65 years who presented with headache, proptosis and ptosis for past five days. She was a known patient of DM for past 12 years, under oral hypoglycemic agents, irregular in treatment and poor control of blood sugar.

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Figure 3. Female patient showing palatal ulceration.

Figure 2. Male patient oral cavity with palatal ulceration.

Figure 4. Female patient with total ophthalmoplegia.

Figure 5. CT scan female patient showing opacification of antrum, nose and orbit.

Figure 1. Male patient with left eye total ophthalmoplegia.

On examination, vision right eye no perception of light, RE ptosis, proptosis, total ophthalmoplegia, mature cataract, with loss of corneal sensation. Other cranial nerves were normal.

Vision left eye 3/60 not improving with glass, with cataract. No fundus view. Oral cavity examination showed palatal ulceration with black eschar. Urgent CT was done and showed similar picture as in the first case involving maxilla, nasal cavity and orbit right side. ENT, Neurology and Internal Medicine consultations were done, clinical diagnosis of orbital apex syndrome made and aggressive treatment was planned by a team of these experts. Case was admitted and treated with insulin and IV amphotericin B and planned for surgical debridement. But this patient did not want to undergo surgery and left the hospital against medical advice.

Discussion

Mucormycosis, also called ‘zycomycosis’ is a serious, aggressive and lethal invasive mycoses involving respiratory tract, gastrointestinal tract, skin and spreading to nearby structures like sinuses, orbit and brain. Mucor is not the most common, rather

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Rhizomucor are the genera usually present in these patients. The spores of these fungi are found in the soil and, usually nonpathogenic. They are inhaled and in normal persons, the spores are prevented to germinate into hyphae by alveolar macrophages. In poorly controlled diabetic patients and immunocompromised patients, the spores form hyphae and invade the surrounding tissues and blood vessels, leading to thrombosis and tissue necrosis. In this devitalized tissue, the hyphae continue to grow and angioinvasion gives rise to black eschar. The black eschar of the palate is widely described as a hallmark of rhinoorbital mucormycosis. The angioinvasion of the retinal artery results in blindness, cranial nerve involvement, ptosis and later mass lesion resulting in proptosis. The infection further progresses into the brain resulting in the formation of brain abscesses. Proper management consists of treating the immunocompromised conditions, aggressive surgical debridement and aggressive antifungal therapy. Careful follow-up should continue for at least one year to confirm that there is no evidence of recurrent infection.

Conclusion

Mucormycosis cases, even though appear to be rare now, are bound to be more common in the future due to various causes like high incidence of diabetes, AIDS,

organ transplantation, radiotherapy and chemotherapy. These cases may come to any specialty depending upon the organs involved. Proper clinical examination and suspicion, especially in immunocompromised patients can save the life of the patients.

Suggested ReadingLiang KP, Tleyjeh IM, Wilson WR, Roberts GD, Temesgen Z. Rhino-orbitocerebral mucormycosis caused by Apophysomyces elegans. J Clin Microbiol 2006;44(3):892-8.O’Neill BM, Alessi AS, George EB, Piro J. Disseminated rhinocerebral mucormycosis: a case report and review of the literature. J Oral Maxillofac Surg 2006;64(2):326-33.Hickner JM, Bartlett JG, Besser RE, Gonzales R, Hoffman JR, Sande MA; AAFP, ACP-ASIM; CDC; IDSA. Principles of appropriate antibiotic use for acute rhinosinusitis in adults: background. Ann Intern Med 2001;134(6):498-505. Piccirillo JF. Clinical practice. Acute bacterial sinusitis. N Engl J Med 2004;351(9):902-10.Rafei K, Lichenstein R. Airway infectious disease emergencies. Pediatr Clin North Am 2006;53(2): 215-42.Schwartz B, Marcy SM, Phillips WR, Gerber MA, Dowell SF. Pharyngitis - principles of judicious use of antimicrobial agents. Pediatrics 1998;101:171-4.

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Holt-Oram syndrome is rare congenital anomaly of the musculoskeletal and the cardiovascular systems. The prevalence of this

syndrome is 1/1,00,000 population. The commonest findings are absent thumb and radius, atrial septal defect.

Holt-Oram syndrome is also known as heart hand syndrome, cardiac limb syndrome, atrio-digital syndrome or ventriculo-radial syndrome. In this syndrome 75% of the cases have cardiovascular problem. The commonest cause of mortality and morbidity is cardiovascular malformation.

Case Summary

An unbooked rural habitat multigravida of 31-32 weeks of gestational period was admitted to the labor room with pain in abdomen and bleeding per vaginum since three days. She was first treated by a private practitioner who referred her to the medical college for further management.

According to her last menstrual period, her gestational age was 32 weeks and seven days. She had no antenatal check-up during this period. She had received two doses of TT injection. She had family history of consanguineous marriages. She was G4P3L3. First three are living, full term normal deliveries. Out of three, two are female and one is male. These children don’t have congenital abnormality.

She had pain in abdomen which was colicky in nature associated with nausea and bleeding per vaginum. Bleeding was moderate, fresh blood, since three days. She also had one bout of unconsciousness.

On examination: She was average built with moderate pallor, tachycardia bilateral pedal edema, BP was 170/110 mmHg. Rest all her vitals are normal. She received tablet nifedipine (10 mg) t.d.s.

P/A - showed uterus of 32 weeks with good relaxation, and a fetus with cephalic presentation. Inspection of the vulva showed moderate bleeding. Per vaginum examination was not done due to excessive bleeding.

USG showed live fetus of 32 weeks, severe oligo-hydramnios, cephalic presentation, placenta lying anteriorly with Grade 2 maturity. FHS 140/min. Mother’s investigation revealed Hb 9 g, TLC - 5,400/mm3, ESR - 20 mm. Blood group Tridot negative. LFT and RFT were normal. Urine showed traces of albumin.

A male baby weighing 1.7 kg was delivered by lower segment cesarean section. Baby cried immediately after birth. His HR - 35/min, RR - 40/min. His color was pink, there was no cyanosis and reflexes were normal. Placenta and cord were normal.

On inspection following abnormalities were found in the baby (Fig. 1):

Absence of thumb on both sidesWidely spaced eyesLow set earsHypoplastic receding mandibleSingle palmar creaseHigh arched palate.

