Showing papers in "Indian Journal of Medical Research in 2011"

Rationalizing antibiotic use to limit antibiotic resistance in India.

Abstract: Antibiotic resistance, a global concern, is particularly pressing in developing nations, including India, where the burden of infectious disease is high and healthcare spending is low. The Global Antibiotic Resistance Partnership (GARP) was established to develop actionable policy recommendations specifically relevant to low- and middle-income countries where suboptimal access to antibiotics - not a major concern in high-income countries - is possibly as severe a problem as is the spread of resistant organisms. This report summarizes the situation as it is known regarding antibiotic use and growing resistance in India and recommends short and long term actions. Recommendations aim at (i) reducing the need for antibiotics; (ii) lowering resistance-enhancing drug pressure through improved antibiotic targeting, and (iii) eliminating antibiotic use for growth promotion in agriculture. The highest priority needs to be given to (i) national surveillance of antibiotic resistance and antibiotic use - better information to underpin decisions on standard treatment guidelines, education and other actions, as well as to monitor changes over time; (ii) increasing the use of diagnostic tests, which necessitates behavioural changes and improvements in microbiology laboratory capacity; (iii) setting up and/or strengthening infection control committees in hospitals; and (iv) restricting the use of antibiotics for non-therapeutic uses in agriculture. These interventions should help to reduce the spread of antibiotic resistance, improve public health directly, benefit the populace and reduce pressure on the healthcare system. Finally, increasing the types and coverage of childhood vaccines offered by the government would reduce the disease burden enormously and spare antibiotics.

Hand hygiene: back to the basics of infection control.

Abstract: Health care associated infections are drawing increasing attention from patients, insurers, governments and regulatory bodies. This is not only because of the magnitude of the problem in terms of the associated morbidity, mortality and cost of treatment, but also due to the growing recognition that most of these are preventable. The medical community is witnessing in tandem unprecedented advancements in the understanding of pathophysiology of infectious diseases and the global spread of multi-drug resistant infections in health care set-ups. These factors, compounded by the paucity of availability of new antimicrobials have necessitated a re-look into the role of basic practices of infection prevention in modern day health care. There is now undisputed evidence that strict adherence to hand hygiene reduces the risk of cross-transmission of infections. With "Clean Care is Safer Care" as a prime agenda of the global initiative of WHO on patient safety programmes, it is time for developing countries to formulate the much-needed policies for implementation of basic infection prevention practices in health care set-ups. This review focuses on one of the simplest, low cost but least accepted from infection prevention: hand hygiene.

Assessing the adhesion of putative indigenous probiotic lactobacilli to human colonic epithelial cells.

Abstract: Background & objectives: Adherence of bacteria to epithelial cells and mucosal surfaces is a key criterion for selection of probiotic. We assessed the adhesion property of selected indigenous probiotic Lactobacillus strains based on their hydrophobicity and ability to adhere to human epithelial cells. Methods: Five human faecal Lactobacillus isolates, one from buffalo milk and one from cheese were assessed for hydrophobicity following the microbial adhesion to hydrocarbons (MATH) method and colonization potentials based on their adherence to Caco2 and HT-29 colonic adenocarcinomal human intestinal epithelial cell lines. Lactobacillus strains that adhered to Caco2 and HT-29 cell lines were quantified by plating after trypsinization and simultaneously the adhered bacteria were also examined microscopically after staining with Geimsa stain and counted in different fields. Results: Among the tested faecal isolates, L. plantarum Lp91 showed maximum percentage hydrophobicity (35.73±0.40 for n-hexadecane and 34.26±0.63 for toluene) closely followed by L. plantarum Lp9 (35.53±0.29 for n-hexadecane and 33.00±0.57 for toluene). Based on direct adhesion to epithelial cells, L. plantarum Lp91 was the most adhesive strain to HT-29 and Caco2 cell lines with per cent adhesion values of 12.8 ± 1.56 and 10.2 ± 1.09, respectively. L. delbrukeii CH4, was the least adhesive with corresponding figures of 2.5 ± 0.37 and 2.6 ± 0.20 per cent on HT-29 and Caco2 cell lines. Adhesion of the six isolated Lactobacillus strain to HT-29 cell and Caco2 lines as recorded under microscope varied between 131.0 ± 13.9 (Lp75) to 342.7 ± 50.52 (Lp91) and 44.7 ± 9.29 (CH4) to 315.7± 35.4 (Lp91), respectively. Interpretation & conclusions: Two Indigenous probiotic Lactobacillus strains (Lp9, Lp91) demonstrated their ability to adhere to epithelial cell and exhibited strong hydrophobicity under in vitro conditions, and thus could have better prospects to colonize the gut with extended transit

