Influence of 24-Week Yoga Intervention on Cardiovascular Risk Factors and Inflammatory Markers in Type 2 Diabetes.

Background and Aims: Persistent hyperglycemia, dyslipidemia, inflammation, and oxidative stress are important in cardiovascular risk in type-2 diabetes mellitus (DM). To evaluate the effect of 24-week yoga intervention on anthropometry and biochemical markers in DM patients, we performed a study. Methods: A hospital-based prospective randomized study in 104 participants with DM divided into control (n = 52) and intervention (n = 52) groups was performed. Patients in the intervention group performed 40 min of multifaceted individualized yoga exercises 5 days/week for 24 weeks. Anthropometric measurements and biochemical analysis were performed at baseline and after 24 weeks in both groups. Descriptive statistics are reported. Results: Baseline characteristics were similar in both groups. At 24 weeks, participants in the intervention versus controls had lower body mass index (25.6 ± 2.9 vs. 28.0 ± 3.2 kg/m2), waist-hip ratio (0.94 ± 0.06 vs. 0.99 ± 0.05), systolic blood pressure (121.2 ± 11.7 vs. 139.3 ± 19.1 mmHg), fasting glucose (142.7 ± 45.3 vs. 175.7 ± 45.4 mg/dL), glycated hemoglobin (7.2 ± 1.8 vs. 9.4 ± 1.9%), low-density lipoprotein cholesterol (167.5 ± 38.1 vs. 192.2 ± 51.4 mg/dL), nonhigh-density lipoprotein cholesterol (136.8 ± 35.3 vs. 158.6 ± 47.2 mg/dL), interleukin-6 (32.0 ± 21.5 vs. 43.5 ± 34.3 pg/mL), and high-sensitivity C-reactive protein (5.1 ± 3.7 vs. 9.5 ± 15.6 mg/L) (P ≤ 0.05). In the intervention group, higher levels of high-density lipoprotein cholesterol (49.2 ± 15.0 vs. 40.4 ± 7.2 mg/dL) and serum total antioxidants (1.9 ± 0.4 vs. 1.4 ± 0.4 mmol/L) were observed (P < 0.001). Conclusion: A short-term yoga intervention led to reduced glycemia, dyslipidemia, and inflammatory markers and increased antioxidant status in patients with type-2 DM.

Educational status and COVID-19 related outcomes in India: hospital-based cross-sectional study.

OBJECTIVE: Association of educational status, as marker of socioeconomic status, with COVID-19 outcomes has not been well studied. We performed a hospital-based cross-sectional study to determine its association with outcomes. METHODS: Successive patients of COVID-19 presenting at government hospital were recruited. Demographic and clinical details were obtained at admission, and in-hospital outcomes were assessed. Cohort was classified according to self-reported educational status into group 1: illiterate or ≤primary; group 2: higher secondary; and group 3: some college. To compare intergroup outcomes, we performed logistic regression. RESULTS: 4645 patients (men 3386, women 1259) with confirmed COVID-19 were recruited. Mean age was 46±18 years, most lived in large households and 30.5% had low educational status. Smoking or tobacco use was in 29.5%, comorbidities in 28.6% and low oxygen concentration (SpO2 <95%) at admission in 30%. Average length of hospital stay was 6.8±3.7 days, supplemental oxygen was provided in 18.4%, high flow oxygen or non-invasive ventilation 7.1% and mechanical ventilation 3.6%, 340 patients (7.3%) died. Group 1 patients had more tobacco use, hypoxia at admission, lymphocytopaenia, and liver and kidney dysfunction. In group 1 versus groups 2 and 3, requirement of oxygen (21.6% vs 16.7% and 17.0%), non-invasive ventilation (8.0% vs 5.9% and 7.1%), invasive ventilation (4.6% vs 3.5% and 3.1%) and deaths (10.0% vs 6.8% and 5.5%) were significantly greater (p<0.05). OR for deaths were higher in group 1 (1.91, 95% CI 1.46 to 2.51) and group 2 (1.24, 95% CI 0.93 to 1.66) compared with group 3. Adjustment for demographic and comorbidities led to some attenuation in groups 1 (1.44, 95% CI 1.07 to 1.93) and 2 (1.38, 95% CI 1.02 to 1.85); this persisted with adjustments for clinical parameters and oxygen support in groups 1 (1.38, 95% CI 0.99 to 1.93) and 2 (1.52, 95% CI 1.01 to 2.11). CONCLUSION: Low educational status patients with COVID-19 in India have significantly greater adverse in-hospital outcomes and mortality. TRIAL REGISTRATION NUMBER: REF/2020/06/034036.