*Professor and Head**Assistant Lecturer Dept. of Pediatrics Padma Shri Dr Vithalrao Vikhe Patil Memorial Hospital and Medical College, Ahmednagar, Maharashtra

AbstrAct

Holt-Oram syndrome is a heart-upper limb malformation complex with an autosomal dominant inheritance and near-complete penetrance but variable expression.

Key words: Holt-Oram syndrome, atrial septal defect, radial hypoplasia

Holt-Oram Syndrome

Sunil Mhaske*, Sandeep Mhaske**

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Figure 1. Inspection of the body revealed findings suggestive of Holt-Oram syndrome.

Figure 2. X-ray of spine showing hemivertebra.

Baby was given to the mother for feeding after two hours. Afterwards opinion of orthopedics, ENT and ophthalmology department was taken. Following investigations were done:

X-ray of both wrist - AP and lateral view showed absent radiusX-ray of spine - hemivertebra (Fig. 2) X-ray of chest - normalUSG abdomen and pelvis - absence of left kidneyUSG cranium - normal

We did the 2D Echo after 4th day, but it did not show any cardiac abnormality.

The patient was discharged and advised follow-up after 15 days, but patient did not comeback.

Discussion

Holt-Oram syndrome was discovered by Mary Holt and Samul Oram in 1960. Clinical features of Holt-Oram syndrome vary depending upon the severity of cardiac and limb malformations.

Musculoskeletal Defects

Upper limbs are usually affected. Although bilateral, the left side is more commonly affected. The most severe form is phocomelia with rudimentary limbs. Mildest forms include clinodactyly, limited supination and sloping shoulders. The most common defects include radial thumb anomalies ranging from absent thumbs to displaced duplicated or triphalangeal thumbs. Hypoplasia of the radius manifests as short deformed forearm. Sprengel deformity (upward displacement of the scapula) and hypoplasia of the shoulders and clavicles may also be present. Associated muscular hypoplasia involves the hypothenar, wrist extensor, supinator, biceps brachii and triceps brachii.

Heart Defects

The reported incidence ranges from 50 to 95%. The most common lesion is a secundum atrial septal defect. Other lesions include ventricular septal defect, atrioventricular block (AV block), pulmonic stenosis and mitral valve prolapse. Approximately 17% of patient have more complex cardiac malformations, such as tetralogy of Fallot, hypoplastic left heart, endocardial cushion defect and truncus arteriosus. Cardiac arrhythmias including paroxysmal tachycardia, prolonged PR interval, wandering atrial pacemaker, atrial ectopics, AV block and sinus bradycardia may be present. According to Mglinets, a specific feature of the syndrome is a changes in the main palmar lines and their termination on the radial border of the hand. Pulmonary hypoplasia has occasionally been reported and can present with neonatal respiratory distress.

Intelligence is Normal

A scoring system to assess severity has been recommended by Gall et al and modified by Gladstone and Sybert as follows.

Scoring system to assess skeletal abnormalities in Holt-Oram syndrome.

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0. No abnormality on physical or radiological examination.

1. Minor abnormalities, including reduced thenar eminence, clinodactyly or hypoplasia of thumb.

2. Present arms and forearms, with one or more bones missing.

3. Phocomelia.

A scoring system to assess cardiac abnormalities in Holt-Oram syndrome.0. Asymptomatic, with no abnormal physical

findings.1. Conduction defect2. Structural heart abnormality that doesn’t require

surgery.3. Structural heart abnormality that requires surgery.4. Potentially lethal malformations.

Pathophysiology

Defective development of the embryonic radial ray (aplasia, hypoplasia, fusion) results in a wide-spectrum of phenotypes, including triphalangeal or absent thumb, foreshortened arms and phocomelia. The syndrome is associated with defective development of cardiac structures that results in atrial septal defect, most commonly, secundum type; heart block of varying degree or both.

The responsible gene has been mapped to band 12q 24.1, which encodes the human transcription factor TBX-5. One of the recently added loci is c.373 G > A, with results in the missense mutation p.Gly125 Arg, a novel mutation. A cardiomelic developmental field has also been postulated to relate the genetic heterogeneity of Holt-Oram syndrome, to a cascade of molecules, including the brachyury, sonic hedgehog homolog, bone morphogenetic protein,

retinoic acid receptor and transforming growth factor beta families.

Suggested ReadingBasson CT, Bachinsky DR, Lin RC, Levi T, Elkin JA, Soults J, et al. Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet 1997;15(1):30-5. Basson CT, Huang T, Lin RC, Bachinsky DR, Weremowicz, S, Vaglio A, et al. Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations. Proc Nat Acad Sci USA 1999;96(6):2919-24.Borozdin W, Bravo-Ferrer Acosta AM, Seemanova E, Leipoldt M, Bamshad MJ, et al. Contiguous hemizygous deletion of TBX5, TBX3, and RBM19 resulting in a combined phenotype of Holt-Oram and ulnar- mammary syndromes. Am J Med Genet A 2006;140A(17):1880-6. Braulke I, Herzog S, Thies U, Zoll B. Holt-Oram syndrome in four half-siblings with unaffected parents: brief clinical report. Clin Genet 1991;39(4):241-4. Davies P. Obituary: S Oram, Brit Med J 1992;304:500. Fryns JP, Bonnet D, De Smet L. Holt-Oram syndrome with associated postaxial and central polydactyly. Further evidence for genetic heterogeneity in the Holt-Oram syndrome. Genet Couns 1996;7(4):323-4. Gruenauer-Kloevekorn C, Froster UG. Holt-Oram syndrome: a new mutation in the TBX5 gene in two unrelated families. Ann Genet 2003;46(1):19-23. Hurst JA, Hall CM, Baraitser M. The Holt-Oram syndrome. J Med Genet 1991;28(6):406-10. Kantaputra PN, Yamasaki K, Ishida T, Kishino T, Niikawa N. A dominantly inherited malformation syndrome with short stature, upper limb anomaly, minor craniofacial anomalies, and absence of TBX5 mutations: report of a Thai family. Am J Med Genet 2002;111(3):301-6.

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clinicAl study

Skin diseases have only recently been considered as a possible health problem in developing countries. Data supporting this issue is

sparse. The available data are mostly on the clinical ground. The general concept in the developing countries about the skin diseases is ‘it is incurable and the patient has to visit the doctor frequently’. And, this is a costly affair in terms of money, time and labor. Drugs used in dermatological practice are costly and are taken for longer duration and/or at frequent intervals. Such kind of concept of general population needs to be taken seriously and trial must be done to ameliorate it. This study has tried to improve the diagnostic accuracy by using different diagnostic modalities in dermatological practice specially ‘skin biopsy’. This study specially presents a report of the experience of a superspecialized dermatological center in New Delhi, India, which has a well-equipped histopathology center.

