Tyrosine Nitration of PA700 Links Proteasome Activation to Endothelial Dysfunction in Mouse Models with Cardiovascular Risk Factors

Oxidative stress is believed to cause endothelial dysfunction, an early event and a hallmark in cardiovascular diseases (CVD) including hypertension, diabetes, and dyslipidemia. However, the targets for oxidative stress-mediated endothelial dysfunction in CVD have not been completely elucidated. Here we report that 26S proteasome activation by peroxynitrite (ONOO−) is a common pathway for endothelial dysfunction in mouse models of diabetes, hypertension, and dyslipidemia. Endothelial function, assayed by acetylcholine-induced vasorelaxation, was impaired in parallel with significantly increased 26S proteasome activity in aortic homogenates from streptozotocin (STZ)-induced type I diabetic mice, angiotensin-infused hypertensive mice, and high fat-diets -fed LDL receptor knockout (LDLr−/−) mice. The elevated 26S proteasome activities were accompanied by ONOO−-mediated PA700/S10B nitration and increased 26S proteasome assembly and caused accelerated degradation of molecules (such as GTPCH I and thioredoxin) essential to endothelial homeostasis. Pharmacological (administration of MG132) or genetic inhibition (siRNA knockdown of PA700/S10B) of the 26S proteasome blocked the degradation of the vascular protective molecules and ablated endothelial dysfunction induced by diabetes, hypertension, and western diet feeding. Taken together, these results suggest that 26S proteasome activation by ONOO−-induced PA700/S10B tyrosine nitration is a common route for endothelial dysfunction seen in mouse models of hypertension, diabetes, and dyslipidemia

Diagnostic guidelines for the histological particle algorithm in the periprosthetic neo-synovial tissue

Background The identification of implant wear particles and non-implant related particles and the characterization of the inflammatory responses in the periprosthetic neo-synovial membrane, bone, and the synovial-like interface membrane (SLIM) play an important role for the evaluation of clinical outcome, correlation with radiological and implant retrieval studies, and understanding of the biological pathways contributing to implant failures in joint arthroplasty. The purpose of this study is to present a comprehensive histological particle algorithm (HPA) as a practical guide to particle identification at routine light microscopy examination. Methods The cases used for particle analysis were selected retrospectively from the archives of two institutions and were representative of the implant wear and non-implant related particle spectrum. All particle categories were described according to their size, shape, colour and properties observed at light microscopy, under polarized light, and after histochemical stains when necessary. A unified range of particle size, defined as a measure of length only, is proposed for the wear particles with five classes for polyethylene (PE) particles and four classes for conventional and corrosion metallic particles and ceramic particles. Results All implant wear and non-implant related particles were described and illustrated in detail by category. A particle scoring system for the periprosthetic tissue/SLIM is proposed as follows: 1) Wear particle identification at light microscopy with a two-step analysis at low (× 25, × 40, and × 100) and high magnification (× 200 and × 400); 2) Identification of the predominant wear particle type with size determination; 3) The presence of non-implant related endogenous and/or foreign particles. A guide for a comprehensive pathology report is also provided with sections for macroscopic and microscopic description, and diagnosis. Conclusions The HPA should be considered a standard for the histological analysis of periprosthetic neo-synovial membrane, bone, and SLIM. It provides a basic, standardized tool for the identification of implant wear and non-implant related particles at routine light microscopy examination and aims at reducing intra-observer and inter-observer variability to provide a common platform for multicentric implant retrieval/radiological/histological studies and valuable data for the risk assessment of implant performance for regional and national implant registries and government agencies

Pledging integrity:Oaths as forms of business management

The global financial crisis has led to a surprising interest in professional oaths in business. Examples are the MBA Oath (Harvard Business School), the Economist’s Oath (George DeMartino) and the Dutch Banker’s Oath, which senior executives in the financial services industry in the Netherlands have been obliged to swear since 2010. This paper is among the first to consider oaths from the perspective of business ethics. A framework is presented for analysing oaths in terms of their form, their content and the specific contribution they make to business ethics management: oaths may foster professionalism, facilitate moral deliberation and enhance compliance. This framework is used to analyse and evaluate the MBA Oath, the Economist’s Oath and the Banker’s Oath as well as various other similar initiatives