Investigation of geo-spatial hotspots for the occurrence of tuberculosis in Almora district, India, using GIS and spatial scan statistic

Background  

The World Health Organization has declared tuberculosis a global emergency in 1993. It has been estimated that one third of the world population is infected with Mycobacterium tuberculosis, the causative agent of tuberculosis. The emergence of TB/HIV co-infection poses an additional challenge for the control of tuberculosis throughout the world. The World Health Organization is supporting many developing countries to eradicate tuberculosis. It is an agony that one fifth of the tuberculosis patients worldwide are in India. The eradication of tuberculosis is the greatest public health challenge for this developing country. The aim of the present population based study on Mycobacterium tuberculosis is to test a large set of tuberculosis cases for the presence of statistically significant geographical clusters. A spatial scan statistic is used to identify purely spatial and space-time clusters of tuberculosis.     

Tuftsin-bearing liposomes as rifampin vehicles in treatment of tuberculosis in mice.

The antitubercular activity of rifampin was considerably increased when it was encapsulated in egg phosphatidylcholine liposomes. A further increase in the activity was observed when the macrophage activator tetrapeptide tuftsin was grafted on the surface of the drug-loaded liposomes. Intermittent treatments (twice weekly) with these preparations were significantly more effective than the continuous treatments. Rifampin delivered twice weekly for 2 weeks in tuftsin-bearing liposomes was at least 2,000 times more effective than the free drug in lowering the load of lung bacilli in infected animals. However, pretreatment with drug-free tuftsin-bearing liposomes did not render the pretreated animals resistant to the Mycobacterium tuberculosis infections, neither did it appreciably increase the chemotherapeutic efficacy of the liposomized rifampin. These results clearly demonstrate that liposome targeting to macrophages could considerably increase the antitubercular activity of liposomized drugs such as rifampin. Also, it shows that immunoprophylactic treatment with macrophage activators such as tuftsin does not afford any advantage in treatment of tuberculosis infections, presumably because of inactivation of the primed macrophages by the mycobacterial sulfatides.     

A paradigm shift in EPH receptor interaction: biological relevance of EPHB6 interaction with EPHA2 and EPHB2 in breast carcinoma cell lines

EPH receptors are the largest known family of receptor tyrosine kinases characterized in humans. These proteins are involved in axon guidance, tissue organization, synaptic plasticity, vascular development and the progression of various diseases including cancer. The varied biological effects of EPH receptors are mediated in part by the expression of these proteins and their intracellular binding proteins. The ability of EPH molecules to form heterodimers within their own class has been suggested, although not exhaustively characterized. We have clarified this phenomenon by showing that EPHB6, a kinase-deficient receptor, can interact with EPHB2 in mammalian cells, and more significantly EPHB6 interacts with EPHA2. However, EPHB6 does not interact with another kinase-deficient receptor, EPHA10. The interaction between EPHB6 and EPHA2 is the first demonstration of an A-type receptor interacting with a B-type receptor. Furthermore, we correlated relative expression of EPHB6, EPHB2 and EPHA2 with non-invasive and invasive phenotypes of breast tumor cell lines. Our results indicate that tumor invasiveness-suppressing activity of EPHB6 is mediated by its ability to sequester other kinase-sufficient and oncogenic EPH receptors. These observations suggest that cellular phenotypes may, in part, be attributed to a combinatorial expression of EPH receptors and heteromeric interactions among the same class, as well as between two classes, of EPH receptors. Our results also suggest that EPHA10 may transduce signals by interacting with other kinase-sufficient receptors in a similar manner.     

Synthesis, kinetic studies and pharmacological evaluation of mutual azo prodrug of 5-aminosalicylic acid for colon-specific drug delivery in inflammatory bowel disease

Mutual azo prodrug of 5-aminosalicylic acid with l-tyrosine was synthesized by coupling l-tyrosine with salicylic acid, for targeted drug delivery to the inflamed gut tissue in inflammatory bowel disease. The structure was confirmed by elemental analysis, IR and NMR spectroscopy. In vitro kinetic studies in rat fecal matter showed 87.18% release of 5-aminosalicylic acid with a half-life of 140.28min, following first order kinetics. Therapeutic efficacy of the carrier system and the mitigating effect of the azo conjugate were evaluated in trinitrobenzenesulfonic acid-induced experimental colitis model. Myeloperoxidase activity was determined by the method of Krawisz et al. The synthesized prodrug was found to produce comparable mitigating effect as that of sulfasalazine on colitis in rats.     