Material and Methods

This study has been conducted in a superspecialized hospital of skin diseases in Delhi. This study has been conducted from the data of skin biopsy cases done from August 2003 to February 2004 (seven months)

retrospectively. Cases for skin biopsies were received in the laboratory, which were sent by 8-10 different dermatologists working at the center. The cases were mainly from Delhi and NCR, as this hospital has two subcenters in Delhi and NCR. Some cases were also referred from different cities of other states in India. Cases were of all age group and of both sexes.

We received the prescribed form with brief of clinical presentation and 2-4 provisional diagnoses. It is obvious that the cases which were clinically diagnosed accurately by the dermatologists alone and responded well by drug therapy, were not sent for histo-pathological examination (HPE). We in the laboratory, examined the case and investigated according to the need of the patient and as advised by the clinicians. We did hematological, biochemical and serological investigations. We did special tests for skin diseases as Tzanck smear, India ink preparation, KOH preparation, skin smear examination and Wood Lamp examination. We also used dark ground microscopic examination of smears for the diseases pertaining to Spirochete group. We lastly came to skin biopsy for HPE. We did ‘punch biopsy’ using disposable punch blade measuring 0.5 × 0.5 cm size (length and diameter). Punches were made by taking the inflamed skin together with normal one. Tissues were processed and routine hematoxylin and eosin (H&E) staining was done. It was examined by light microscopy. The final HPE report was made by the same histopathologist. The second opinion was taken by a Dermatopathologist working at the center whenever needed. In most of the cases provisional

Assistant ProfessorDept. of Pathology, Govt. Medical College, ChandigarhAddress for correspondenceDr Amar Ranjan Dept. of Pathology1202A/32B, Govt. Medical College, Chandigarh - 160 030E-mail: [email protected]

AbstrAct

Objective: To highlight the importance of histopathology in clinical practice of skin diseases specially in developing countries. Study design: Data of skin biopsy cases collected retrospectively (of previous years). It was analyzed in terms of number and kinds of cases which required skin biopsy for diagnosis and differential diagnosis. Result: Seventy percent of biopsy cases correlated with 2-4 provisional diagnoses given by the clinicians. Rest 30% couldn’t be diagnosed with confirmation, which needed follow-up. It showed mostly cases of psoriasis, lichen planus, leprosy and tuberculosis in decreasing order. Conclusion: Promotion of skin biopsy practices will improve the diagnostic accuracy in dermatology practices.

Key words: Skin diseases, urban population, suburban population, developing countries

Biopsy of Skin Diseases in Urban and Suburban PopulationAmar Ranjan

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diagnoses given by the dermatologists correlated well with the clinical diagnoses. Histopathologist also suggested possible diagnoses to the dermatologists (clinicians) after looking at the histopathological picture wherever it was possible, i.e., there was a good correlation between the pathologist and the clinicians.

All the biopsy specimens were examined by using routine H&E stain. Special stains were done wherever needed. These are Verhoeff-Van Gieson stain and Periodic Acid-Schiff stain for collagen fibers, Zeihl-Neilsen stain for tuberculous and lepra bacilli. Serial sectioning was also done wherever required. Special cases were confirmed by immunofluorescence technique as well.

Results

We performed skin biopsies of total 622 cases. It was noticed that out of 622 cases, in 430 (69.2%) cases, the histopathological report matched well with any one of the provisional diagnoses given by the clinicians. This figure included the diagnoses suggested by the dermatologist to the pathologist or vice versa.

In the rest 192 cases (30.8%), provisional clinical diagnoses couldn’t be correlated with histopathological report. In the cases where the diagnosis couldn’t be made either clinically or histopathologically, was reported as ‘Descriptive’. This study has focused over the diagnosed cases histopathologically as well as clinically. The important skin diseases are shown in Table 1.

Discussion

It has been noted that a large number cases in dermatological practices need confirmation by histopathology. As in this case, clinicians put 2-4 provisional diagnoses. In approximately 70% of cases any one of the provisional diagnoses were confirmed by HPE. The rest 30% cases couldn’t be confirmed. These cases were kept under close follow-up. Reason behind these undiagnosed cases may be the partial treatment of the cases, which may have morphed the lesion. Secondly, the disease may be in early or late stage.

As the tertiary care center received a number of referred cases. So, there is the possibility that they had been already treated by dermatologists in their primary

phase of treatment. Now, we look at the diagnosed cases. Current study (based on biopsy) has been summarized in Table 2.

Similar kind of study was conducted in a Karnataka village area by Kuruvilla1 et al in 1997, which has been shown in Table 3.

In the current study (Table 2), psoriasis and lichen planus top the list where as the Table 3 shows these two as minor problem. This is because the skin diseases have been categorized on the basis of clinical diagnoses mainly. Biopsy was also done in the required cases in this study as well. Our study reflects the cases, which were sent for HPE only. Clinically diagnosed cases or cases diagnosed by minor noninvasive procedures e.g. Tzanck smear; were excluded from our study. Like scabies can be diagnosed on history and clinical ground only. Study from rural area of Assiut Governorate, Upper Egypt (Abdel-Hafez3 et al 2003) gave data (in descending order of prevalence), which have been shown in Table 4.

This data is more or less similar to the findings of Table 3, as eczema and fungal infection top the list. The increased incidence of pigmentary lesions and nevoid diseases may be due to racial and geographical variation in the pattern of skin diseases.

Infectious diseases are directly associated with personal hygiene, socioeconomic status and overcrowding.

Data, form a study conducted at University Teaching Hospital, Addis Ababa, Ethiopia by Shibeshi6 in 2000, has been shown (in descending order of prevalence) in Table 5.

As marked in data, most of the allergic and infectious diseases do not need biopsy and are made on clinical ground as well as by hematological and biochemical investigations e.g., IgE level, C-reactive protein and ESR, etc.

Data from another study conducted in a hospital in southwestern Saudi Arabia (Shelleh2 et al 2000) has been shown (in decending order of prevalence) in the Table 6.

Most of the cases in this study is based on clinical diagnoses considering age, history of contact, etc.

Pattern of skin diseases in Imphal, India, studied by Devi7 2006 has been shown in Table 7. This study is also based on clinical diagnoses.

