Computer simulated screening of dentin bonding primer monomers through analysis of their chemical functions and their spatial 3D alignment

Binding interactions between dentin bonding primer monomers and dentinal collagen were studied by an analysis of their chemical functions and their spatial 3D alignment. A trial set of 12 monomers used as primers in dentin adhesives was characterized to assess them for binding to a complementary target. HipHop utility in the Catalyst software from Accelrys was used for the study. Ten hypotheses were generated by HipHop procedures involving (a) conformational generation using a poling technique to promote conformational variation, (b) extraction of functions to remodel ligands as function-based structures, and (c) identification of common patterns of functional alignment displayed by low energy conformations. The hypotheses, designated as pharmacaphores, were also scored and ranked. Analysis of pharmacaphore models through mapping of ligands revealed important differences between ligands. Top-ranked poses from direct docking simulations using type 1 collagen target were mapped in a rigid manner to the highest ranked pharmacophore model. The visual match observed in mapping and associated fit values suggest a strong correspondence between direct and indirect docking simulations. The results elegantly demonstrate that an indirect approach used to identify pharmacaphore models from adhesive ligands without a target may be a simple and viable approach to assess their intermolecular interactions with an intended target. Inexpensive indirect/direct virtual screening of hydrophilic monomer candidates may be a practical way to assess their initial promise for dentin primer use well before additional experimental evaluation of their priming/bonding efficacy. This is also of value in the search/design of new compounds for priming dentin.     

Receptor for AGE (RAGE) and its ligands—cast into leading roles in diabetes and the inflammatory response

The actors in the pathogenesis of diabetes and its complications are many and multifaceted. The effects of elevated levels of glucose are myriad; among these is the generation of advanced glycation end products (AGEs), the products of nonenzymatic glycoxidation of proteins and lipids. The finding that AGEs stimulate signal transduction cascades through the multiligand receptor RAGE unveiled novel insights into diabetes and its complications. Inextricably woven into AGE–RAGE interactions in diabetes is the engagement of the innate and adaptive immune responses. Although glucose may be the triggering stimulus to draw RAGE into diabetes pathology, consequent cellular stress results in release of proinflammatory RAGE ligands S100/calgranulins and HMGB1. We predict that once RAGE is engaged in the diabetic tissue, a vicious cycle of ligand–RAGE perturbation ensues, leading to chronic tissue injury and suppression of repair mechanisms. Targeting RAGE may be a beneficial strategy in diabetes, its complications, and untoward inflammatory responses.     

An improved selective and differential medium for the isolation of Burkholderia pseudomallei from clinical specimens

Isolation and culture of Burkholderia pseudomallei remains the main stay in the diagnosis of melioidosis. Thus, the search for selective and differential media for B. pseudomallei has been ongoing. A number of such media have been reported with varying efficacy. Ashdown medium is the most established selective medium for the isolation of B. pseudomallei. There are no reports of differential media differentiating B. pseudomallei from Burkholderia cepacia. This report documents such a selective and differentiating medium for B. pseudomallei. Of a total of 1042 clinical specimens containing mixed flora and gram-negative isolates that were tested on this medium, 16 of the specimens yielded B. pseudomallei. The isolation rate was found to be 1.5%. This medium was found to be simple and inexpensive, can be made by small laboratories, and called as Francis medium. Based on the colony morphology and color, a preliminary report can be made within 18-24 h for the presence of B. pseudomallei. Our study showed that this medium had an overall sensitivity of 78.4% with a specificity of 92.2%. The use of this medium as an early diagnostic tool will help to reduce mortality and morbidity of melioidosis patients.     

The biology of RAGE and its ligands: Uncovering mechanisms at the heart of diabetes and its complications

The interaction of glucose-modified and inflammation-promoting ligands with the receptor for advanced glycation end products (RAGE) is emerging as a central mechanism contributing to the diverse complications of diabetes. These ligands, particularly in oligomeric form, bind to RAGE and transduce intracellular signals. The consequences of this interaction, as elucidated in cultured cells and animal models, include upregulation of inflammatory and tissue-degradative pathways. Pharmacologic antagonism of RAGE may hold promise for the treatment of diabetic complications.     

Effect of early caffeine on neurodevelopmental outcome of very low-birth weight newborns

Objectives: The objective of this study is to evaluate the effect of early caffeine therapy started within the first 48?h of life on neurodevelopmental outcome in very low birth weight (VLBW) newborns.

Study design: VLBW newborns received either caffeine therapy within first 48?h of life (Early group), after 3rd day of life (Late group) or no caffeine during first month of life as per clinical team. A cohort of these newborns (n?=?160) who survived were evaluated using Bayley Scale of Infant Development III (BSID III) developmental testing between 18 and 22 months of corrected age.

Results: VLBW newborns in the “Early group” had significantly better composite, cognitive, language and motor BSID III scores as compared to those in “Late group” and no caffeine group. Composite BSID III scores were unchanged in the presence or absence of chorioamnionitis for “Early group”, while the BSID III scores were significantly lower in the presence of acute chorioamnionitis in “Late group” and no caffeine group.

Conclusions: Early caffeine therapy was associated with better BSID III scores in a cohort of VLBW newborns. Newborns with acute chorioamnionitis benefited from early caffeine therapy.