An Exploratory Analysis of Voice Hearing in Chronic PTSD: Potential Associated Mechanisms

This research investigated auditory hallucinations (AH) in a sample with chronic posttraumatic stress disorder (PTSD) and examined dissociation and thought suppression as potential associated mechanisms. In all, 40 individuals with PTSD were assessed on the hallucinations subscale of the Positive and Negative Syndrome Scale and on measures of dissociation and thought suppression. Half of the sample reported AH (n = 20, 50%). Those reporting AH had higher general and pathological dissociation scores but did not differ on thought suppression or PTSD symptom severity. Results suggest that (a) AH in chronic PTSD is not a rare phenomenon, (b) dissociation is significantly related to AH, and (c) dissociation may be a potential mediating mechanism for AH in PTSD.

Mechanisms of modified LDL-induced pericyte loss and retinal injury in diabetic retinopathy

Aims/hypothesis: In previous studies we have shown that extravasated, modified LDL is associated with pericyte loss, an early feature of diabetic retinopathy (DR). Here we sought to determine detailed mechanisms of this LDLinduced pericyte loss.

Methods: Human retinal capillary pericytes (HRCP) were exposed to ‘highly-oxidised glycated’ LDL (HOG-LDL) (a model of extravasated and modified LDL) and to 4-hydroxynonenal or 7-ketocholesterol (components of oxidised LDL), or to native LDL for 1 to 24 h with or without 1 h of pretreatment with inhibitors of the following: (1) the scavenger receptor (polyinosinic acid); (2) oxidative stress (N-acetyl cysteine); (3) endoplasmic reticulum (ER) stress (4-phenyl butyric acid); and (4) mitochondrial dysfunction (cyclosporin A). Oxidative stress, ER stress, mitochondrial dysfunction, apoptosis and autophagy were assessed using techniques including western blotting, immunofluorescence, RT-PCR, flow cytometry and TUNEL assay. To assess the relevance of the results in vivo, immunohistochemistry was used to detect the ER stress chaperon, 78 kDa glucose-regulated protein, and the ER sensor, activating transcription factor 6, in retinas from a mouse model of DR that mimics exposure of the retina to elevated glucose and elevated LDL levels, and in retinas from human participants with and without diabetes and DR.

Results: Compared with native LDL, HOG-LDL activated oxidative and ER stress in HRCP, resulting in mitochondrial dysfunction, apoptosis and autophagy. In a mouse model of diabetes and hyperlipidaemia (vs mouse models of either condition alone), retinal ER stress was enhanced. ER stress was also enhanced in diabetic human retina and correlated with the severity of DR.

Conclusions/interpretation: Cell culture, animal, and human data suggest that oxidative stress and ER stress are induced by modified LDL, and are implicated in pericyte loss in DR.

Glycation, glycoxidation, and cross-linking of collagen by glucose. Kinetics, mechanisms, and inhibition of late stages of the Maillard reaction

The Maillard or browning reaction between sugar and protein contributes to the increased chemical modification and cross-linking of long-lived tissue proteins in diabetes. To evaluate the role of glycation and oxidation in these reactions, we have studied the effects of oxidative and antioxidative conditions and various types of inhibitors on the reaction of glucose with rat tail tendon collagen in phosphate buffer at physiological pH and temperature. The chemical modifications of collagen that were measured included fructoselysine, the glycoxidation products N epsilon-(carboxymethyl)lysine and pentosidine and fluorescence. Collagen cross-linking was evaluated by analysis of cyanogen bromide peptides using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by changes in collagen solubilization on treatment with pepsin or sodium dodecylsulfate. Although glycation was unaffected, formation of glycoxidation products and cross-linking of collagen were inhibited by antioxidative conditions. The kinetics of formation of glycoxidation products proceeded with a short lag phase and were independent of the amount of Amadori adduct on the protein, suggesting that autoxidative degradation of glucose was a major contributor to glycoxidation and cross-linking reactions. Chelators, sulfhydryl compounds, antioxidants, and aminoguanidine also inhibited formation of glycoxidation products, generation of fluorescence, and cross-linking of collagen without significant effect on the extent of glycation of the protein. We conclude that autoxidation of glucose or Amadori compounds on protein plays a major role in the formation of glycoxidation products and cross-liking of collagen by glucose in vitro and that chelators, sulfhydryl compounds, antioxidants, and aminoguanidine act as uncouplers of glycation from subsequent glycoxidation and cross-linking reactions.