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A study based on clinical diagnoses on prevalence of skin diseases in a suburban area of Sri Lanka by Perera et al5 showed fungal infection (47.6%) > dermatitis > leprosy > psoriasis.

Study of skin diseases in Bamako (Mali) by Mahé et al4 1998 showed: Infectious dermatitis (41%) > scabies (16.6%) > superficial mycoses (13.6%) > primary pyoderma (5%) > dermatitis (20%) > papular urticaria (4.4%) > acne (4.2%) > pityriasis alba (3.6%) > keratoderma (3.6%) > urticaria (3%).

Diagnoses are based on clinical ground in developing countries like India and skin disease is a major health problem. A general conception is that there is no permanent cure of skin disease. Only selected patients visit the dermatologist. Dermatologists make a diagnosis clinically and try to cure. Blind trial of the drugs results in long-term treatment and treatment costs are high. Even after that a satisfactory result is usually not obtained. General histopathologists have difficulty in diagnosing dermatological diseases. In India, there is

Table 1. The Important Diseases Diagnosed Histopathologically in the StudyName of disease (group) No. of cases Percentage (%)Noninfectious erythematous papular and squamous diseases 190 30.54 Psoriasis 88 14.14

Lichen planus with its variants 76 12.21Bacterial diseases 61 9.80 TB 10 1.61 Leprosy 51 8.91Noninfectious vesiculobullous and vesiculopapular diseases: (It included different types of dermatitis)

37 5.94

Benign pigmented lesions 26 4.18Vesicular diseases 17 2.73Metabolic diseases 13 2.09Inflammatory diseases of epidermal appendages and of cartilages 14 2.25Tumors and cysts of epidermis 17 2.73Congenital diseases 10 1.61Connective tissue diseases 12 1.92Tumors of fatty, muscular and osseous tissue 5 0.80Cutaneous toxicities of drugs 4 0.64Photosensitivity diseases 4 0.64Treponemal diseases 3 0.48Diseases caused by virus 3 0.48Tumors of epidermal appendages 3 0.48Noninfectious granulomas 2 0.32Histiocytoses 2 0.32Tumors of fibrous tissue involving skin 2 0.32Vascular tumors 2 0.32Degenerative and perforating diseases 1 0.16Cutaneous manifestations of nutritional deficiency 1 0.16Fungal diseases 1 0.16Parasitic infection of skin 1 0.16

Pigmentary diseases 1 0.16Cutaneous lymphoma and leukemia 1 0.16Tumors of neural tissue 1 0.16

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no separate specialization for dermatopathology. Whereas in developed countries there is super-specialized branch of dermatopathology.

As per author’s search on internet for articles on skin diseases based on skin biopsy, no literature is available. This kind of study may provide some hidden findings in the field of dermatology.

If, we move on to better diagnostic techniques like skin biopsy, the number of diagnosed cases will

improve and finally cure rates will increase. This study shows approximately 31% of diagnostic failure even after practice of skin biopsy. So, it can be assumed that what will be the percentage of diagnostic failure for the dermatologists who don’t use skin biopsy for diagnosis. The commonly used skin biopsy technique is ‘punch biopsy’, which is an outdoor procedure and doesn’t need any kind of anesthesia. This can be easily be performed by dermatologists himself. However, it is not practiced much in our country.

SummaryLichen planus and psoriasis are an important health problem in India. They both need skin biopsy for correct diagnosis.

Table 5. Data for Study Conducted by Shibeshi, Addis Ababa, EthiopiaName of disease (group) Percentage (%)Allergic diseases 25.5

Infectious diseases 25.4

Photodermatoses 22.9

Papulosquamous diseases (including psoriasis and lichen planus)

11.4

Table 6. Data for Study Conducted by Shelleh et al in Southwestern Saudi ArabiaName of disease (group) Percentage (%)Dermatitis/Eczema 37

Acne 12.75

Vitiligo 7

Viral infection 5.9

Superficial mycoses 5.6

Bacterial infection 5

Psoriasis 1.51

Lichen planus 1.1

Table 7. Data for Study Conducted by Perera et al in Sri LankaName of disease (group) Percentage (%)Eczema/Dermatitis 17.48

Fungal infection 17.19

Pyoderma 9.1

Scabies 8.97

STD 3.6

Genodermatoses 0.01

Table 2. Summary of the Data-based on BiopsyName of disease (group) No. of cases Percentage (%)Psoriasis 88 14.14

Lichen planus with its variants

76 12.21

Leprosy 51 8.91

TB 10 1.61

Dermatitis 37 6.0

Pigmentary lesions 26 4.2

Vascular diseases 17 2.7

Metabolic diseases 13 2.1

Table 3. Data for Study Conducted by Kuruvilla et al in KarnatakaInfectious diseases (42.6%)

Noninfectious diseases (41.5%)

Fungal diseases (24.1%)Pyoderma (7.2%)Scabies (9.5%)Viral infection (1.5%)Leprosy (0.41%)

Eczema (34%)Psoriasis (1.4%)

Lichen planus (1.5%)Collagenous vascular

diseases (0.4%)Pigmentary lesions (4.1%)

Cancer (0.27%)

Table 4. Data for Study Conducted by Abdel-Hafez et al in Assiut Governorate, Upper EgyptName of disease (group) Percentage (%)Dermatitis/Eczema 19.8

Pigmentary lesion 17.68

Fungal infection 16.17

Nevoid disease 16

Hair and scalp disease 12.1

Bacterial diseases 10

Leprosy 1.6/10,000 population

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To promote dermatopathological practices by dermatolosists as well as by histopathologists.To provide knowledge of dermatopathology to postgraduate students at institutional level.In the condition of unavailability of dermato-pathologist, dermatologists must keep in mind the pattern of skin diseases in our country.Pattern of skin diseases are different in India in comparison to other countries as shown by the articles published in journals.A close correlation between pathologist and dermatologist can give better results.

Suggested ReadingKuruvilla M, Sridhar KS, Kumar P, Rao GS. Pattern of skin diseases in Bantwal Taluq, Dakshina Kannada. Indian J Dermatol Venereol Leprol 2000;66:247-8.Shelleh HH, Al-Hatiti HS. Pattern of skin diseases in a hospital in southwestern Saudi Arabia. Saudi Med J 2004;25(4):507-10.Abdel-Hafez K, Abdel-Aty MA, Governorate, Hofny ER. Prevalence of skin diseases in rural areas of Assiut Governorate, Upper Egypt. Int J Dermatol 2003;42(11):887-92.