Cardiovascular risk factors and outcomes in COVID-19: A hospital-based study in India.

BACKGROUND & OBJECTIVES: Presence of cardiovascular (CV) risk factors enhance adverse outcomes in COVID-19. To determine association of risk factors with clinical outcomes in India we performed a study. METHODS: Successive virologically confirmed adult patients of COVID-19 at a government hospital were recruited at admission and data on clinical presentation and in-hospital outcomes were obtained. The cohort was classified according to age, sex, hypertension, diabetes and tobacco use. In-hospital death was the primary outcome. Logistic regression was performed to compared outcomes in different groups. RESULTS: From April to September 2020 we recruited 4645 (men 3386, women 1259) out of 5103 virologically confirmed COVID-19 patients (91.0%). Mean age was 46±18y, hypertension was in 17.8%, diabetes in 16.6% and any tobacco-use in 29.5%. Duration of hospital stay was 6.8±3.7 days, supplemental oxygen was in 18.4%, non-invasive ventilation in 7.1%, mechanical ventilation in 3.6% and 7.3% died. Unadjusted and age-sex adjusted odds ratio(OR) and 95% confidence intervals(CI) for in-hospital mortality, respectively, were: age ≥60y vs <40y, OR 8.47(95% CI 5.87-12.21) and 8.49(5.88-12.25), age 40-59y vs <40y 3.69(2.53-5.38) and 3.66(2.50-5.33), men vs women 1.88(1.41-2.51) and 1.26(0.91-1.48); hypertension 2.22(1.74-2.83) and 1.32(1.02-1.70), diabetes 1.88(1.46-2.43) and 1.16(0.89-1.52); and tobacco 1.29(1.02-1.63) and 1.28(1.00-1.63). Need for invasive and non-invasive ventilation was greater among patients in age-groups 40-49 and ≥60y and hypertension. Multivariate adjustment for social factors, clinical features and biochemical tests attenuated significance of all risk factors. CONCLUSION: Cardiovascular risk factors, age, male sex, hypertension, diabetes and tobacco-use, are associated with greater risk of in-hospital death among COVID-19 patients.

Potential of nanoparticles encapsulated drugs for possible inhibition of the antimicrobial resistance development.

The immune system is a dynamic network of cells and cytokines are the major mediators of immune responses which combat pathogens. Based on the cytokine production, effector T cells differentiate into subsets known as Th1, Th2, Th17, or Treg. This system serves as a barrier to intracellular pathogens, bacterial infections and stimulates the production of reactive oxygen species (ROS), reactive nitrogen intermediates, and nitric oxide, which diffuses across membranes and engulfs intracellular pathogens. Oxidative stress occurs when ROS, reactive nitrogen species (RNS) production, and antioxidant defences become imbalanced. Oxidative stress generated by infected cells produces a substantial amount of free radicals which enables the killing of intracellular pathogens. Intracellular pathogens are exposed to endogenous ROS as part of normal aerobic respiration, also exogenous ROS and RNS are generated by the host immune system in response to infection. Nanoparticles which are designed for drug delivery are capable of trapping the desired drug in the particles which protect the drug from enzymatic degradation in a biological system. The subcellular size of nanoparticles enables higher intracellular uptake of the drug which results in the reduction of the concentration of free drugs reducing their toxic effect. Research on the modulation of immune response and oxidative stress using nanoparticles used to encapsulate drugs has yet to be explored fully. In this review, we illustrate the immune activation and generation of oxidative stress properties which are mediated by nanoparticle encapsulated drug delivery systems which can make the therapy more effective in case of diseases caused by intracellular pathogens.