Molecular mechanisms underlying occult hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection is a complex clinical entity frequently associated with cirrhosis and hepatocellular carcinoma (HCC). The persistence of HBV genomes in the absence of detectable surface antigenemia is termed occult HBV infection. Mutations in the surface gene rendering HBsAg undetectable by commercial assays and inhibition of HBV by suppression of viral replication and viral proteins represent two fundamentally different mechanisms that lead to occult HBV infections. The molecular mechanisms underlying occult HBV infections, including recently identified mechanisms associated with the suppression of HBV replication and inhibition of HBV proteins, are reviewed in detail. The availability of highly sensitive molecular methods has led to increased detection of occult HBV infections in various clinical settings. The clinical relevance of occult HBV infection and the utility of appropriate diagnostic methods to detect occult HBV infection are discussed. The need for specific guidelines on the diagnosis and management of occult HBV infection is being increasingly recognized; the aspects of mechanistic studies that warrant further investigation are discussed in the final section.     

Genetic components in diabetic retinopathy

Diabetic retinopathy (DR) is a serious complication of diabetes, which is fast reaching epidemic proportions worldwide. While tight glycemic control remains the standard of care for preventing the progression of DR, better insights into DR etiology require understanding its genetic basis, which in turn may assist in the design of novel treatments. During the last decade, genomic medicine is increasingly being applied to common multifactorial diseases such as diabetes and age-related macular degeneration. The contribution of genetics to the initiation and progression of DR has been recognized for some time, but the involvement of specific genes and genetic variants remains elusive. Several investigations are currently underway for identifying DR susceptibility loci through linkage studies, candidate gene approaches, and genome-wide association studies. Advent of next generation sequencing and high throughput genomic technologies, development of novel bioinformatics tools and collaborations among research teams should facilitate such investigations. Here, we review the current state of genetic studies in DR and discuss reported findings in the context of biochemical, cell biological and therapeutic advances. We propose the development of a consortium in India for genetic studies with large cohorts of patients and controls from limited geographical areas to stratify the impact of the environment. Uniform guidelines should be established for clinical phenotyping and data collection. These studies would permit identification of genetic loci for DR susceptibility in the Indian population and should be valuable for better diagnosis and prognosis, and for clinical management of this blinding disease.     

Tyrosine kinase-deficient EphB6 receptor-dependent alterations in proteomic profiles of invasive breast carcinoma cells as determined by difference gel electrophoresis

The expression profiles of the erythropoietin producing hepatocellular carcinoma (Eph) receptor family of tyrosine kinases have been previously shown to provide molecular signatures of normal breast cells, breast tumor cells and invasive breast carcinoma cells. In particular, the expression of EphB6 receptor is lost in invasive breast carcinoma cell line MDA-MB-231. The comparative proteomic profiles of native and EphB6-expressing MDA-MB-231 cells using difference gel electrophoresis (DIGE) and liquid chromatography-mass spectrometry of selected proteins are presented in this study. The expression of more than 70 proteins was significantly altered in EphB6-transfected MDA-MB-231 cells. These altered proteins are involved in glycolysis, cell cycle regulation, tumor suppression, cell proliferation, mitochondrial metabolism, mRNA splicing, DNA replication and repair. Although the majority of these proteins have been implicated in tumorigenesis, the impairment of energy homeostasis and altered regulation of signaling pathways appear to be noteworthy targets of EphB6. Based on the identities of altered proteins and the pathways regulated by these proteins, this study suggests that the interactions of EphB6 with a wide variety of proteins lead to altered proteomic profile of EphB6-transfected MDA-MB-231 cells.