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Mahé A, Cissè IA, Faye O, N’Diyae HT, Niamba P. Skin diseases in Bamako (Mali). Int J Dermatol 1998;37(9):673-6.

Perera A, Atukorale DN, Sivayogan S, Ariyaratne VS, Karunaratne LA. Prevalence of skin diseases in suburban Sri Lanka. Ceylon Med J 2000;45(3):123-8.

Shibeshi D. Pattern of skin diseases at the University teaching hospital, Addis Ababa, Ethiopia. Int J Dermatol 2000;39(11)822-5.

Devi TB, Zamzachin G. Pattern of skin diseases in Imphal. Indian J Dermatol 2006;51(2):149-50.

Ogunbiyi AO, Daramola OO, Alese OO. Prevalence of skin diseases in Ibadan, Nigeria. Int J Dermatol 2004;43(1):31-6.

Rao GS, Kumar SS, Sandhya. Pattern of skin diseases in an Indian village. Indian J Med Sci 2003;57(3):108-10.

Tomb RR, Nassar JS. Profile of skin diseases observed in a dept. of dermatology (1995-2000). J Med Liban 2000;48(5)302-9.

Haugstvedt A, Larsen TE, Haheim LL. Biopsy in non-neoplastic skin diseases. Tidsskr Nor Laegeforen 1998;118(7):1038-40.

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AAP Reports on Use of Probiotics and Prebiotics in Children

Source: Adapted from Am Fam Physician. 2011;83(7):849-852.

In recent years there has been increased interest in adding probiotics and prebiotics to nutritional products to optimize intestinal microflora. However,

as with antibiotics, the use of these supplements should be supported by evidence-based medicine. The American Academy of Pediatrics (AAP) recently reviewed the medical uses of probiotics and prebiotics to help guide physicians in counseling parents about the use of these products as dietary supplements added to foods for children, including infant formula.

Infants have sterile gastrointestinal tracts at birth, but bacterial colonization occurs rapidly. Gestational age, mode of delivery, and diet seem to have significant effects on this process. Dysregulation of the intestinal mucosal defense system early in life is believed to be a factor in many chronic conditions, such as atopic diseases (e.g., asthma, eczema, allergic rhinitis) and autoimmune diseases (e.g., multiple sclerosis, type 1 diabetes mellitus, chronic inflammatory bowel disease). Because of their influence on intestinal microflora colonization and immune function, an infant’s early diet and intestinal microbial environment are thought to be pivotal factors in his or her overall health.

Probiotics

Probiotics are supplements containing organisms that change the microflora of the host. These organisms are typically Lactobacillus, Bifidobacterium, and Streptococcus species. They are able to predominate and prevail over potential pathogenic microorganisms in the human digestive tract, and are thought to produce metabolic byproducts that function as immune modulators.

As of December 2010, at least two infant formulas that contained probiotics were being sold in the United States. One contained Bifidobacterium lactis, and the other contained Lactobacillus rhamnosus GG (LGG). The addition of probiotics to powdered infant formula

has not been proven harmful to healthy term infants. However, there is no evidence of clinical effectiveness, and the routine use of these formulas is not recommended. No studies have compared the health benefits of using these formulas versus breastfeeding.

Probiotics should not be given to children who are seriously or chronically ill until the safety of these products has been established. The optimal duration of probiotic supplementation is not known, nor is the optimal dosage or species. The long-term effects on intestinal microflora in children also are not known.

Acute Infectious Diarrhea

The use of probiotics early in the course of diarrhea from acute viral gastroenteritis may reduce its duration by one day in otherwise healthy infants and young children. This benefit is strain-dependent; LGG is the most effective probiotic reported. However, the evidence does not support the routine use of probiotics to prevent infectious diarrhea unless there are special circumstances (e.g., in child care centers). The use of the new pentavalent rotavirus vaccine will likely be more effective than the use of probiotics in preventing the most common form of acute infectious diarrhea in infants.

Antibiotic-associated Diarrhea

There is some evidence to support the use of probiotics to prevent antibiotic-associated diarrhea, but there is no evidence that it is effective for treatment. LGG, B. lactis, Streptococcus thermophilus, and Saccharomyces boulardii were the most common probiotics used in randomized controlled trials (RCTs). There have been no RCTs examining the effects of probiotic use in children with Clostridium difficile antibiotic-associated diarrhea.

Atopic Diseases

The intestinal bacterial flora of children with atopic disease has been proven to have more Clostridium and

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fewer Bifidobacterium organisms than that of children without atopic disease. For this reason, it has been hypothesized that the administration of probiotics to infants at risk of atopic disease—particularly those who are formula fed—would be beneficial. There is some evidence supporting the prophylactic maternal use of probiotics during pregnancy and the continuation of therapy in the mother and infant during lactation, but further studies are needed. Probiotic use has not been proven effective in the treatment of eczema.

Necrotizing Enterocolitis

Preterm infants often have delayed and aberrant acquisition of normal digestive microflora, possibly because of restricted enteral feedings and frequent administration of antibiotics. These factors are thought to contribute to an increased risk of necrotizing enterocolitis in preterm infants. There is some evidence to support the use of probiotics in very low-birth-weight infants (birth weight of 1,000 to 1,500 g [2 lb, 4 oz to 3 lb, 5 oz]). However, the amount and specific type of probiotic are difficult to determine.

Chronic Inflammatory Bowel Disease

It is estimated that up to 70 percent of children and adults with chronic inflammatory bowel disease (i.e., Crohn disease or chronic ulcerative colitis) routinely use complementary and alternative medicine, including probiotics, as adjunctive or replacement therapy for prescribed medications. Theoretically, probiotics may be beneficial in the treatment of these conditions. However, the long-term benefit of using probiotics to treat Crohn disease requires further study and is not recommended in children. The results of RCTs in which probiotics were used to treat chronic ulcerative colitis are encouraging, but require further confirmation.

Other Conditions

The sustained or long-term benefit of using probiotics to treat disorders such as irritable bowel syndrome, constipation, and extraintestinal infections requires further study; currently, use is not recommended in children. There is some evidence that probiotics may be beneficial in treating children with Helicobacter pylori gastritis and infantile colic; however, further study is needed before recom-mendations can be made. Probiotics have not been proven beneficial in treating or preventing cancer. There are safety concerns with the use of probiotics in infants and children who are immunocompromised, chronically debilitated, or seriously ill and who have indwelling medical devices.