Efficacy of IVRS-based mHealth intervention in reducing cardiovascular risk in metabolic syndrome: A cluster randomized trial.

AIMS: Efficacy of mobile-phone based intervention for reducing cardiovascular risk in metabolic syndrome (MetSyn). METHODS: We screened adults 20-60 years in 10 villages in India for MetSyn using stratified cluster sampling. Lifestyle and biochemical risk factors were assessed. International Harmonized Criteria were used for diagnosis. Villages were randomized with 5 each in control and intervention groups. Interactive voice response system (IVRS) in Hindi was developed. In intervention clusters two messages for promotion of healthy lifestyle and medical treatment were broadcast daily over 12-months and risk factors reassessed. RESULTS: 1012/1200(84%) persons were screened and MetSyn diagnosed in 286(28.3%). Villages were divided into 5 control(n = 136) and 5 intervention(n = 147) clusters. Baseline characteristics in both clusters were similar. Acceptability of intervention was >60% in 80% participants. At 12 months, significantly greater participants in intervention vs control clusters had healthier lifestyle (healthy diet 28.8vs14.7%, physical activity 25.9vs13.1%, tobacco 13.7vs32.5%), anthropometry (waist circumference 85.7 ± 6.3vs88.6 ± 14.0 cm, body mass index 21.9 ± 2.8vs23.1 ± 2.9 kg/m2), systolic BP 123.6 ± 7.7vs128.6 ± 14.1 mmHg, fasting glucose 95.6 ± 19.4vs109.4 ± 43.7 mg/dl, cholesterol 175.5 ± 36.5vs186.4 ± 43.3 mg/dl, and triglycerides 147.6 ± 48.3vs159.5 ± 60.7 mg/dl (p < 0.01). Prevalence of metabolic syndrome declined in intervention group by 22.3%vs3.9%, p < 0.001). CONCLUSION: An interactive voice response system based technology significantly reduced multiple cardiovascular risk factors and prevalence of metabolic syndrome.

Genotypic diversity of Mycobacterium tuberculosis isolates from North-Central Indian population.

BACKGROUND: Different strains of Mycobacterium tuberculosis (MTB) are known to have different epidemiological and clinical characteristics. Some of them are widely distributed and associated with drug resistance, whereas others are locally predominated. Molecular epidemiological investigations have always been beneficial in identifying new strains and studying their transmission dynamics. Sahariya a primitive tribe of North Madhya Pradesh, India, has already been reported to have high prevalence of tuberculosis (TB) than their non-tribal neighbours. However, the information about MTB genotypes prevalent in Sahariya tribe and their non-tribal neighbours is not available. METHODS: A total of 214 clinical isolates representing Sahariya tribe and non-tribes were analyzed by spoligotyping and MIRU-VNTR typing. RESULTS: The EAI3_IND/SIT11 genotype was observed as major genotype in Sahariya tribe followed by CAS1_Delhi/SIT26 genotype. A 3.04 fold higher risk of getting TB with EAI3_IND/SIT11 genotype was observed in Sahariya as compared to the non-tribal population. The EAI_IND/SIT11 genotype also found to have more number of MDR-TB cases in Sahariya as well as true and possible transmission links. In Sahariya tribe, 3 clusters (6 isolates) reflected true transmission links, whereas 8 clusters consisted of 26 isolates revealed possible transmission links within the same geographical location or nearby houses. CONCLUSION: The present study highlighted the predominance of EAI3_IND/SIT11 genotype in Sahariya tribe followed by CAS1_Delhi/SIT26 genotype. Combined approach of MIRU-VNTR typing and spoligotyping was observed more favourable in discrimination of MTB genotypes. Further, longitudinal studies using whole genome sequencing can provide more insights into genetic diversity, drug resistance and transmission dynamics of these prevalent genotypes.

