Influence of arterial wall-stenosis compliance on the coronary diagnostic parameters

Functional diagnostic parameters such as Fractional Flow Reserve (FFR), which is calculated from pressure measurements across stenosed arteries, are often used to determine the functional severity of coronary artery stenosis. This study evaluated the effect of arterial wall-stenosis compliance, with limiting scenarios of stenosis severity, on the diagnostic parameters. The diagnostic parameters considered in this study include an established index, FFR and two recently developed parameters: Pressure Drop Coefficient (CDP) and Lesion Flow Coefficient (LFC). The parameters were assessed for rigid artery (RR; signifying high plaque elasticity), compliant artery with calcified plaque (CC; intermediate plaque elasticity) and compliant artery with smooth muscle cell proliferation (CS; low plaque elasticity), with varying degrees of epicardial stenosis. A hyperelastic Mooney-Rivlin model was used to model the arterial wall and plaque materials. Blood was modeled as a shear thinning, non-Newtonian fluid using the Carreau model. The arterial wall compliance was evaluated using the finite element method. The present study found that, with an increase in stenosis severity, FFR decreased whereas CDP and LFC increased. The cutoff value of 0.75 for FFR was observed at 78.7% area stenosis for RR, whereas for CC and CS the cutoff values were obtained at higher stenosis severities of 81.3% and 82.7%, respectively. For a fixed stenosis, CDP value decreased and LFC value increased with a decrease in plaque elasticity (RR to CS). We conclude that the differences in diagnostic parameters with compliance at intermediate stenosis (78.7-82.7% area blockage) could lead to misinterpretation of the stenosis severity.     

Precancerous and non-cancer disease endpoints of chronic arsenic exposure: the level of chromosomal damage and XRCC3 T241M polymorphism

Genetic variants are expected to play an important role in arsenic susceptibility. Our previous study revealed deficient DNA repair capacity to be a susceptibility factor for arsenicism. T241M polymorphism in XRCC3 (a homologous recombination repair pathway gene) is widely studied for its association with several cancers. We have investigated the association of XRCC3 T241M polymorphism with arsenic-induced precancerous and non-cancer disease outcomes. The present study evaluated the association of T241M polymorphism with arsenic-induced skin lesions, peripheral neuropathy (neurodegenerative changes), conjunctivitis and other ocular diseases. A case-control study was conducted in West Bengal, India, involving 206 cases with arsenic-induced skin lesions and 215 controls without arsenic-induced skin lesions having similar arsenic exposure. XRCC3 T241M polymorphism was determined using conventional PCR-sequencing method. Chromosomal aberration assay, arsenic-induced neuropathy and ocular diseases were also evaluated. The data revealed that presence of at least one Met allele (Met/Met or Thr/Met) was protective towards development of arsenic-induced skin lesions [OR=0.45, 95% CI: 0.30-0.67], peripheral neuropathy [OR=0.49; 95%CI: 0.30-0.82] and conjunctivitis [OR=0.60; 95%CI: 0.40-0.92]. A significant correlation was also observed between protective genotype and decreased frequency of chromosomal aberrations. Thus the results indicate the protective role of Met allele against the arsenic-induced skin lesions, chromosomal instability, peripheral neuropathy and conjunctivitis.     

The combination of VEGF inhibitors and anti-oestrogen therapies in breast cancer

Despite effective treatments for oestrogen receptor-positive breast cancers, drug resistance is common and remains a significant clinical challenge. Targeting tumour vasculature by blockade of the vascular endothelial growth factor (VEGF) has proved successful in a variety of cancers. Phase III clinical trials of bevacizumab in combination with chemotherapy showed some efficacy in breast cancer. Concomitant targeting of the VEGF and oestrogen signalling pathways has the potential to provide enhanced therapeutic benefit in oestrogen receptor-positive breast cancer, and this strategy is under evaluation in clinical trials. This article summarises the rationale for this approach and clinical studies so far.     

<Emphasis Type="Italic">Nicotiana tabacum</Emphasis> overexpressing γ-ECS exhibits biotic stress tolerance likely through NPR1-dependent salicylic acid-mediated pathway

The elaborate networks and the crosstalk of established signaling molecules like salicylic acid (SA), jasmonic acid (JA), ethylene (ET), abscisic acid (ABA), reactive oxygen species (ROS) and glutathione (GSH) play key role in plant defense response. To obtain further insight into the mechanism through which GSH is involved in this crosstalk to mitigate biotic stress, transgenic Nicotiana tabacum overexpressing Lycopersicon esculentum gamma-glutamylcysteine synthetase (LeECS) gene (NtGB lines) were generated with enhanced level of GSH in comparison with wild-type plants exhibiting resistance to pathogenesis as well. The expression levels of non-expressor of pathogenesis-related genes 1 (NPR1)-dependent genes like pathogenesis-related gene 1 (NtPR1), mitogen-activated protein kinase kinase (NtMAPKK), glutamine synthetase (NtGLS) were significantly enhanced alongwith NtNPR1. However, the expression levels of NPR1-independent genes like NtPR2, NtPR5 and short-chain dehydrogenase/reductase family protein (NtSDRLP) were either insignificant or were downregulated. Additionally, increase in expression of thioredoxin (NtTRXh), S-nitrosoglutathione reductase 1 (NtGSNOR1) and suppression of isochorismate synthase 1 (NtICS1) was noted. Comprehensive analysis of GSH-fed tobacco BY2 cell line in a time-dependent manner reciprocated the in planta results. Better tolerance of NtGB lines against biotrophic Pseudomonas syringae pv. tabaci was noted as compared to necrotrophic Alternaria alternata. Through two-dimensional gel electrophoresis (2-DE) and image analysis, 48 differentially expressed spots were identified and through identification as well as functional categorization, ten proteins were found to be SA-related. Collectively, our results suggest GSH to be a member in cross-communication with other signaling molecules in mitigating biotic stress likely through NPR1-dependent SA-mediated pathway.     