Haemoglobinopathies in Southeast Asia

Abstract: In Southeast Asia α-thalassaemia, β-thalassaemia, haemoglobin (Hb) E and Hb Constant Spring (CS) are prevalent. The abnormal genes in different combinations lead to over 60 different thalassaemia syndromes, making Southeast Asia the locality with the most complex thalassaemia genotypes. The four major thalassaemic diseases are Hb Bart's hydrops fetalis (homozygous α-thalassaemia 1), homozygous β-thalassaemia, β-thalassaemia/Hb E and Hb H diseases. α-Thalassaemia, most often, occurs from gene deletions whereas point mutations and small deletions or insertions in the β-globin gene sequence are the major molecular defects responsible for most β-thalassaemias. Clinical manifestations of α-thalassaemia range from asymptomatic cases with normal findings to the totally lethal Hb Bart's hydrops fetalis syndrome. Homozygosity of β-thalassaemia results in a severe thalassaemic disease while the patients with compound heterozygosity, β-thalassaemia/Hb E, present variable severity of anaemia, and some can be as severe as homozygous β-thalassaemia. Concomitant inheritance of α-thalassaemia and increased production of Hb F are responsible for mild clinical phenotypes in some patients. However, there are still some unknown factors that can modulate disease severity in both α- and β-thalassaemias. Therefore, it is possible to set a strategy for prevention and control of thalassaemia, which includes population screening for heterozygotes, genetic counselling and foetal diagnosis with selective abortion of affected pregnancies.

Vancomycin resistance among methicillin resistant Staphylococcus aureus isolates from intensive care units of tertiary care hospitals in Hyderabad

Abstract: Background & objectives: Multidrug resistant methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of nosocomial and community acquired infections and is on the rise. The glycopeptide vancomycin has been proposed as the drug of choice for treating such infections. The present study aimed at identifying the vancomycin resistance both phenotypically and genotypically among the MRSA isolates from two tertiary care hospitals in Hyderabad, south India. Methods: MRSA were isolated and identified from different clinical samples collected from ICUs of tertiary care hospitals in Hyderabad using conventional methods. Antibiogram of the isolates and vancomycin MIC were determined following CLSI guidelines. vanA was amplified by PCR using standard primers. Results: All vancomycin resistant S. aureus (VRSA) isolates were MRSA. The VRSA isolates were positive for vanA gene, except one which was negative. All VRSA had a vancomycin MIC in the range of 16-64 mg/l. Interpretation & conclusions: The increase in vancomycin resistance among MRSA and excessive use of antimicrobial agents have worsened the sensitivity. Larger studies need to be done in various geographical regions of the country to better define the epidemiology, mechanism of vancomycin resistance in S. aureus and its clinical implications.

Cholera toxin — A foe & a friend

Abstract: After De΄s pivotal demonstration in 1959 of a diarrhoeogenic exo-enterotoxin in cell-free culture filtrates from Vibrio cholerae (of classical biotype), much insight has been gained about cholera toxin (CT), which is arguably now the best known of all microbial toxins. The subunit structure and function of CT, its receptor (the GM1 ganglioside), and its effects on the cyclic AMP system and on intestinal secretion were defined in the 1970s, and the essential aspects of the genetic organization in the 1980s. Recent findings have generated additional perspectives. The 3D-crystal structure of CT has been established, the CT-encoding operon has been shown to be carried by a non-lytic bacteriophage, and in depth knowledge has been gained on how the bacterium controls CT gene expression in response to cell density and various environmental signals. The mode of entry into target cells and the intracellular transport of CT are becoming clearer. CT has become the prototype enterotoxin and a widely used tool for elucidating important aspects of cell biology and physiology, e.g., cell membrane receptors, the cyclic AMP system, G proteins, as well as normal and pathological ion transport mechanisms. In immunology, CT has emerged as a potent, widely used experimental adjuvant, and the strong oral-mucosal immunogenicity of the non-toxic B-subunit (CTB) has led to the use of CTB as a protective antigen together with killed vibrios in a widely licensed oral cholera vaccine. CTB has also been shown to promote immunological tolerance against certain types of mucosally co-administered antigens, preferably tissue antigens linked to the CTB molecule; this has stimulated research and development to use CTB in this context for treatment of autoimmune and allergic diseases. In summary, in the 50 years after De΄s discovery of CT, this molecule has emerged from being the cholera patient΄s "foe" to also becoming a highly useful scientist΄s "friend".

Involvement of nitric oxide in learning & memory processes

Abstract: Nitric oxide (NO), synthesized from the amino acid, L-arginine by nitric oxide synthase (NOS) has received attention as a neurotransmitter in the brain. NO has been found to induce cognitive behaviour in experimental animals. In order to show evidence for the involvement of NO in learning and memory processes, the reports indicating the effects of its precursor, donors, and inhibitors of its synthesis in mammals, birds, fishes and invertebrates have been reviewed. Further, learning and memory impairment occurring in man and animals due to defective NO activity in the brain due to pathological conditions such as epilepsy, stress, diabetes and side effects of therapeutic agents and reversal of this condition by L-arginine and NO donors have been included. In addition, the reports that indicate ageing-induced impairment of cognition that is known to occur in Alzheimer's disease due to deposition of the toxic protein, beta amyloid and the effect of L-arginine and NO donors in preventing dementia in these patients have been reviewed.