Potential of adjunctive Mycobacterium w (MIP) immunotherapy in reducing the duration of standard chemotherapy against tuberculosis.

INTRODUCTION: The need to shorten the treatment duration in tuberculosis has always been felt. Immunotherapy in combination with chemotherapy has been considered a promising approach for this purpose into tuberculosis. We studied the adjuvant immunotherapeutic activity of Mycobacterium indicus pranii (MIP or Mw) in combination with conventional chemotherapy using guinea pig of pulmonary tuberculosis infected with Mycobacterium tuberculosis H37Rv via aerosol. METHODS: Experimental animals treated with standard chemotherapy and immunotherapy (MIP) separately and in combination of both. Guinea pig lungs evaluated following infection and subsequent therapy at predefine time point. Various cytokine mRNA expressions levels were quantified by quantitative reverse transcriptase PCR at the 4th, 8th and 12th week post-infection of M. tuberculosis. RESULTS: We determined the time required for bacterial clearance from guinea pig lungs. Standard chemotherapy (RvCh) compared to the animals where chemotherapy plus Mw immunotherpay (RvChMwT) was given. It took 12 weeks to achieve bacterial clearance in the RvCh group while this was achieved in 8 weeks in RvChMwT group. Pro-inflammatory cytokines (IFN-γ, IL-2, IL-12p35 and TNF-α) level were higher in RvCh, RvChMwT and RvMwT group, while the IL-10 and TGF-ß were suppressed. CONCLUSION: Cytokine expression level showed that Mw in conjunction with chemotherapy enhances the effect of pro-inflammatory cytokines (such as, IFN-γ, IL-2, IL-12 and TNF-α) and reduces the production and effect of anti-inflammatory cytokines (like IL-10 and TGF-ß) thereby restoring the pro-inflammatory / anti-inflammatory cytokines balance. Thus, the present study indicates that subject to rigorous testing by other parameters, Mw (MIP) as adjunct immunotherapy has potential for reducing treatment duration.

Association of Toll like receptor 2 and 9 gene variants with pulmonary tuberculosis: exploration in a northern Indian population.

Tuberculosis (TB) is a disease of global importance. There is an increasing recognition of the role of Toll like receptors, important pattern recognition receptors of host immune system, in determining the susceptibility or resistance to TB in various populations. In an attempt to examine the importance of Toll like receptors in immune response to Mycobacterium tuberculosis infection, we explored two variants each of TLR2 and TLR9 in a population residing in Uttar Pradesh, India. Genotyping was performed to detect -196 to -174 del polymorphism and G2258A SNP (Arg753Gln, rs5743708) in TLR2 gene and -T1237C (rs5743836) and G2848A (rs352140) SNP in TLR9 gene in patients with pulmonary TB and healthy controls. The A allele of G2848A SNP in TLR9 gene was found with a marginally higher frequency among TB patients as compared to healthy controls, suggesting that A allele at position 2848 of TLR9 gene may be associated with susceptibility to TB in North Indian population [p = 0.05, Mantel-Haenszel OR = 1.34, 95% CI (1.0-1.82)].

Comparative study of genotypes of Mycobacterium tuberculosis from a Northern Indian setting with strains reported from other parts of India and neighboring countries.