Prebiotics

Prebiotics are supplements containing a nondigestible ingredient—usually in the form of oligosaccharides—that selectively stimulates the favorable growth or activity of indigenous probiotic bacteria. Although prebiotics are indigestible, their presence in the digestive tract enhances the proliferation of probiotic bacteria in the colon, especially Bifidobacterium species.

Human milk contains substantial quantities of prebiotics and is preferred for infants up to six months of age. The addition of oligosaccharides as prebiotics to infant formula is not unreasonable, but lacks evidence showing clinical effectiveness. It is not known whether their use is cost-effective.

The use of prebiotics in preventing or treating diseases in children has not been tested extensively in RCTs, but the available evidence shows that there may be some long-term benefit for the prevention of atopic eczema and common infections in healthy infants. However, confirmatory studies, especially in children who are given formula that is not partially hydrolyzed, are needed before recommendations can be made.

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From the Journals ...

Valsartan may Decrease the Incidence of Diabetes Mellitus

Background: Several trials have reported that inhibiting the renin-angiotensin system (i.e., with angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs]) may prevent patients with hypertension or other cardiovascular disease from developing diabetes mellitus. However, this effect was not a primary outcome of most trials, and results were not confirmed by systematic glucose measurements. McMurray and colleagues used the NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) trial to study the effectiveness of ACE inhibitors and ARBs at reducing the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance.

The Study: Investigators randomized 9,306 patients to receive valsartan in dosages of 80-160 mg daily or placebo. All patients participated in a lifestyle intervention program designed to reduce the risk of diabetes. In addition to having impaired glucose tolerance, all eligible participants had preexisting cardiovascular disease or at least one risk factor for cardiovascular disease. Exclusion criteria included the use of antidiabetic medications within the previous five years, or the use of an ACE inhibitor or ARB for hypertension.

Three coprimary outcomes were evaluated: the incidence of diabetes; a composite cardiovascular outcome including development of heart failure, nonfatal myocardial infarction or stroke, unstable angina, arterial revascularization, or cardiovascular-associated death; and a similar composite cardiovascular outcome that excluded unstable angina and the need for revascularization.

Results: Diabetes was less likely to develop in the valsartan group than in the placebo group (33.1 versus 36.8 percent, respectively; hazard ratio = 0.86). Fasting and two-hour postload glucose levels were also lower in the valsartan group (−0.59 mg per dL [0.03 mmol

per L] versus −3.15 mg/dL [0.17 mmol per L] in the placebo group). However, cardiovascular outcomes remained similar between the groups (14.5 versus 14.8 percent for placebo).

Conclusion: The authors conclude that valsartan therapy (in a dosage up to 160 mg daily) reduces the likelihood that patients with impaired glucose tolerance will develop diabetes (relative risk reduction = 14 percent). This translates into roughly 26 patients needing to be treated for five years to prevent one new case of diabetes. However, valsartan does not reduce the risk of cardiovascular events.

Am Fam Physician. 2011;83(3):311.

Probiotics vs Antibiotics to Treat Lactation-associated Mastitis

Background: Mastitis affects up to 33 percent of lactating mothers and is a common reason why women stop breastfeeding. It can also be difficult to treat because of its polymicrobial nature. Several strains of lactobacilli have shown promise as probiotic agents that might be useful in treating mastitis. Arroyo and colleagues compared the effectiveness of probiotic and antibiotic therapies in women with lactation-associated mastitis.

The Study: A total of 352 women with mastitis symptoms were randomized to receive one of three treatments: a daily capsule with 200 mg of a freeze-dried probiotic containing 9 log10 colony-forming units (CFUs) per mL of Lactobacillus fermentum (CECT5716), a similar amount of Lactobacillus salivarius (CECT5713), or an antibiotic prescribed by their physician. Patients were followed for 21 days, with pain scores and breast milk samples obtained at the beginning and end of the study. All patients had breast inflammation, painful breastfeeding, and initial milk bacterial counts of more than 4 log10 CFU per mL. Women with mammary abscesses, Raynaud syndrome, or any other breast-related pathology were excluded.

Results: Initial pain scores and bacterial counts were similar among the three groups. The three most

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common bacterial species identified were Staphylococcus epidermidis, Staphylococcus aureus, and Streptococcus mitis in statistically similar proportions among groups. By day 21, a greater bacterial reduction occurred in women receiving probiotics compared with antibiotics, with the greatest reduction in the L. salivarius group. Breast pain scores were also significantly lower in the probiotic groups, with complete recovery in 88 percent of the L. fermentum and 85 percent of the L. salivarius group by day 21, compared with 28.7 percent of the antibiotic group. Recurrence of mastitis was also significantly more common in the antibiotic group than in the L. fermentum or L. salivarius group (30.7, 10.5, and 7.1 percent, respectively).Conclusion: The authors conclude that L. fermentum or L. salivarius is an effective alternative to antibiotics for the treatment of infectious mastitis during lactation.

Am Fam Physician. 2011;83(3):311-316.

Early vs Delayed Treatment of Anterior Cruciate Ligament TearsBackground: An anterior cruciate ligament (ACL) tear is associated with joint instability, decreased activity, and an increased risk of developing osteoarthritis of the knee. Although treatment usually involves early surgical reconstruction combined with physical therapy, it is unclear whether this improves clinical outcomes. Frobell and colleagues performed a randomized controlled trial to determine if rehabilitation with early ACL reconstructive surgery was more effective than rehabilitation with delayed ACL reconstructive surgery.

The Study: The authors recruited 121 healthy persons 18 to 35 years of age presenting with a new ACL injury to participate in the Knee Anterior Cruciate Ligament, Non-surgical versus Surgical Treatment Study. All participants received physical rehabilitation, but were randomized to receive early ACL reconstructive surgery within 10 weeks postinjury, or to be monitored for up to two years with the option for ACL repair surgery if they remained symptomatic. Persons with total collateral ligament rupture and full-thickness knee cartilage lesions were excluded. The primary outcome was the change from baseline to two years in the average Knee Injury and Osteoarthritis Outcome Score regarding pain, symptoms, difficulty in sports and recreational activities, and quality of life.

Results: Of the 59 participants in the delayed reconstruction group, 23 ultimately received ACL reconstructive surgery an average of 11.6 months after randomization. Both groups showed similar clinical improvement, with no significant differences in the score between groups during the two-year period. No differences were noted between groups regarding knee-related outcomes or the return to preinjury activity levels.