The need for obtaining accurate nationwide estimates of diabetes prevalence in India - Rationale for a national study on diabetes

Abstract: According to the World Diabetes Atlas, India is projected to have around 51 million people with diabetes. However, these data are based on small sporadic studies done in some parts of the country. Even a few multi-centre studies that have been done, have several limitations. Also, marked heterogeneity between States limits the generalizability of results. Other studies done at various time periods also lack uniform methodology, do not take into consideration ethnic differences and have inadequate coverage. Thus, till date there has been no national study on the prevalence of diabetes which are truly representative of India as a whole. Moreover, the data on diabetes complications is even more scarce. Therefore, there is an urgent need for a large well-planned national study, which could provide reliable nationwide data, not only on prevalence of diabetes, but also on pre-diabetes, and the complications of diabetes in India. A study of this nature will have enormous public health impact and help policy makers to take action against diabetes in India.

Screening donated blood for transfusion-transmissible infections, recommendations

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ICMR-DBT Guidelines for Evaluation of Probiotics in Food

Abstract: There has been an increased influx of probiotic products in the Indian market during the last decade. However, there has been no systematic approach for evaluation of probiotics in food to ensure their safety and efficacy. An initiative was, therefore, taken by the Indian Council of Medical Research (ICMR) along with the Department of Biotechnology (DBT) to formulate guidelines for regulation of probiotic products in the country. These guidelines define a set of parameters required for a product/strain to be termed as 'probiotic'. These include identification of the strain, in vitro screening for probiotic characteristics, animal studies to establish safety and in vivo animal and human studies to establish efficacy. The guidelines also include requirements for labeling of the probiotic products with strain specification, viable numbers at the end of shelf life, storage conditions, etc., which would be helpful to the consumers to safeguard their own interest.

Diagnosis & treatment of tuberculosis in HIV co-infected patients

Abstract: Human immunodeficiency virus (HIV) associated tuberculosis (TB) remains a major global public health challenge, with an estimated 1.4 million patients worldwide. Co-infection with HIV leads to challenges in both the diagnosis and treatment of tuberculosis. Further, there has been an increase in rates of drug resistant tuberculosis, including multi-drug (MDR-TB) and extensively drug resistant TB (XDRTB), which are difficult to treat and contribute to increased mortality. Because of the poor performance of sputum smear microscopy in HIV-infected patients, newer diagnostic tests are urgently required that are not only sensitive and specific but easy to use in remote and resource-constrained settings. The treatment of co-infected patients requires antituberculosis and antiretroviral drugs to be administered concomitantly; challenges include pill burden and patient compliance, drug interactions, overlapping toxic effects, and immune reconstitution inflammatory syndrome. Also important questions about the duration and schedule of anti-TB drug regimens and timing of antiretroviral therapy remain unanswered. From a programmatic point of view, screening of all HIV-infected persons for TB and vice-versa requires good co-ordination and communication between the TB and AIDS control programmes. Linkage of co-infected patients to antiretroviral treatment centres is critical if early mortality is to be prevented. We present here an overview of existing diagnostic strategies, new tests in the pipeline and recommendations for treatment of patients with HIV-TB dual infection.

Visceral leishmaniasis: Experimental models for drug discovery

Abstract: Visceral leishmaniasis (VL) or kala-azar is a chronic protozoan infection in humans associated with significant global morbidity and mortality. The causative agent is a haemoflagellate protozoan Leishmania donovani, an obligate intracellular parasite that resides and multiplies within macrophages of the reticulo-endothelial system. Most of the existing anti-leishmanial drugs have serious side effects that limit their clinical application. As an alternate strategy, vaccination is also under experimental and clinical trials. The in vitro evaluation designed to facilitate rapid testing of a large number of drugs has been focussed on the promastigotes milt little attention on the clinically relevant parasite stage, amastigotes. Screening designed to closely reflect the situation in vivo is currently time consuming, laborious, and expensive, since it requires intracellular amastigotes and animal model. The ability to select transgenic Leishmania expressing reporter proteins, such as the green fluorescent proteins (GFP) or the luciferase opened up new possibilities for the development of drug screening models. Many experimental animal models like rodents, dogs and monkeys have been developed, each with specific features, but none accurately reproduces what happens in humans. Available in vitro and in vivo methodologies for antileishmanial drug screening and their respective advantages and disadvantages are reviewed.