This study was carried out to characterize Mycobacterium tuberculosis population in Ghatampur, Kanpur, North India, by spoligotyping and Mycobacterial Interspersed Repetitive Units-Variable Number of Tandem Repeats (MIRU-VNTRs) typing. A total of 335 isolates were genotyped by spoligotyping and Central Asian (CAS) sub-lineage was the most prevalent, comprising 59.1% of all isolates. Other lineages were: East-African Indian (EAI) (19.10%), T (5.07%), Beijing (3.28%), Manu (2.98%), X (2.68%), S (0.89%), H3 (0.59%), Ural (0.59%), LAM 9 (0.29%) and unknown (5.37%). This data was compared with 8444 clinical isolates from other parts of India and neighboring countries. Thanks to interrogation of the SITVIT2 database, which shows that China is unique in having a predominance of Beijing lineage; Iran in having an almost equal proportion of Ural and CAS lineages; while the rest of the Middle-East and Indian subcontinent shows a gradient of CAS lineage predominating in the north of tropic of cancer, and the ancestral EAI lineage in South India and South-East Asia. Additionally, 12 loci MIRU-VNTR typing efficiently discriminated 13 spoligotype-defined clusters into 92 patterns; 53 isolates showed >70% homology. It was observed that Beijing lineage strains were more frequently associated with MDR strains (p-value = 0.001). A multi-step application of combination of spoligotyping and MIRU-VNTR typing for analyzing the molecular epidemiology of TB may provide a better means of fingerprinting and studying transmission dynamics.

Genetic diversity & drug sensitivity profiles of Mycobacterium tuberculosis isolates from two slums of Jaipur city, Rajasthan, India.

BACKGROUND & OBJECTIVES: Slums are considered as hotspots of tuberculosis (TB). The study of genetic diversity and drug susceptibility profile of Mycobacterium tuberculosis (MTB) will help understand the transmission dynamics and can be used for better prevention and control of the disease. The aim of this study was to determine the drug susceptibility profiles and genetic diversity using the random amplified polymorphic DNA (RAPD) and mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU VNTR) of MTB isolates from sputum samples of pulmonary TB patients residing in the two slums of Jaipur city in Rajasthan, India. METHODS: Sputum samples collected from pulmonary TB patients, their contacts and suspects during 2010-2012 were processed for microscopy and mycobacterial culture. Drug susceptibility testing was done by one per cent indirect proportion method on Lowenstein-Jensen medium for first-line anti-TB drugs rifampicin, isoniazid, ethambutol and streptomycin. MTB DNA was extracted by physicochemical method, and DNA fingerprinting was done by RAPD and MIRU VNTR analysis. RESULTS: Among 175 sputum samples collected, 75 were positive (43.8%) for acid-fast bacilli, 83 for MTB culture and four were contaminated. Fifty two isolates (62.7%) were fully sensitive to four drugs, and five (6%) were multidrug resistant (MDR). RAPD analysis of 81 isolates revealed six clusters containing 23 (28.4%) isolates, and 58 (71.6%) were unique. MIRU VNTR analysis clustered 20 (24.7%) isolates, and 61 (75.3%) were unique. INTERPRETATION & CONCLUSIONS: About 62.7 per cent isolates from the sputum samples from slum areas were sensitive to four drugs; six per cent of isolates were MDR. Poly-resistance other than MDR was high (16%). About one-fourth isolates were clustered by either method. RAPD was rapid, less expensive but had low reproducibility. MIRU VNTR analysis could identify to greater extent the epidemiological link in the population studied.

Mapping of health research funding in India.