A Report on the ‘51st Annual Conference of Association of Microbiologists of India (AMI) (December 14–17, 2010; Venue: Birla Institute of Technology,Mesra, Ranchi,India)

Indian Journal of Microbiology -     

Drug resistance in epilepsy and the ABCB1 gene: The clinical perspective

Multidrug resistance is one of the most serious problems in the treatment of epilepsy that is likely to have a complex genetic and acquired basis. Various experimental data support the hypothesis that over-expression of antiepileptic drug (AED) transporters may play a pivotal role in drug resistance. Hyyt 6however, key questions concerning their functionality remain unanswered. The idea that P-glycoprotein, encoded by the ABCB1 gene, might mediate at least part of the drug resistance was met with both enthusiasm and skepticism. As in oncology, initial optimism has been clouded subsequently by conflicting results. The first study reporting a positive association between genetic variation in the P-glycoprotein and multidrug-resistant epilepsy was published in 2003. Since then, several other genetic association studies have attempted to verify this result. However, taken overall, the role of P-glycoprotein in drug resistance in epilepsy still remains uncertain. We intend to critically review the inherent problems associated with epilepsy pharmacogenetic studies in general and with ABCB1 polymorphisms studies in particular. The lessons learnt from the ABCB1 studies can help us to guide future association genetics studies to investigate AED resistance, and thereby taking us closer to the cherished dream of personalized AED therapy.     

Functional co-evolutionary study of glucosamine-6-phosphate synthase in mycoses causing fungi

Invasive fungal opportunistic infections or mycoses have been on the rise with increase in the number of immuno-compromised patients accounting for associated high morbidity and mortality rates. The antifungal drugs are not completely effective due to increased resistance and varied susceptibility of fungi. Hence, the functional diversification study of novel targets has to be carried out. The enzyme glucosamine-6-phosphate synthase [EC 2.6.1.16], a novel drug target, catalyzes the rate-limiting step of the fungal cell-wall biosynthetic pathway, comprising four conserved domains, two glutaminase and sugar-isomerising (SIS) domains with active site. The amino acids within these domains tend to mutate simultaneously and exert mutual selective forces which might result in untoward fungal adaptations that are fixed through random genetic drift over time. The current study is an attempt to investigate such 'non-independent' coevolving residues which play critical functional and structural role in the protein. Residues with Shannon entropy ≦1 (calculated by the Protein Variability Server) were considered and subsequently, positional correlations were estimated by InterMap3D 1.3 server. It was observed that majority of coevolving pairs of first SIS domain involved interactions with hydrophobic leucine and found to be spatially coupled in 3-dimensional structure of the enzyme. The coevolving groups of Aspergillus niger and Rhizopus oryzae species might play a role in drug resistance. Such coevolutionary analysis is important for understanding the receptor-ligand interactions and effective drug designing.     

Vibrio cholerae hemolysin. Implication of amphiphilicity and lipid-induced conformational change for its pore-forming activity.

Vibrio cholerae hemolysin (HlyA), a water-soluble protein with a native monomeric relative molecular mass of 65 000, forms transmembrane pentameric channels in target biomembranes. The HlyA binds to lipid vesicles nonspecifically and without saturation; however, self-assembly is triggered specifically by cholesterol. Here we show that the HlyA partitioned quantitatively to amphiphilic media irrespective of their compositions, indicating that the toxin had an amphiphilic surface. Asialofetuin, a beta1-galactosyl-terminated glycoprotein, which binds specifically to the HlyA in a lectin-glycoprotein type of interaction and inhibits carbohydrate-independent interaction of the toxin with lipid, reduced effective amphiphilicity of the toxin significantly. Resistance of the HlyA to proteases together with the tryptophan fluorescence emission spectrum suggested a compact structure for the toxin. Fluorescence energy transfer from the HlyA to dansyl-phosphatidylethanolamine required the presence of cholesterol in the lipid bilayer and was synchronous with oligomerization. Phospholipid bilayer without cholesterol caused a partial unfolding of the HlyA monomer as indicated by the transfer of tryptophan residues from the nonpolar core of the protein to a more polar region. These observations suggested: (a) partitioning of the HlyA to lipid vesicles is driven by the tendency of the amphiphilic toxin to reduce energetically unfavorable contacts with water and is not affected significantly by the composition of the vesicles; and (b) partial unfolding of the HlyA at the lipid-water interface precedes and promotes cholesterol-induced oligomerization to an insertion-competent configuration.