Larvicidal activity of medicinal plant extracts against Anopheles subpictus & Culex tritaeniorhynchus

Abstract: Mosquitoes are the major vector for the transmission of malaria, dengue fever, yellow fever, filariasis, schistosomiasis and Japanese encephalitis (JE)1. In India, malaria is one of the most important causes of direct or indirect infant, child and adult mortality with approximately two to three million new cases arising every year. Anopheles subpictus Grassi is distributed throughout India, Afghanistan, Borneo, China, Malaysia, Philippines, Sri Lanka, Java and Indonesia. It is a dominant species in Haryana and Uttaranchal states2. Though it is a non-vector species, same infected specimens with malarial parasite have been reported from India, Indonesia and Java3. An. culicifacies is the main vector of malaria, and An. subpictus is a significant secondary vector in Sri Lanka4. An. subpictus is recognized as the secondary vector of malaria in South East Asia, with a large number of cases being reported from India. 2,400 million (about 40%) of the world's population5,6. India contributes 77 per cent of the total malaria in Southeast Asia7. Cx. tritaeniorhynchus is a primary vector of Japanese encephalitis (JE) virus, with a distribution throughout Southeast Asia and South Asia. Keiser et al8 have reported that global annual incidence and mortality estimates for JE are 30,000 to 50,000 and 10,000 respectively. Annona squamosa, commonly known as custard apple is a native of West Indies and is cultivated throughout India, mainly for its edible fruit. Das et al9 reported that the ethanol leaf extract of A. squamosa was found to have the most promising larvicidal activity against Cx. quinquefasciatus larvae. The larvicidal and mosquitocidal activities of ethanolic water mixture extract of A. squamosa and Centella asiaticai were effective against larvae of An. stephensi10. The leaves methanolic extract and the seeds petroleum ether extract of A. squamosa showed larvicidal activity when tested against An. stephensi, Cx. quinquefasciatus and Aedes aegypti11. Chrysanthemum indicum is a traditional herb used to treat various disorders, hypertension symptoms and several infectious diseases in Korean and Chinese medicine12. Beninger et al13 reported that the leaves of C. morifolium extracted sequentially with hexane, ethyl acetate, and methanol were found to reduce the growth of Trichoplusia ni larvae. Tridax procumbens is commonly used in Indian traditional medicine as anticoagulant, antifungal and insect repellent, in bronchial catarrh, diarrhoea and dysentery14. The entire plant is used for the treatment of malaria, leishmaniasis, vaginitis, dysentery and gastrointestinal disorders15. Though larvicides play a vital role in controlling mosquitoes in their breeding sites, these also show a negative impact in areas of beneficial and non-target organisms. In view of an increasing interest in developing plant origin insecticides as an alternative to chemical insecticide, this study was undertaken to assess the larvicidal potential of the extracts from the medicinal plants against two medically important species of malaria vector, An. subpictus and JE vector, Cx. tritaeniorhynchus.

Age at initiation & prevalence of tobacco use among school children in Noida, India: a cross-sectional questionnaire based survey.

Abstract: Background & objectives : Tobacco use among school children is becoming a serious problem in developing countries. The early age of initiation underscores the urgent need to intervene and protect this vulnerable group from falling prey to this addiction. The present study was thus undertaken to assess the prevalence of tobacco habits among school children, determine the age of initiation of these habits, and compare the age of initiation between students who were more than 15 and ≤ 15 yr of age. Methods: Data on tobacco use were collected from 4786 students of class 7 to 12 (age: 11-19 yr) studying in different private and government schools of Noida city during July- December 2005, through cluster and random sampling using a self-administered questionnaire. Results: Any kind of tobacco use was found in 537 (11.2%) students; 419 (8.8%) were 'ever smokers (including current smokers)' 219 (4.6%) were 'ever tobacco chewers (including current chewers)', 179 (3.7%) were 'exclusive smokers' and 118 (2.5%) were 'exclusive tobacco chewers'. The mean age of initiation of these habits was around 12.4 yr. More than 50 per cent of tobacco chewers reported use of khaini at least once. Nearly 70 per cent of boys and 80 per cent of girls ≤ 15 yr initiated the habit of tobacco before the age of 11 yr. A significant early uptake of tobacco chewing was reported from private school students as compared to government school students (P Interpretation & conclusions : Tobacco addiction is emerging as a big threat among children. Our findings indicate a recent downward shift in the age at initiation of tobacco uptake and rising prevalence among girls. Such data need to be collected from different parts of the country to develop anti-tobacco campaigns and take policy decision.

