Glucose-induced cellular dysfunction: The role of protein kinase C.

This thesis is divided into four sections. The first section contains the introductory overview in which I review the previous hypotheses that have implicated high extracellular glucose concentrations in the pathogenesis of cellular dysfunction and injury. These previous studies set the stage for the presentation of my work in which I have explored the novel hypothesis that glucose-induced protein kinase C activation may provide a final common path for many aspects of cellular dysfunction in diabetes mellitus. The second section contains my published works which reported the first detailed characterisation of glucose-induced protein kinase C activity and subsequently explored the potential biological significance of this ubiquitous intracellular signalling pathway with regard to a variety of pathophysiological changes in cell function. The third section of this thesis also contains my published works which illustrate how my studies have subsequently developed with specific reference to our description of the potentially important role of a recently discovered vascular permeability factor in the development of vascular dysfunction in diabetes mellitus. This section culminates in the presentation of my latest study which has just been submitted for publication to the Journal of Clinical Investigation. This study demonstrates that high extracellular glucose concentrations directly stimulate vascular permeability gene expression and peptide production by human vascular smooth muscles via a protein kinase C-dependent mechanism. In so doing, this latest study illustrates the consistency of the theme that began and continues throughout this thesis; notably, the role of protein kinase C in mediating many diverse aspects of glucose-induced cellular dysfunction. Finally, in section four, I conclude the thesis by reviewing the main features of the published works contained within it and I describe how future work could extend these observations and provide the basis for possible new therapeutic interventions designed to attenuate glucose-induced cellular injury

MOESM1 of Understanding immune phenotypes in human gastric disease tissues by multiplexed immunohistochemistry

Additional file 1. Supplemental methods, supplementary tables for patients. Figure S1. H&E staining of the two TMAs. Figure S2. Comparison of the results of ImageJ software and the score by pathologists

Biochemical Screening for Nonadherence Is Associated With Blood Pressure Reduction and Improvement in Adherence.

We hypothesized that screening for nonadherence to antihypertensive treatment using liquid chromatography-tandem mass spectrometry-based biochemical analysis of urine/serum has therapeutic applications in nonadherent hypertensive patients. A retrospective analysis of hypertensive patients attending specialist tertiary care centers was conducted in 2 European countries (United Kingdom and Czech Republic). Nonadherence to antihypertensive treatment was diagnosed using biochemical analysis of urine (United Kingdom) or serum (Czech Republic). These results were subsequently discussed with each patient, and data on follow-up clinic blood pressure (BP) measurements were collected from clinical files. Of 238 UK patients who underwent biochemical urine analysis, 73 were nonadherent to antihypertensive treatment. Their initial urinary adherence ratio (the ratio of detected to prescribed antihypertensive medications) increased from 0.33 (0-0.67) to 1 (0.67-1) between the first and the last clinic appointments. The observed increase in the urinary adherence ratio in initially nonadherent UK patients was associated with the improved BP control; by the last clinic appointment, systolic and diastolic BPs were ≈19.5 and 7.5 mm Hg lower than at baseline (P=0.001 and 0.009, respectively). These findings were further corroborated in 93 nonadherent hypertensive patients from Czech Republic-their average systolic and diastolic BPs dropped by ≈32.6 and 17.4 mm Hg, respectively (P<0.001), on appointments after the biochemical analysis. Our data show that nonadherent hypertensive patients respond to liquid chromatography-tandem mass spectrometry-based biochemical analysis with improved adherence and significant BP drop. Such repeated biochemical analyses should be considered as a therapeutic approach in nonadherent hypertensive patients