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Satyanarayana M.L.,Osmania University | Deepa S.R.,Center for Molecular and Cellular Biology | Advithi R.,Osmania University | Venkateshwari A.,Institute of Genetics and Hospital for Genetic Diseases | And 2 more authors.
International Journal of Human Genetics | Year: 2013

Hypertrophic Cardiomyopathy (HCM) is a primary cardiac disease characterized by increased thickness of the left ventricular walls in the absence of secondary causes and manifested by mutations in sarcomeric genes. Dilated Cardiomyopathy (DCM) is associated with dilation and impaired contraction of the ventricles and is associated with sarcomeric and cytoskeletal gene mutations. The present study is focused on screening for genetic variations in the sarcomeric genes viz., Myosin Heavy Chain gene (MYH7), Troponin I3 (TNNI3), Troponin T2 (TNNT2), Alpha-Actin (ACTC), Myosin Regulatory Light Chain (MYL2) and Myosin Essential Light Chain (MYL3) by SSCP and sequencing in 100 HCM, 97 DCM and 200 controls to elucidate the phenotypic plasticity associated with cardiomyopathy. Common variations were observed in exons 7, 12, 19 and 20 of MYH7; exon 9 and intron 16 of TNNT2; intron1, intron2, exon 5 and exon 7 of TNNI; exon 1 of MYL3 gene/s in both HCM and DCM cases. This can be explained on the basis of impaired energy compromise or dose effect of the mutant protein or environmental factors wherein a HCM could progress to a DCM phenotype affecting both the right and left ventricles, leading to heart failure. Genotype-phenotype correlations can be best explained by phenotypic plasticity where in mutations/ variations in the same gene and even same variations in a different environmental background may lead to HCM / DCM dispartite phenotypes. © Kamla-Raj 2013. Source


Gallant C.J.,McGill University | Cobat A.,French Institute of Health and Medical Research | Cobat A.,University of Paris Descartes | Simkin L.,McGill University | And 16 more authors.
Chest | Year: 2010

Background: Although many studies have compared in vitro TB diagnostic tests with the venerable tuberculin skin test (TST), there is little understanding of the quantitative relationship between critical measures of antimycobacterial immunity used to detect TB infection. We, therefore, decided to determine the degree of redundancy between quantitative read-outs of in vivo and in vitro assays of antimycobacterial immunity. Methods: We enrolled 475 healthy HIV-negative children and young adults living in a hyperendemic area of TB. We measured in vivo TST responses, and a 1:10 diluted 3-or 7-day whole-blood assay was used to determine the in vitro antigen-specific interferon (IFN)-γ cytokine release. The frequency of antigen-specific IFN-γ + CD4 + and IFN-γ + CD8 + cells was tested using intracellular cytokine staining after 1 day incubation. Results: In vivo TST responses segregated into two well-separated groups with either no measurable response (TST induration, 5 mm; n = 164) or a normally distributed group with TST indurations ≥ 5 mm with peak at 15 mm (n = 260). In vitro assays provided a less pronounced separation of responders and nonresponders. Correlation analysis of responses among persons with TST ≥ 5 mm demonstrated that extent of TST response was poorly correlated with IFN-γ release (coefficients of correlation ρ = 0.17-0.22) and frequency of IFN-γ + CD4 +/CD8 + cells (ρ = 0.05-0.17) across three stimulating antigens (Mycobacterium bovis bacillus Calmette-Guérin, purified protein derivative, early-secreted antigenic target-6). Conclusion: We conclude that in vivo and in vitro assays are nonredundant, complementary measures of antimycobacterial immunity. Both TST and in vitro assays provided valuable information about antimycobacterial immunity and by inference latent TB in the studied high-incidence TB settings. © 2010 American College of Chest Physicians. Source


Cliff J.M.,London School of Hygiene and Tropical Medicine | Lee J.-S.,London School of Hygiene and Tropical Medicine | Constantinou N.,London School of Hygiene and Tropical Medicine | Cho J.-E.,London School of Hygiene and Tropical Medicine | And 9 more authors.
Journal of Infectious Diseases | Year: 2013