Sickle cell disease in Middle East Arab countries

Abstract: The sickle cell (HbS) gene occurs at a variable frequency in the Middle Eastern Arab countries, with characteristic distribution patterns and representing an overall picture of blood genetic disorders in the region. The origin of the gene has been debated, but studies using β-globin gene haplotypes have ascertained that there were multiple origins for HbS. In some regions the HbS gene is common and exhibits polymorphism, while the reverse is true in others. A common causative factor for the high prevalence and maintenance of HbS and thalassaemia genes is malaria endemicity. The HbS gene also co-exists with other haemoglobin variants and thalassaemia genes and the resulting clinical state is referred to as sickle cell disease (SCD). In the Middle Eastern Arab countries, the clinical picture of SCD expresses two distinct forms, the benign and the severe forms, which are related to two distinct β-globin gene haplotypes. These are referred to as the Saudi-Indian and the Benin haplotypes, respectively. In a majority of the Middle Eastern Arab countries the HbS is linked to the Saudi-Indian haplotype, while in others it is linked to the Benin haplotype. This review outlines the frequency, distribution, clinical feature, management and prevention as well as gene interactions of the HbS genes with other haemoglobin disorders in the Middle Eastern Arab countries.

HIV & immune reconstitution inflammatory syndrome (IRIS)

Abstract: Antiretroviral therapy (ART) initiation in HIV-infected patients leads to recovery of CD4+T cell numbers and restoration of protective immune responses against a wide variety of pathogens, resulting in reduction in the frequency of opportunistic infections and prolonged survival. However, in a subset of patients, dysregulated immune response after initiation of ART leads to the phenomenon of immune reconstitution inflammatory syndrome (IRIS). The hallmark of the syndrome is paradoxical worsening of an existing infection or disease process or appearance of a new infection/disease process soon after initiation of therapy. The overall incidence of IRIS is unknown, but is dependent on the population studied and the burden of underlying opportunistic infections. The immunopathogenesis of the syndrome is unclear and appears to be result of unbalanced reconstitution of effector and regulatory T-cells, leading to exuberant inflammatory response in patients receiving ART. Biomarkers, including interferon-γ (INF-γ), tumour necrosis factor-α (TNF-α), C-reactive protein (CRP) and inter leukin (IL)-2, 6 and 7, are subject of intense investigation at present. The commonest forms of IRIS are associated with mycobacterial infections, fungi and herpes viruses. Majority of patients with IRIS have a self-limiting disease course. ART is usually continued and treatment for the associated condition optimized. The overall mortality associated with IRIS is low; however, patients with central nervous system involvement with raised intracranial pressures in cryptococcal and tubercular meningitis, and respiratory failure due to acute respiratory distress syndrome (ARDS) have poor prognosis and require aggressive management including corticosteroids. Paradigm shifts in management of HIV with earlier initiation of ART is expected to decrease the burden of IRIS in developed countries; however, with enhanced rollout of ART in recent years and the enormous burden of opportunistic infections in developing countries like India, IRIS is likely to remain an area of major concern.

Evaluating PCR, culture & histopathology in the diagnosis of female genital tuberculosis.

Abstract: Background & objectives: Genital tuberculosis (GTB) is one of the major causes for severe tubal disease leading to infertility. Unlike pulmonary tuberculosis, the clinical diagnosis of GTB is difficult because in majority of cases the disease is either asymptomatic or has varied clinical presentation. Routine laboratory values are of little value in the diagnosis. An absolute diagnosis cannot be made from characteristic features in hysterosalpingogram (HSG) or laparoscopy. Due to the paucibacillary nature of GTB, diagnosis by mycobacterial culture and histopathological examination (HPE) have limitations and low detection rate. The objective of this study was to evaluate the efficacy of PCR technique, culture and histopathological examination in the diagnosis of GTB in female infertility.

Hb E/beta-thalassaemia: a common & clinically diverse disorder.

Abstract: Haemoglobin E-beta thalassaemia (Hb E/β-thalassaemia) is the genotype responsible for approximately one-half of all severe beta-thalassaemia worldwide. The disorder is characterized by marked clinical variability, ranging from a mild and asymptomatic anaemia to a life-threatening disorder requiring transfusions from infancy. The phenotypic variability of Hb E/β-thalassaemia and the paucity of long-term clinical data, present challenges in providing definitive recommendations for the optimal management of patients. Genetic factors influencing the severity of this disorder include the type of beta-thalassaemia mutation, the co-inheritance of alpha-thalassaemia, and polymorphisms associated with increased production of foetal haemoglobin. Other factors, including a variable increase in serum erythropoietin in response to anaemia, previous or ongoing infection with malaria, previous splenectomy and other environmental influences, may be involved. The remarkable variation, and the instability, of the clinical phenotype of Hb E beta-thalassaemia suggests that careful tailoring of treatment is required for each patient, and that therapeutic approaches should be re-assessed over-time.

