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Yim J.-J.,Seoul National University | Selvaraj P.,Tuberculosis Research Center
Respirology | Year: 2010

The importance of host genetic factors in determining susceptibility to tuberculosis (TB) has been studied extensively using various methods, such as case-control, candidate gene and genome-wide linkage studies. Several important candidate genes like human leucocyte antigen/alleles and non-human leucocyte antigen genes, such as cytokines and their receptors, chemokines and their receptors, pattern recognition receptors (including toll-like receptors, mannose binding lectin and the dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin), solute carrier family 11A member 1 (formerly known as natural resistance-associated macrophage protein 1) and purinergic P2X7 receptor gene polymorphisms, have been associated with differential susceptibility to TB in various ethnic populations. This heterogeneity has been explained by host-pathogen and gene-environment interactions and evolutionary selection pressures. Although the achievements of genetics studies might not yet have advanced the prevention and treatment of TB, researchers have begun to widen their scope of investigation to encompass these practical considerations. © 2009 Asian Pacific Society of Respirology. Source


Kumar D.,Tuberculosis Research Center | Narayanan S.,Tuberculosis Research Center
Infection, Genetics and Evolution | Year: 2012

Mycobacterium tuberculosis, an intracellular pathogen that causes tuberculosis has developed multifactorial mechanisms to evade host signaling responses. Apoptosis, an important innate host immune response that clears the invading pathogen is suppressed by M. tuberculosis to gain persistence.Here, we examined the various apoptotic events suppressed by Protein Kinase E, (pknE) a Serine Threonine Protein Kinase (STPK) of M. tuberculosis in macrophages infected with ΔpknE, a deletion mutant of pknE vs. the wild type strain H 37Rv using microarray. The data showed increased expression of genes involved in apoptosis and chemokines with suppressed pro-inflammatory cytokines, co-stimulatory molecules, arginase1 and iNOS. The microarray data was validated using qRT-PCR, PCR array, oligoGE array, arginase assay and/or ELISA. Furthermore, we analyzed the phosphorylation of Akt that promotes cell survival using western blotting. ΔpknE infected macrophages reduced the phosphorylation of Akt that correlates with the observed apoptotic responses.Experiments performed using exogenous nitrate donor, sodium nitro prusside to demonstrate the role of pknE during nitrate stress showed similar apoptotic responses to that of endogenous nitrate stress in Δ. pknE infected macrophages. Our data confirms the role of pknE in the intra cellular survival of M. tuberculosis by suppressing apoptosis during nitrate stress. © 2011 Elsevier B.V.. Source


Swaminathan S.,Tuberculosis Research Center | Rekha B.,Tuberculosis Research Center
Clinical Infectious Diseases | Year: 2010

Tuberculosis (TB) is among the top 10 causes of death among children worldwide; however, children with TB are given low priority in most national health programs and are neglected in this epidemic. Recent technological advancements in diagnosis of TB in adults have not been validated in children. Similarly, trials of new drugs and development of pediatric formulations of standard first- and second-line drugs are lagging behind. Among human immunodeficiency virus (HIV)-coinfected children, the optimal timing for highly active antiretroviral therapy initiation and drug combinations that have minimal interactions with anti-TB drugs need further study. Although bacille Calmette-Guérin vaccine, the only vaccine available for TB, protects against disseminated and severe forms of the disease in young children, its safety in the HIV-infected population has been questioned. Multicentric trials are urgently required to help develop improved diagnostic strategies and formulate shorter, more effective, safe, and evidence-based regimens for treatment and prevention of drug-susceptible and drug-resistant TB. © 2010 by the Infectious Diseases Society of America. All rights reserved. Source


Thangappah R.B.P.,Women and Children Hospital | Paramasivan C.N.,Tuberculosis Research Center | Narayanan S.,Tuberculosis Research Center
Indian Journal of Medical Research | Year: 2011

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. Methods: This study included 72 infertile women who met the inclusion and exclusion criteria. After a detailed history and clinical examination all patients were subjected to investigations including pelvic sonogram, HSG and laparoscopy. Endometrial samples from were allocated for AFB smear, culture and HPE examination. Only 49 samples were available for PCR using IS 6110 and TRC4 primers. In seven patients peritoneal fluid was also taken for culture and PCR. Based on the clinical profile and laparoscopic findings, a diagnostic criteria was derived to suspect GTB. Specific diagnostic tests were evaluated against this diagnostic criterion. Results: Laparoscopy was suggestive of tuberculosis in 59.7 per cent of cases, AFB smear was positive in 8.3 per cent, culture was positive in 5.6 per cent, HPE positive in 6.9 per cent and PCR was positive in 36.7 per cent of cases. Based on the diagnostic criteria, GTB was suspected in 28 of the 49 cases. On evaluating against the diagnostic criteria, the sensitivity of PCR, HPE and culture were 57.1, 10.7, 7.14 per cent respectively. The concordance of results between the clinical criteria and specific diagnostic tests were analysed by Kappa measure of agreement. The culture and HPE showed mild agreement with the clinical criteria, whereas PCR showed a moderate agreement. PCR was positive in Two of the 21 cases in whom GTB was not suspected. False positive PCR in these two cases were ruled out by multiple areas of sampling and re-sampling in one case. The PCR results were negative in 12 of the 28 cases. PCR using TRC4 primers had a higher sensitivity (46.4%) than IS 6110 primers (25%) in detecting clinically suspected GTB. Interpretation & conclusions: Our results showed that conventional methods of diagnosis namely, HPE, AFB smear and culture have low sensitivity. PCR was found to be useful in diagnosing early disease as well as confirming diagnosis in clinically suspected cases. False negative PCR was an important limitation in this study. Source


Syed Ahamed Kabeer B.,Tuberculosis Research Center | Sikhamani R.,Government Hospital of Thoracic Medicine | Raja A.,Tuberculosis Research Center
Diagnostic Microbiology and Infectious Disease | Year: 2011

We aimed to compare the positivity of the QuantiFERON TB gold in-tube (QFT-IT antigens) specific interferon gamma (IFN-γ/QFT-IT) and IFN-γ-inducible protein-10 (IP-10/QFT-IT) assays with tuberculin skin test (TST) among human immunodeficiency virus (HIV)-infected individuals in a TB endemic setting. A total of 180 HIV-infected subjects, with no evidence of active TB, were recruited. IFN-γ and IP-10 levels specific to QFT-IT antigens were measured in plasma from QFT-IT tubes. The overall positivity of TST at the 5-mm cut-off point (19%) was significantly lower when compared to IFN-γ/QFT-IT (38%) and IP-10/QFT-IT (45%) assays. The positivity of IP-10/QFT-IT was significantly higher than that of IFN-γ/QFT-IT (P = 0.038). Indeterminate results for IFN-γ/QFT-IT and IP-10/QFT-IT were more frequent in subjects with CD4 count <100 cells/μL than in those with >100 cells/μL. IFN-γ/QFT-IT (9%) yielded significantly higher number of indeterminate results than IP-10/QFT-IT (5%). The frequency of these responses is higher than the proportion of individuals with positive TST results. However, 6 IFN-γ/QFT-IT- or IP-10/QFT-IT-negative subjects were positive for TST at the 5-mm cut-off point. Prospective and prognostic studies are required to clarify the significance of these data. © 2011 Elsevier Inc. Source

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