RAGE: a new frontier in chronic airways disease

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand–RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions.     

Redefining the R1 resection for pancreatic ductal adenocarcinoma: tumour lymph nodal burden and lymph node ratio are the only prognostic factors associated with survival

Introduction: The presence of positive nodal disease (LND) and the number of lymph nodes involved (LNB) are known to be significant prognostic markers for resected adenocarcinoma of the pancreas. In addition, the ratio of the number of involved nodes to the number of nodes resected known as the lymph node ratio (LNR) is emerging as an important prognostic marker. The role of the resection margin (RM) as presently defined (R1 ≤ 1 mm) is unclear as results differ based on the dataset. The aim of this study was to assess the impact of nodal disease and a redefined RM on outcome.Material and methods: Retrospective analysis of pancreatic head resections for adenocarcinomas from 2003–2009. The RM was re-analysed based on tumour clearance and categorized into: histopathological evidence of a tumour; ≤0.5 mm, ≤1 mm, ≤1.5 mm, or ≤2.0 mm of the actual surgical resection margin. The impact of histopathological variables on cancer-specific survival (CSS) and disease-free survival (DFS) was analysed.Results: LND, LNB and LNR were independent prognostic markers for CSS (P = 0.048, 0.003, 0.016) but, did not influence DFS. A LNR < 0.143 was associated with a higher CSS [38.16 ± 4.69 versus 20.59 ± 2.20 months, P = 0.0042, hazard ratio (HR) 3.74 (95% confidence interval (CI) 1.52–9.23)]. An R1 RM was not associated with CSS or DFS on multivariate analysis, irrespective of the distance. LNB and LNR maintained independent significance irrespective of the size of the RM.Conclusion: LNB and LNR are the only prognostic factors for CSS in patients with pancreatic head adenocarcinoma, but do not predict recurrence. Microscopic RMs does not seem to influence the outcome even when redefined. Further prospective studies are indicated to substantiate these findings.     

Chemometric Evaluation of Near Infrared,Fourier Transform Infrared,and Raman Spectroscopic Models for the Prediction of Nimodipine Polymorphs

The objective of this study was to assess the performance of the chemometric model to predict the proportion of the recrystallized polymorphs of nimodipine from the cosolvent formulations. Ranging from 100% to 0% (w/w) of polymorph I, the two polymorphs mixtures were prepared and characterized spectroscopically using Fourier transformed infrared spectroscopy (FTIR), near-infrared spectroscopy (NIR), and Raman spectroscopy. Instrumental responses were treated to construct multivariate calibration model using principal component regression (PCR) and partial least square regression approaches. Treated data showed better model fitting than without treatment, which demonstrated higher correlation coefficient (R²) and lower root mean square of standard error (RMSE) and standard error (SE). Multiple scattering correction and standard normal variate exhibited higher R² and lower RMSE and SE values than second derivative. Goodness of fit for FTIR and NIR (R² ~ 0.99) data was better than Raman (R² ~ 0.95). Furthermore, the models were applied on the recrystallized polymorphs obtained by storing nimodipine-cosolvent formulations at selected stability conditions. The relative composition of the polymorphs differed with storage conditions. NIR-chemical imaging on recrystallized sample of nimodipine at 15°C qualitatively corroborated the model-based prediction of the two polymorphs. Therefore, these studies strongly suggest the importance of the potential utility of the chemometric model in predicting nimodipine polymorphs.     

Prophylactic Peritoneal Dialysis After the Arterial Switch Operation: A Retrospective Cohort Study

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Novel Risk Factors for Progression of Diabetic and Nondiabetic CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study

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Quasi-reversible two-electron reduction of oxygen at iodine submonolayer-coated gold electrode in alkaline media

Oxygen reduction reaction (ORR) was investigated using polycrystalline gold (Au (poly)) electrode modified with chemisorbed iodine (I_(ads)) submonolayer (sub I_(ads)) in O₂-saturated 0.1 M KOH solution. The sub I_(ads) was tailored by potential-dependent partial reductive desorption of I_(ads) from its full monolayer. The Au (1 1 1) facet of the Au (poly) electrode was considered to remain bared at the sub I_(ads)/Au (poly) electrode. The interesting finding of the present study is that (unlike the bare Au (poly) electrode) the sub I_(ads)/Au (poly) electrode exhibited a quasi-reversible two-electron reduction of O₂ in alkaline media. The probable origin of the observed quasi-reversible behavior of the ORR is discussed. Experimental investigations were performed using cyclic and steady-state voltammetric, amperometric and coulometric techniques.