GHMP Kinases - Structures, Mechanisms and Potential for Therapeutically Relevant Inhibition

The GHMP kinases are a structurally related family of small molecule kinases named after four of its members - galactokinase, homoserine kinase, mevalonate kinase and phosphomevalonate kinase. The group also includes the enzymes N-acetylgalactosamine kinase, arabinose kinase, mevalonate 5-diphosphate decarboxylase, archeal shikimate kinase and 4-(cytidine 5'-diphospho)-2-c-methyl-D-erythritol kinase. In addition the group includes two members not known to be catalytically active, the Caenorhabditis elegans sex-fate determining protein XOL-1 and the Saccharomyces cerevisiae transcriptional activator Gal3p. Two catalytic mechanisms have been proposed for GHMP kinases. The structure of mevalonate kinase suggests that an aspartate residue acts as an active site base, removing a proton from the substrate to facilitate attack on the ? phosphate of MgATP. In contrast, in homoserine kinase there is no potential catalytic base and it is proposed that catalysis is driven by transition state stabilisation. Potential chemotherapeutic interventions against GHMP kinases fall into three main categories: inhibition of galactokinase to assist suffers of galactosemia, inhibition of mevalonate kinase or mevalonate 5-diphosphate decarboxylase to reduce flux through the cholesterol biosynthesis pathway and inhibition of bacterial GHMP kinases for novel anti-microbial therapies. These are in the early stages of development, but the accumulation of structural and mechanistic data will assist future progress.

Influence of test methodology and probe geometry on nanoscale fatigue mechanisms of diamond-like carbon thin film

The aim of this paper is to investigate the mechanism of nanoscale fatigue using nano-impact and multiple-loading cycle nanoindentation tests, and compare it to previously reported findings of nanoscale fatigue using integrated stiffness and depth sensing approach. Two different film loading mechanism, loading history and indenter shapes are compared to comprehend the influence of test methodology on the nanoscale fatigue failure mechanisms of DLC film. An amorphous 100 nm thick DLC film was deposited on a 500 μm silicon substrate using sputtering of graphite target in pure argon atmosphere. Nano-impact and multiple-load cycle indentations were performed in the load range of 100 μN to 1000 μN and 0.1 mN to 100 mN, respectively. Both test types were conducted using conical and Berkovich indenters. Results indicate that for the case of conical indenter, the combination of nano-impact and multiple-loading cycle nanoindentation tests provide information on the life and failure mechanism of DLC film, which is comparable to the previously reported findings using the integrated stiffness and depth sensing approach. However, the comparison of results is sensitive to the applied load, loading mechanism, test-type and probe geometry. The loading mechanism and load history is therefore critical which also leads to two different definitions of film failure. The choice of exact test methodology, load and probe geometry should therefore be dictated by the in-service tribological conditions, and where necessary both test methodologies can be used to provide better insights of failure mechanism. Molecular dynamics (MD) simulations of the elastic response of nanoindentation is reported, which indicates that the elastic modulus of the film measured using MD simulation was higher than that experimentally measured. This difference is attributed to the factors related to the presence of material defects, crystal structure, residual stress, indenter geometry and loading/unloading rate differences between the MD and experimental results.

Corporate Mechanisms and the Presumption of Accountability

This paper seeks to draw out this focus on form in British public administration reform by focusing on the role that the idea of the corporate form has played in reform. Drawing on the codification of Foundation Trusts in the English NHS, I argue that, while accountability ought to be considered as a 'social space' in which conduct conducive to particular interests emerges, reformers tend to regard accountability as a function of appropriate procedures and forms. The turn to the corporate form relies on a hope that it will deliver various 'accountability' benefits will emerge. This hope, I argue, is misplaced