Cholera toxin: A paradigm of a multifunctional protein

Abstract: Cholera toxin (CT) was discovered exactly half a century ago by S.N. De. We have come a long way since this epoch-making discovery. Retrospectively, science had to wait a long time since Koch's prediction of the existence of a toxin, and its actual discovery by De. CT is not just another enterotoxin that causes the signs and symptoms of the dreaded disease, cholera. It is unique in many respects, starting from its structure to its functions. CT is a multifunctional protein that is capable of influencing the immune system in many ways. It not only has remarkable adjuvant properties, but also acts as an anti-inflammatory agent, by modulating specific signal transduction pathways. Its immunomodulatory properties can be harnessed for treatment of various autoimmune disorders, and have shown great promise in the area of immunotherapeutics. CT can truly be considered as a paradigm of a multifunctional protein.

Validation of bedside methods in evaluation of diabetic peripheral neuropathy.

Abstract: Results: The prevalence of peripheral neuropathy was 34.9 per cent with VPT. Foot care practices were followed by only 214 (20.5%) of the study population. When compared with VPT, ankle reflex was the most sensitive (90.7%) but least specific (37.3%). The tuning fork and monofilament tests respectively had lower sensitivity (62.5 and 62.8%) but better specificity (95.3 and 92.9%) and accuracy (78.9 and 77.9%). Significant correlations were observed between the VPT score and the DNE (r = 0.532, P<0.001) and DNS (r = 0.546, P<0.001) scores and absent tuning fork sensation (r= 0.590; P<0.001), monofilament sensation (r= 0.573; P<0.001) and ankle reflex (r = 0.377, P= 0.01). Interpretation & conclusions: The present findings show that simple bed side tests are useful for assessing peripheral diabetic neuropathy, even in those subjects in whom foot care practices are not followed.

An understanding of the genetic basis of asthma.

Abstract: Asthma is the most common chronic childhood disease in developed nations and its prevalence has increased in the world over the last 25 years. It is a complex disease with both genetic and environmental risk factors. Asthma is caused by multiple interacting genes, some having a protective effect and others contributing to the disease pathogenesis, with each gene having its own tendency to be influenced by the environment. This article reviews the current state of the genetics of asthma in six categories, viz. epidemiology, management, aetiology, family and twin studies, segregation and linkage studies, and candidate genes and single nucleotide polymorphisms (SNPs).

Outcome of standardized treatment for patients with MDR-TB from Tamil Nadu, India

Abstract: Background & objectives : Programmatic management of MDR-TB using a standardized treatment regimen (STR) is being implemented under the Revised National Tuberculosis Control Programme (RNTCP) in India. This study was undertaken to analyse the outcomes of MDR-TB patients treated at the Tuberculosis Research Centre, Chennai, with the RNTCP recommended 24 months STR, under programmatic conditions. Methods : Patients failed to the category II re-treatment regimen and confirmed to have MDR-TB, were treated with the RNTCP's STR in a prospective field trial on a predominantly ambulatory basis. Thirty eight patients were enrolled to the trial from June 2006 to September 2007. Results : Time to culture conversion was two months or less for 82 per cent of patients. Culture conversion rates at 3 and 6 months were 84 and 87 per cent respectively. At the end of treatment, 25 (66%) were cured, 5 defaulted, 3 died and 5 failed. At 24 months, 30 (79%) patients, including 5 defaulters, remained culture negative for more than 18 months. Twenty two (58%) patients reported adverse drug reactions (ADRs) which required dose reduction or termination of the offending drug. No patient had XDR-TB initially, but 2 failure cases emerged as XDR-TB during treatment. Interpretation & conclusions: Outcomes of this small group of MDR-TB patients treated with the RNTCP's STR is encouraging in this setting. Close attention needs to be paid to ensure adherence, and to the timely recognition and treatment of ADRs.

Recent developments in treatment of latent tuberculosis infection

Abstract: Latent tuberculosis infection (LTBI) can be detected with immune based tests such as the tuberculin skin test (TST) or interferon gamma release assays (IGRA). Therapy for those with positive tests can reduce the subsequent risk of re-activation and development of active TB. Current standard therapy is isoniazid (INH) which reduce the risk of active TB by as much as 90 per cent if taken daily for 9 months. However, this lengthy duration of therapy discourages patients, and the risk of serious adverse events such as hepatotoxicity, discourages both patients and providers. As a result completion of INH therapy is less than 50 per cent in many programmes. However, programmes that offer close follow up with supportive staff who emphasize patient education, have reported much better results. The problems with INH have stimulated development and evaluation of several shorter regimens. One alternative was two months daily rifampin and pyrazinamide; this regimen has been largely abandoned due to unacceptably high rates of hepatotoxicity and poor tolerability. The combination of INH and rifampin, taken for 3 or 4 months, has efficacy equivalent to 6 months INH albeit with somewhat increased hepatotoxicity. Four months rifampin has efficacy at least equivalent to 6 months INH but there are inadequate trial data on efficacy. The safety of this regimen has been demonstrated repeatedly. Most recently, a regimen of 3 months INH rifapentine taken once weekly under direct observation has been evaluated in a large scale trial. Results have not yet been published, but if this regimen is as effective as INH, this may be a very good alternative. However, close monitoring and surveillance is strongly suggested for the first few years after its introduction. Evidence from several randomized trials has shown that the benefits of LTBI therapy is only in individuals who are tuberculin skin test (TST) positive even among those with HIV infection. Hence, LTBI therapy should be given only to those with positive tests for LTBI. We conclude that LTBI therapy is considerably underutilized in many settings, particularly in low and middle income countries.