BACKGROUND.: We aimed to estimate the total annual funding available for health research in India. We also examined the trends of funding for health research since 2001 by major national and international agencies. METHODS.: We did a retrospective survey of 1150 health research institutions in India to estimate the quantum of funding over 5 years. We explored the Prowess database for industry spending on health research and development and gathered data from key funding agencies. All amounts were converted to 2015 constant US$. RESULTS.: The total health research funding available in India in 2011-12 was US$ 1.42 billion, 0.09% of the gross domestic product (GDP) including only 0.02% from public sources. The average annual increase of funding over the previous 5 years (2007-08 to 2011-12) was 8.8%. 95% of this funding was from Indian sources, including 79% by the Indian pharmaceutical industry. Of the total funding, only 3.2% was available for public health research. From 2006-10 to 2011-15 the funding for health research in India by the three major international agencies cumulatively decreased by 40.8%. The non-industry funding for non-communicable diseases doubled from 2007-08 to 2011-12, but the funding for some of the leading causes of disease burden, including neonatal disorders, cardiovascular disease, chronic respiratory disease, mental health, musculoskeletal disorders and injuries was substantially lower than their contribution to the disease burden. CONCLUSION.: The total funding available for health research in India is lower than previous estimates, and only a miniscule proportion is available for public health research. The non industry funding for health research in India, which is predominantly from public resources, is extremely small, and had considerable mismatches with the major causes of disease burden. The magnitude of public funding for health research and its appropriate allocation should be addressed at the highest policy level.

Early detection of multidrug resistant (MDR) Mycobacterium tuberculosis in a single tube with in-house designed fluorescence resonance energy transfer (FRET) probes using real-time PCR.

Rapid and correct diagnosis is crucial for the management of multidrug resistance (MDR) in Mycobacterium tuberculosis (MTB). The present study aims at rapid diagnosis for identification of multidrug resistance tuberculosis (MDR-TB) using real-time PCR. FRET hybridization probes targeting most prominent four selected codons for rpoB526 and 531 and for katG314 and 315 genes were designed and evaluated on 143 clinical MTB isolates and paired sputa for rapid detection of MDR-TB. The results of real-time PCR were compared with gold standard L-J proportion method and further validated by DNA sequencing. Of the 143 MTB positive cultures, 85 and 58 isolates were found to be 'MDR' and 'pan susceptible', respectively by proportion L-J method. The sensitivity of real-time PCR for the detection of rifampicin (RIF) and isoniazid (INH) were 85.88 and 94.11%, respectively, and the specificity of method was found to be 98.27%. DNA sequencing of 31 MTB isolates having distinct melting temperature (Tm) as compared to the standard drug susceptible H37Rv strain showed 100% concordance with real-time PCR results. DNA sequencing revealed the mutations at Ser531Leu, His526Asp of rpoB gene and Ser315Thr, Thr314Pro of katG gene in RIF and INH resistance cases. This real-time PCR assay that targets limited number of loci in a selected range ensures direct and rapid detection of MDR-TB in Indian settings. However, future studies for revalidation as well as refinement are required to break the limitations of MDR-TB detection.

Assessing genetic diversity of Mycobacterium tuberculosis by spoligotyping and IS6110-based restriction fragment length polymorphism in North India.

OBJECTIVE/BACKGROUND: Molecular epidemiology methods are very useful for differentiating between strains, assessing their diversity, and measuring the prevalence of the most circulating strain in an area. Various molecular typing methods using different molecular markers have been utilized worldwide, such as restriction fragment length polymorphism (RFLP), spoligotyping, Mycobacterial Interspersed Repetitive Unit - Variable Number of Tandem Repeat (MIRU-VNTR), and Double repetitive element-PCR (DRE-PCR) typing, for simultaneous detection and epidemiologic typing of Mycobacterium tuberculosis. The present study is conducted to assess the genetic diversity of M. tuberculosis by IS6110-RFLP and spoligotyping in patients attending a tertiary care hospital in eastern Uttar Pradesh, North India. METHODS: A total of 83 representative isolates of M. tuberculosis were included in this study. These isolates were subjected to spoligotyping and IS6110-RFLP DNA fingerprinting techniques as described previously. RESULTS: The spoligotype patterns were compared with SpolDB4.0; patterns of 64 out of 83 M. tuberculosis isolates were matched with the available data, while 19 isolates were found to be orphan, that is, absent in the SpolDB4.0 database. The majority of the M. tuberculosis strains (56.5%) belong to central Asian (32.5%), ill defined T (13.2%), and Beijing (10.8%) families. On IS6110-RFLP analysis, in 19.2% (16/83) of these isolates, IS6110 element was not found (0 copy number strains). Further, 15.6% (13/83) isolates were found to be low-copy-number strains having less than six copies of IS6110 element, and the remaining 65.0% (54/83) were multiple-copy-number strains with six or more copies of the element. On comparing the results of spoligotyping and IS-6110-RFLP, a total of 47 isolates were clustered by spoligotyping; out of these isolates, 40 were found to be unique by IS6110-RFLP. CONCLUSION: Spoligotype analysis resulted in the grouping of a much larger number of isolates within apparently identical clusters compared with IS6110-RFLP typing, while IS6110-RFLP was not found to effectively distinguish between zero- and low-copy-number isolates. Therefore, we concluded that, in India, the use of both the techniques simultaneously for DNA fingerprinting of M. tuberculosis could be a better approach.