Background. Accurate assessment of treatment efficacy would facilitate clinical trials of new antituberculosis drugs. We hypothesized that early alterations in peripheral immunity could be measured by gene expression profiling in tuberculosis patients undergoing successful conventional combination treatment. Methods. Ex vivo blood samples from 27 pulmonary tuberculosis patients were assayed at diagnosis and during treatment. RNA was processed and hybridized to Affymetrix GeneChips, to determine expression of over 47 000 transcripts. Results. There were significant ≥2-fold changes in expression of >4000 genes during treatment. Rapid, largescale changes were detected, with down-regulated expression of 1261 genes within the first week, including inflammatory markers such as complement components C1q and C2. This was followed by slower changes in expression of different networks of genes, including a later increase in expression of B-cell markers, transcription factors, and signaling molecules. Conclusions. The fast initial down-regulation of expression of inflammatory mediators coincided with rapid killing of actively dividing bacilli, whereas slower delayed changes occurred as drugs acted on dormant bacilli and coincided with lung pathology resolution. Measurement of biosignatures during clinical trials of new drugs could be useful predictors of rapid bactericidal or sterilizing drug activity, and would expedite the licensing of new treatment regimens. © The Author 2012. Source


Diacon A.H.,Stellenbosch University | Diacon A.H.,University of Cape Town | Dawson R.,University of Cape Town | Von Groote-Bidlingmaier F.,Stellenbosch University | And 9 more authors.
The Lancet | Year: 2012

Background New drugs, but also shorter, better-tolerated regimens are needed to tackle the high global burden of tuberculosis complicated by drug resistance and retroviral disease. We investigated new multiple-agent combinations over the fi rst 14 days of treatment to assess their suitability for future development. Methods In this prospective, randomised, early bactericidal activity (EBA) study, treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis were admitted to hospitals in Cape Town, South Africa, between Oct 7, 2010, and Aug 19, 2011. Patients were randomised centrally by computer-generated randomisation sequence to receive bedaquiline, bedaquiline-pyrazinamide, PA-824-pyrazinamide, bedaquiline-PA-824, PA-824-moxifl oxacinpyrazinamide, or unmasked standard antituberculosis treatment as positive control. The primary outcome was the 14-day EBA assessed in a central laboratory from the daily fall in colony forming units (CFU) of M tuberculosis per mL of sputum in daily overnight sputum collections. Bilinear regression curves were fi tted for each group separately and groups compared with ANOVA for ranks, followed by pair-wise comparisons adjusted for multiplicity. Clinical staff were partially masked but laboratory personnel were fully masked. This study is registered, NCT01215851. Findings The mean 14-day EBA of PA-824-moxifl oxacin-pyrazinamide (n=13; 0233 [SD 0128]) was signifi cantly higher than that of bedaquiline (14; 0061 [0068]), bedaquiline- pyrazinamide (15; 0131 [0102]), bedaquiline-PA-824 (14; 0114 [0050]), but not PA-824-pyrazinamide (14; 0154 [0040]), and comparable with that of standard treatment (ten; 0140 [0094]). Treatments were well tolerated and appeared safe. One patient on PA-824-moxifl oxacinpyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecifi ed in the protocol. Interpretation PA-824-moxifl oxacin-pyrazinamide is potentially suitable for treating drug-sensitive and multidrugresistant tuberculosis. Multiagent EBA studies can contribute to reducing the time needed to develop new antituberculosis regimens. Funding The Global Alliance for TB Drug Development (TB Alliance). Source


Cliff J.M.,London School of Hygiene and Tropical Medicine | Cho J.-E.,London School of Hygiene and Tropical Medicine | Cho J.-E.,Daegu Health College | Lee J.-S.,London School of Hygiene and Tropical Medicine | And 8 more authors.
Journal of Infectious Diseases | Year: 2016

Background. Currently, there are no tools to accurately predict tuberculosis relapse. This study aimed to determine whether patients who experience tuberculosis relapse have different immune responses to mycobacteria in vitro than patients who remain cured for 2 years. Methods. Patients with an initial episode of pulmonary tuberculosis were recruited in South Africa. Diluted blood, collected at diagnosis and after 2 and 4 weeks of treatment, was cultured with live Mycobacterium tuberculosis for 6 days, and cellular RNA was frozen. Gene expression in samples from 10 patients who subsequently experienced relapse, confirmed by strain genotyping, was compared to that in samples from patients who remained cured, using microarrays. Results. At diagnosis, expression of 668 genes was significantly different in samples from patients who experienced relapse, compared with expression in patients who remained successfully cured; these differences persisted for at least 4 weeks. Gene ontology and biological pathways analyses revealed significant upregulation of genes involved in cytotoxic cell-mediated killing. Results were confirmed by real-time quantitative reverse-transcription polymerase chain reaction analysis in a wider patient cohort. Conclusions. These data show that patients who will subsequently experience relapse exhibit altered immune responses, including excessively robust cytolytic responses to M. tuberculosis in vitro, at the time of diagnosis, compared with patients who will achieve durable cure. Together with microbiological and clinical indices, these differences could be exploited in drug development. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. Source

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