Prevalence & correlates of primary infertility among young women in Mysore, India.

Abstract: Background & objectives : There are sparse data on the prevalence of primary infertility in India and almost none from Southern India. This study describes the correlates and prevalence of primary infertility among young women in Mysore, India. Methods: The baseline data were collected between November 2005 through March 2006, among 897 sexually active women, aged 15-30 yr, for a study investigating the relationship of bacterial vaginosis and acquisition of herpes simplex virus type-2 (HSV-2) infection. A secondary data analysis of the baseline data was undertaken. Primary infertility was defined as having been married for longer than two years, not using contraception and without a child. Logistic regression was used to examine factors associated with primary infertility. Results: The mean age of the women was 25.9 yr (range: 16-30 yr) and the prevalence of primary infertility was 12.6 per cent [95% Confidence Interval (CI): 10.5-15.0%]. The main factor associated with primary infertility was HSV-2 seropositivity (adjusted odds ratio: 3.41; CI: 1.86, 6.26). Interpretation & conclusions : The estimated prevalence of primary infertility among women in the study was within the range reported by the WHO and similar to other estimates from India. Further research is needed to examine the role of HSV-2 in primary infertility.

Association of hypertension with risk factors & hypertension related behaviour among the aboriginal Nicobarese tribe living in Car Nicobar Island, India

Abstract: Background & objectives : There are no composite estimates on prevalence of hypertension among indigenous tribes in India. The present study was carried out to estimate the prevalence of hypertension, its association with determinants, and to assess the hypertension related behaviour of the Nicobarese aborigines. Methods: This cross-sectional survey was carried during 2007 and 2009. Subjects were chosen by two stage design. Total 975 subjects of 1270 (response rate of 76.8%) were investigated (M: 43.5%; F: 56.5%). The data were collected by history, clinical examination (blood pressure), and examination (weight and height). The association of hypertension with age, education, tobacco, alcohol consumption and their dependency status (KF score, QF value, and AUDIT score) and nutritional status was estimated by bivariate regression analysis; the increasing trend in the prevalence of hypertension with increasing age and decreasing educational status was analysed by χ2 for linear trend. Significant variables in bivariate regression analysis (age, education, alcohol consumption status, and nutritional status) were subjected to multiple logistic regression analysis (MLR). Results: The prevalence of hypertension was 50.5 per cent [95% CI 46.1-54.9 (M: 50.7%; F: 50.3%)]. The prevalence of tobacco, alcohol consumption, and overweight/obesity was 88, 54, and 37 per cent respectively. The bivariate analysis has shown association between hypertension and age, education subcategories, alcohol consumption, and overweight/obesity (P Interpretation & conclusions: The findings of the present study highlight high prevalence of hypertension among Nicobarese aborigenes.

From cholera to enterotoxigenic Escherichia coli (ETEC) vaccine development

Abstract: It was shown earlier that immune responses against cholera toxin (CT) as well as Vibrio cholerae lipopolysaccharide (LPS) or whole bacterial cells (WC) were protective and that these different antibody specificities co-operated synergistically for protection against experimental cholera. Similarly, antibodies against the heat-labile toxin (LT) and major colonization factors (CFs) of enterotoxingenic Escherichia coli (ETEC) co-operated synergistically for protection against LT-producing ETEC expressing homologous CFs. Studies in humans revealed that repeated oral antigen administration was optimal in inducing intestinal immune responses. Based on these findings oral inactivated vaccines consisting of toxin antigen and whole cells, i.e. the licensed recombinant cholera B subunit (rCTB)-WC cholera vaccine Dukoral®, and candidate ETEC vaccines have been developed. In different trials the rCTB-WC cholera vaccine has provided very high (85-100%) short term protection, which was significantly higher than that induced by the WC component alone, whereas rCTB-WC and WC alone provided comparable (50-60%), long term protection. An oral ETEC vaccine consisting of rCTB and formalin-inactivated E. coli bacteria expressing major CFs was shown to be safe and immunogenic in adults and children in different countries. The vaccine also induced significant protection against non-mild ETEC diarrhoea, i.e. diarrhoea interfering with daily activity in American travellers but not against ETEC diarrhoea in young children in Egypt. Against this background, a modified ETEC vaccine consisting of recombinant E. coli strains overexpressing the major CFs and a more LT like hybrid toxoid (LCTBA) has been developed. This vaccine will be tested soon alone and together with a mucosal adjuvant, i.e. dmLT, in clinical trials.