TlyA protein of Mycobacterium leprae: a probable bio-marker of active infection.

The extent of pathogenicity of the mycobacterial infections depends on virulence factors that mediate survival inside macrophages. Virulence factors are generally believed to be specific for pathogenic species and mutated/non-functional in nonpathogenic strains. Mycobacterial TlyA can modulate the phagolysosome maturation pathway, immediately after entry into macrophages. Over-expression of open reading frame (ORF) ML1358 (tlyA) in tissues of leprosy patients by partial DNA chip and real time PCR analysis during active infection attracted our interest to explore the properties of this gene at molecular and serological levels, to understand its role in the host. Molecular properties were studied by cloning and expression of the corresponding gene in pASK-iba 43(þ) expression vector in E. coli and bioinformatics tools while sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and ELISA were applied to investigate the serological significance of rTlyA protein in different clinical states of leprosy. We observed that TlyA has a close relation among mycobacteria with specific protein domains in slow growing intracellular adapted pathogenic species. The presence of trans-membrane domains indicates its association to the cell membrane. The study revealed its highly significant sero-reactivity (P value , 0·001) in borderline lepromatous (BL) patients, and those with reversal reaction (RR) and erythema nodosum leprosum (ENL). Its role in active infection, association with the cell membrane, presence in pathogenic species and high sero-reactivity, suggested the tlyA gene as a strong disease progression marker.

Mycobacterium tuberculosis secretory proteins downregulate T cell activation by interfering with proximal and downstream T cell signalling events.

BACKGROUND: Mycobacterium tuberculosis (M. tuberculosis) modulates host immune response, mainly T cell responses for its own survival leading to disease or latent infection. The molecules and mechanisms utilized to accomplish immune subversion by M. tuberculosis are not fully understood. Understanding the molecular mechanism of T cell response to M. tuberculosis is important for development of efficacious vaccine against TB. METHODS: Here, we investigated effect of M. tuberculosis antigens Ag85A and ESAT-6 on T cell signalling events in CD3/CD28 induced Peripheral blood mononuclear cells (PBMCs) of PPD+ve healthy individuals and pulmonary TB patients. We studied CD3 induced intracellular calcium mobilization in PBMCs of healthy individuals and TB patients by spectrofluorimetry, CD3 and CD28 induced activation of mitogen activated protein kinases (MAPKs) in PBMCs of healthy individuals and TB patients by western blotting and binding of transcription factors NFAT and NFκB by Electrophorectic mobility shift assay (EMSA). RESULTS: We observed CD3 triggered modulations in free intracellular calcium concentrations in PPD+ve healthy individuals and pulmonary TB patients after the treatment of M. tuberculosis antigens. As regards the downstream signalling events, phosphorylation of MAPKs, Extracellular signal-regulated kinase 1 and 2 (ERK1/2) and p38 was curtailed by M. tuberculosis antigens in TB patients whereas, in PPD+ve healthy individuals only ERK1/2 phosphorylation was inhibited. Besides, the terminal signalling events like binding of transcription factors NFAT and NFκB was also altered by M. tuberculosis antigens. Altogether, our results suggest that M. tuberculosis antigens, specifically ESAT-6, interfere with TCR/CD28-induced upstream as well as downstream signalling events which might be responsible for defective IL-2 production which further contributed in T-cell unresponsiveness, implicated in the progression of disease. CONCLUSION: To the best of our knowledge, this is the first study to investigate effect of Ag85A and ESAT-6 on TCR- and TCR/CD28- induced upstream and downstream signalling events of T-cell activation in TB patients. This study showed the effect of secretory antigens of M. tuberculosis in the modulation of T cell signalling pathways. This inflection is accomplished by altering the proximal and distal events of signalling cascade which could be involved in T-cell dysfunctioning during the progression of the disease.