Conclusion: The authors conclude that for acute ACL tears in young, active adults, structured rehabilitation with optional delayed reconstructive surgery results in similar clinical outcomes compared with an early ACL repair strategy. In this study, surgery was avoided in 61 percent of the delayed reconstruction group, without adversely affecting outcomes.

Am Fam Physician. 2011;83(7):842-844.

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From the eMedinewS

Biomarker Predicts Colon Cancer Survival in Obese Patients

A protein biomarker may predict better chances of survival for obese patients with colorectal cancer, but the biomarker held no prognostic value for nonobese patients, researchers found (April 27 issue of the Journal of the American Medical Association). Patients with a body mass index of 30 kg/m2 or more were 76% less likely to die from colorectal cancer when positive for cadherin-associated protein beta-1 (CTNNB1 or beta-catenin, p < 0.001 for interaction) in analysis of nearly 1,000 prospectively-followed patients.

Antifibrotic may Slow Diabetic Nephropathy

Diabetic nephropathy may not just slow but may actually improve with the novel antifibrotic agent pirfenidone, researchers found in a preliminary study. Kidney function continued to drop in diabetic kidney disease patients without treatment, but rose significantly with a low-dose of pirfenidone over one year, Kumar Sharma, MD, of the University of California San Diego and VA Medical Center in La Jolla, Calif., and colleagues reported online in the Journal of the American Society of Nephrology.

Some Benefit Seen for Ovary Removal at Hysterectomy

Removing the ovaries at the same time as the uterus made a small risk of subsequent ovarian cancer even smaller without significantly increasing other risks, results of a large observational study showed.

Breaking News: Person Revived after 96 Minutes of CPR

A 54-year-old man with post-MI ventricular fibrillation regained spontaneous circulation after a dozen defibrillator shocks and continuous CPR for 96 minutes with full physical and neurological recovery reports Dr Roger D White at the Mayo Clinic in Rochester, Minn in a case report published online April 20 in the Mayo Clinic Proceedings.

The patient was resuscitated for initial 31 minutes by the emergency staff along with DC shocks. At the 31st minute a helicopter transport crew arrived and continued applying defibrillator shocks to the man who did not have a pulse, yet showed signs of systemic blood flow as measured by an end-tidal carbon dioxide sensor. The team administered a total of 12 defibrillator shocks and kept the patient’s blood flowing with continuous chest compressions.

A key piece of technology on the scene was capnography, which measures how much blood is flowing through the lungs and subsequently to other organs. Capnography has been used to monitor patients in operating rooms but is not often used by ER when treating cardiac arrest. As the measurement remained sufficiently high, the rescuers were encouraged to continue resuscitation efforts.

At the hospital, he was stabilized and taken to the cath lab and was stented for 100% occlusion in the mid-left anterior descending coronary artery. The persistent low blood pressure was stabilized with an intra-aortic balloon pump (IABP). The patient was discharged after 10 days with no neuro damage.

Lessons LearnedIt’s the only case where a person has been revived after 96 minutes of clinical death.We had a similar case where CPR was continued for 45 minutes.GB Pant reports a similar case with revival after an hour and with stenting (Dr Vijay Trehan)Medicolegal implications: Do not stop resuscitation for upto 100 minutes and make sure you measure E tube CO2 levelsTransport the patient to nearest cardiac hospital for possible angiography and IABP, if required.

Too much Television may Increase Future Cardiovascular Risk for Children

Young children who spend too much time watching TV or playing computer games have narrower eye

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arteries than kids who are more physically active, according to a study published online in Arteriosclerosis, Thrombosis and Vascular Biology: Journal of the American Heart Association.

Young Indian Adults Developing more Risk Factors for Heart Disease

Increasingly, young adults residing in urban areas of India are developing hypertension, obesity and diabetes, which suggests that the country may soon experience an increase in heart disease rates, according to a study published in the Journal of the American College of Cardiology.

Higher Death Rates Seen in Kidney Failure Patients through Central Line Catheter

Ass per the American Society of Nephrology wrote, Patients on peritoneal dialysis (PD) typically have a higher early survival rate than patients on hemodialysis (HD). New data suggest that this difference may be explained by a higher risk of early deaths among patients undergoing HD with central venous catheters, according to a study appearing in an upcoming issue of the Journal of the American Society of Nephrology.

Access Type may Impact Hemodialysis Patient Survival

Central venous catheters may account for the poorer survival among HD patients, according to an analysis, which included 40,526 adults, in the Journal of the American Society of Nephrology. Use of a central port for dialysis was associated with 80% elevated one-year mortality risk compared with PD, the researchers found.

An Inspirational Story

Reach for Your Star

Do not take anything as being forever, because forever is only as long as today. Know that the people who are the richest are not those who have the most, but those who need the least. That we are at our strongest when life is at it’s worst, and at our weakest when life no longer offers a challenge. That it is wiser not to expect, but to hope, for in expecting you ask for disappointment, whereas in hoping you invite surprise. That unhappiness doesn’t

come from not having something you want, but from the lack of something inside that you need. That there are things to hold and things to let go, and letting go doesn’t mean you lose, but that you acquire that which has been waiting around the corner.

Most of all ...... remember to use your dreams as a way of knowing yourself better, and as an inspiration to reach for Your Star!

—Dr Prachi Garg

WHO Warns of Enormous Burden of Chronic Disease

Chronic illnesses like cancer, heart disease and diabetes have reached global epidemic proportions and now cause more deaths than all other diseases combined, the World Health Organization (WHO) said on Wednesday. In its first worldwide report on so–called noncommunicable diseases, or NCDs, the United Nations health body said the conditions caused more than half of all deaths in 2008 and pose a greater threat than infectious diseases such as malaria, HIV and tuberculosis (TB) - even in many poorer countries. NCDs, which include heart disease, lung diseases, cancer and diabetes, accounted for 36 million or 63%, of the 57 million deaths worldwide in 2008. Millions of lives could be saved and much suffering avoided if people did more to avoid risk factors like smoking, drinking and being overweight, the WHO said.

First Autologous Organ

The race is on to build the first complex organ. Describing what it will take to achieve this momentous milestone was Doris Taylor, PhD, Director of the Center for Cardiovascular Repair, Medtronic Bakken Professor of Integrative Biology and Physiology, and Professor of Medicine at the University of Minnesota, during Monday’s State-of-the-Art Address, ‘Rebuilding Autologous Organs: Cells, Scaffold, Organ.’ Rebuilding an organ involves collecting appropriate types and numbers of cells, selecting the right scaffold, decellularizing the scaffold and seeding the scaffold with the cells.