Pathophysiological insights in sickle cell disease

Abstract: The first coherent pathophysiological scheme for sickle cell disease (SCD) emerged in the sixties-seventies based on an extremely detailed description of the molecular mechanism by which HbS in its deoxy-form polymerises and forms long fibres within the red blood cell that deform it and make it fragile This scheme explains the haemolytic anaemia, and the mechanistic aspects of the vaso-occlusive crises (VOCs), but, even though it constitutes the basic mechanism of the disease, it does not account for the processes that actually trigger VOCs This paper reviews recent data which imply: red blood cell dehydration, its abnormal adhesion properties to the endothelium, the participation of inflammatory phenomenon and of a global activation of all the cells present in the vessel, and finally, abnormalities of the vascular tone and of nitric oxide metabolism These data altogether have shed a new light on the pathophysiology of the first molecular disease ie sickle cell disease

Distribution pattern of HCV genotypes & its association with viral load

Abstract: Background & objectives: Hepatitis C virus (HCV) has emerged as a leading cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. Genotyping and assessment of the viral load in HCV patients is important for designing the therapeutic strategies. Thus the present study was designed to determine the distribution pattern of HCV genotypes in chronic hepatitis patients and their association with the viral load and biochemical profiles. Methods: Seventy one HCV RNA positive patients were included in the study. HCV genotyping was carried out by restriction fragment length polymorphism (RFLP) followed by the direct sequencing of the core region. Viral load estimation was carried out by Taqman real time PCR system. Results: Sixty three per cent (45/71) of cases were infected with genotype 3 followed by genotype 1 in 30.98 per cent (22/71) and genotype 2 in 5.63 per cent (4/71) of cases. Genotype 1 was associated with a significantly (P Interpretation & conclusions: The present study revealed that HCV genotype 3 and 1 accounted for approximately 95 per cent of the HCV infection in Delhi and surrounding areas. Also two atypical subtypes like 3i and 3f were identified. Genotype 1 was associated with more severity of liver disease as compared to genotypes 3 and 2 as assessed by viral load.

Effect of efflux pump inhibitors on drug susceptibility of ofloxacin resistant Mycobacterium tuberculosis isolates.

Abstract: Mycobacterium tuberculosis, the aetiological agent of tuberculosis (TB), has re-emerged as a killer pathogen in western countries after the increase of HIV-AIDS cases and development of resistance to various anti-tubercular drugs. This increase in the number of multi-drug resistant M. tuberculosis isolates has drawn the attention towards the identification of alternate drugs like fluoroquinolones (FQs) for the treatment of TB. It is known that M. tuberculosis commonly acquires drug resistant phenotype by accumulation of mutations in the structural genes encoding the drug target or the enzymes involved in drug activation. Other known cause of drug resistance in mycobacteria is efflux of drug molecules1. The principal cellular target of the FQs is the DNA gyrase encoded by gyrA and gyrB genes. Mutation in the quinolone resistance determining region (QRDR) of gyrA was the most common cause of FQ resistance in various organisms2,3. However, studies carried out in India have reported that only 11.74 and 45 per cent5 of ofloxacin resistant M. tuberculosis isolates harbour mutations in their gyrA gene and no mutation was found in gyrB gene. As mutations in DNA gyrase alone do not account for the mechanism(s) of resistance in a significant proportion of FQs resistant M. tuberculosis isolates, it suggests the need to investigate the role of alternate mechanisms, like efflux pumps. The upregulation of efflux systems can significantly decrease the intracellular concentration of many antibiotics, reducing their clinical efficacy. For this reason attention has been focused on identifying inhibitors of the efflux systems of Gram-negative and Gram-positive bacteria that could potentially be used in combination with antibiotics to improve efficacy and abolish resistance1. Banerjee and co-workers6 observed that carbonyl cyanide m chlorophenyl hydrazone (CCCP), verapamil and 2,4-dinitro phenol (DNP) increased the accumulation of drug possibly due to inhibition of active efflux. Several mycobacterial efflux pumps associated with FQs resistance have been described. These efflux pumps include the pumps of Major Facilitator Superfamily (MFS) family (lfrA, Rv1634 and Rv1258c) and ATP Binding Cassette (ABC) transporters (DrrAB, PstB and Rv2686c-2687c-2688c)1. For better understanding of drug resistance and to find out the newer drugs and/or identify suitable drug targets for better treatment of TB, there is a need to understand the exact mechanism(s) of resistance to FQs in M. tuberculosis. In the present study we have studied the effect of certain efflux inhibitors on in vitro susceptibility levels in ofloxacin (OFL)-resistant clinical M. tuberculosis isolates.