Consensus & Evidence-based INOSA Guidelines 2014 (First edition).

Obstructive sleep apnoea (OSA) and obstructive sleep apnoea syndrome (OSAS) are subsets of sleep-disordered breathing. Awareness about OSA and its consequences amongst the general public as well as the majority of primary care physcians across India is poor. This necessiated the development of the INdian initiative on Obstructive Sleep Apnoea (INOSA) guidelines under the auspices of Department of Health Research, Ministry of Health & Family Welfare, Government of India. OSA is the occurrence of an average five or more episodes of obstructive respiratory events per hour of sleep with either sleep related symptoms or comorbidities or ≥ 15 such episodes without any sleep related symptoms or comorbidities. OSAS is defined as OSA associated with daytime symptoms, most often excessive sleepiness. Patients undergoing routine health check-up with snoring, daytime sleepiness, obesity, hypertension, motor vehicular accidents and high risk cases should undergo a comprehensive sleep evaluation. Medical examiners evaluating drivers, air pilots, railway drivers and heavy machinery workers should be educated about OSA and should comprehensively evaluate applicants for OSA. Those suspected to have OSA on comprehensive sleep evaluation should be referred for a sleep study. Supervised overnight polysomnography (PSG) is the "gold standard" for evaluation of OSA. Positive airway pressure (PAP) therapy is the mainstay of treatment of OSA. Oral appliances are indicated for use in patients with mild to moderate OSA who prefer oral appliances to PAP, or who do not respond to PAP or who fail treatment attempts with PAP or behavioural measures. Surgical treatment is recommended in patients who have failed or are intolerant to PAP therapy.

Consensus and evidence-based Indian initiative on obstructive sleep apnea guidelines 2014 (first edition).

Obstructive sleep apnea (OSA) and obstructive sleep apnea syndrome (OSAS) are subsets of sleep-disordered breathing. Awareness about OSA and its consequences among the general public as well as the majority of primary care physicians across India is poor. This necessitated the development of the Indian initiative on obstructive sleep apnea (INOSA) guidelines under the auspices of Department of Health Research, Ministry of Health and Family Welfare, Government of India. OSA is the occurrence of an average five or more episodes of obstructive respiratory events per hour of sleep with either sleep-related symptoms or co-morbidities or ≥15 such episodes without any sleep-related symptoms or co-morbidities. OSAS is defined as OSA associated with daytime symptoms, most often excessive sleepiness. Patients undergoing routine health check-up with snoring, daytime sleepiness, obesity, hypertension, motor vehicular accidents, and high-risk cases should undergo a comprehensive sleep evaluation. Medical examiners evaluating drivers, air pilots, railway drivers, and heavy machinery workers should be educated about OSA and should comprehensively evaluate applicants for OSA. Those suspected to have OSA on comprehensive sleep evaluation should be referred for a sleep study. Supervised overnight polysomnography is the "gold standard" for evaluation of OSA. Positive airway pressure (PAP) therapy is the mainstay of treatment of OSA. Oral appliances (OA) are indicated for use in patients with mild to moderate OSA who prefer OA to PAP, or who do not respond to PAP or who fail treatment attempts with PAP or behavioral measures. Surgical treatment is recommended in patients who have failed or are intolerant to PAP therapy.