When this concept works, the end result is an organ that performs its appropriate function (American Transplant Congress, 2100).

682

emedinews section


Pediatric Update

What is the Classical Presentation of Appendicitis in a Child?

Pain begins in periumbilical or epigastric region, due to appendiceal distension and referred pain.

Pain localizes to the RLO as the parietal peritoneum in the area becomes irritated.

Anorexia and nausea occur almost uniformly after the pain.

The classical presentation occurs in only 50% of patients.

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

Neglect, Under Treatment Ails Headache Disorders

Three in every four adults, aged between 18 and 65, suffered from some form of headache disorder, including migraine and tension-type headaches, last year. WHO says headaches are the most common health disorders across the world, but they are often neglected and under-treated. According to the world’s first ‘Atlas of Headache Disorders 2011’ brought out by the WHO, 50% suffering from headaches opt for self-medication, oblivious to bouts of pain.

Neurologists examine only 10% headache patients, and the rate is even lower in Africa and South-East Asia. The report says, over 10% of those suffering frequent headaches have migraine, and 1.7-4% of the adult population is affected by headache for 15 or more days every month. Information on the societal impact of headache exists in only 18% of countries that responded for the report. Three types of headache disorders have been underlined as most frequent - migraine, tension-type and those caused by medication-overuse.

—Source: TOI, May 5, 2011

Health - Important TipsDo not drink coffee TWICE a day.Do not take pills with COOL water.Do not have HUGE meals after 5 pm.Reduce the amount of OILY food you consume.Drink more WATER in the morning, less at night.Keep your distance from hand phone CHARGERS.Do not use headphones/earphone for LONG period of time.Best sleeping time is from 10 pm at night to 6 am in the morning.Do not lie down immediately after taking medicine before sleeping.When battery is down to the LAST grid/bar, do not answer the phone as the radiation is 1,000 times.

—Dr Monica and Brahm Vasudev)

General - Fit Facts and Tips for Specific Populations

Regular physical activity reduces the risk of many adverse health outcomes.

Some physical activity is better than none.

For most health outcomes, additional benefits occur as the amount of physical activity increases through higher intensity, greater frequency and/or longer duration.

Most health benefits occur with at least 150 minutes (2 hours and 30 minutes) a week of moderate-intensity physical activity, such as brisk walking. Additional benefits occur with more physical activity.

Both aerobic (endurance) and muscle-strengthening (resistance) physical activity are beneficial.

Health benefits occur for children and adolescents, young and middle-aged adults, older adults and those in every studied racial and ethnic group.

The health benefits of physical activity occur for people with disabilities.

The benefits of physical activity far outweigh the possibility of adverse outcomes.


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

Covering letter

– The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper.

– Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors.

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

Manuscript– Three complete sets of the manuscript should be

submitted and preferably with a CD; typed double spaced throughout (including references, tables and legends to figures).

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

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

Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors.

Title pageShould contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the

departments and institutions where the work was performed, name of the corresponding authors, acknowledgment of financial support and abbreviations used.– The title should be of no more than 80 characters and

should represent the major theme of the manuscript. A subtitle can be added if necessary.

– A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included.

– The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page.

– A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text.

Summary– The summary of not more than 200 words. It must

convey the essential features of the paper.– It should not contain abbreviations, footnotes or

references.

Introduction– The introduction should state why the study was carried

out and what were its specific aims/objectives.

Methods– These should be described in sufficient detail to permit

evaluation and duplication of the work by others.– Ethical guidelines followed by the investigations should

be described.

StatisticsThe following information should be given:– The statistical universe i.e., the population from which

the sample for the study is selected.– Method of selecting the sample (cases, subjects, etc.

from the statistical universe).– Method of allocating the subjects into different

groups.– Statistical methods used for presentation and analysis of

data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques.

– Confidence intervals for the measurements should be provided wherever appropriate.

Results– These should be concise and include only the tables

and figures necessary to enhance the understanding of the text.

Information for Authors

Indian Journal of

CliniCalPraCtiCe


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.

ReferencesThese 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:

ArticlesPaintal 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.

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

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

Tables– These should be typed double spaced on separate

sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.

Legends– These should be typed double spaces on a separate

sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text.

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

Figures– Two complete sets of glossy prints of high quality

should be submitted. The labelling must be clear and neat.

– All photomicrographs should indicate the magnification of the print.

– Special features should be indicated by arrows or letters which contrast with the background.

– The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen.

– Color illustrations will be accepted if they make a contribution to the understanding of the article.

– Do not use clips/staples on photographs and artwork.

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

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

summary, etc.)_______________________________2. Total number of pages ________________________3. Number of tables ____________________________4. Number of figures ___________________________5. Special requests _____________________________6. Suggestions for reviewers (name and postal address) Indian 1. ___________Foreign 1. _______________ 2. ___________ 2. _______________ 3. ___________ 3. _______________ 4. ___________ 4. _______________7. All authors’ signatures________________________8. Corresponding author’s name, current postal and

e-mail address and telephone and fax numbers __________________________________________

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PPIs may Cause Bone Fractures When Used for More Than One-year or at Higher Doses: FDA

High 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.

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.

Dr KK AggarwalPadma Shri and Dr BC Roy Awardee

Sr Physician and Cardiologist, Moolchand MedcityPresident, Heart Care Foundation of India

Group Editor-in-Chief, IJCP GroupChief Editor, eMedinewS

Member, Delhi Medical CouncilDirector, IMA AKN Sinha Institute (08-09)

Hony. Finance Secretary, IMA (07-08)Chairman, IMA AMS (06-07)

President, Delhi Medical Association (05-06)[email protected]

E D I T O R I A L

MAKE SUREDURING MEDICAL PRACTICE

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Minor Changes in Lifestyle are All That is Required for Good Health

Middle-aged women who move around more in their daily life have lower levels of intra-abdominal fat,

a risk factor for heart disease. Minor modifications in daily routine such as reducing the time watching TV or increasing the walk time to work, can make a difference in the long-term health.

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.

I N S I D E

A terminally ill patient who develops bed sores, is given only systemic antibiotics.

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

KK Aggarwal

Please changethe position of the patient

frequently and keep the skinclean and dry.

Evidence-based 3Medicine

Preparing for Commonwealth 9Games Illnesses

News & Views 10

Expert’s Opinion 11

FDA Update 13

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