Very late antigen-4 in CD18-independent neutrophil emigration during acute bacterial pneumonia in mice

This study tested the hypothesis that very late antigen (VLA)-4 mediates CD18-independent neutrophil emigration into the airspaces induced by either Streptococcus pneumoniae, a stimulus that induces primarily CD18-independent neutrophil emigration, or Escherichia coli, toward which only 20-30% of the total number of neutrophils emigrate through CD18-independent pathways. In wild-type (WT) mice, VLA-4 expression was less on neutrophils that emigrated into the airspaces than on circulating neutrophils. Vascular cell adhesion molecule-1 (VCAM-1) mRNA, the major endothelial cell ligand for VLA-4, increased more in E. coli than in S. pneumoniae pneumonia. VCAM-1 protein expression was not detected in capillaries, the major site of neutrophil emigration. Neutrophil emigration during E. coli or S. pneumoniae pneumonia was similar in mice given antibodies against both CD18 and VLA-4 compared with mice given the anti-CD18 antibody and a control antibody. However, in hematopoietically reconstituted mice with both WT and CD18-deficient neutrophils in their blood, the migration of CD18-deficient neutrophils in response to S. pneumoniae was slightly but significantly less in animals pretreated with the anti-VLA-4 antibody than in those receiving a control antibody. These data suggest that VLA-4 plays a small role in CD18-independent neutrophil emigration, but the majority of CD18-independent neutrophil emigration induced by bacteria in the lungs occurs through VLA-4-independent mechanisms.     

The life cycle of the steroidogenic acute regulatory (StAR) protein: from transcription through proteolysis

The Steroidogenic Acute Regulatory (StAR) protein is a mitochondrial protein required for the transport of cholesterol substrate to the P450scc enzyme located in the inner mitochondrial membranes of steroid producing cells. This study suggests that the acute regulation of the rodent StAR gene in the ovary is mediated by two factors, C/EBPbeta and GATA-4. Once translated, the StAR precursor protein is either imported into the mitochondria, or it is rapidly degraded in the cytosol. We predicted that in order to perpetuate StAR activity cycles, imported StAR should turn over rapidly to avoid a potentially harmful accumulation of the protein in sub-mitochondrial compartments. Pulse-chase experiments in metabolically labeled cells showed that: (a) the turnover rate of mature mitochondrial StAR protein (30 kDa) is much faster (t(1/2) = 4-5 h) than that of other mitochondrial proteins; (b) dissipation of the inner membrane potential (-delta psi) by carbonyl cyanide m-chlorophenylhydrazone (mCCCP) accelerates the mitochondrial degradation of StAR; (c) unexpectedly, the mitochondrial degradation of StAR is inhibited by MG132 and lactacystin, but not by epoxomicin. Furthermore, StAR degradation becomes inhibitor-resistant two hours after import. Therefore, these studies suggest a bi-phasic route of StAR turnover in the mitochondria. Shortly after import, StAR is degraded by inhibitor-sensitive protease(s) (phase I), whereas at later times, StAR turnover proceeds to completion through an MG132-resistant proteolytic activity (phase II). Collectively, this study defines StAR as a unique protein that can authentically be used to probe multiple proteolytic activities in mammalian mitochondria.     

Rural family medicine training site: Proposed framework

Objective

To develop a framework for a successful rural family medicine training program and to assess the potential for a rural family medicine residency training program using the Weyburn and Estevan areas of Saskatchewan as test sites.

Design

A mixed-method design was used; however, the focus of this article was on the qualitative data collected. Questions formulated for the semistructured interviews evolved from the literature.

Setting

Rural Saskatchewan.

Participants

Community physicians and representatives from the Sun Country Regional Health Authority, the Saskatchewan Ministry of Health, and the University of Saskatchewan.

Methods

The data were documented during the interviews using a laptop computer, and the responses were reviewed with participants at the end of their interviews to ensure accuracy. The qualitative data collected were analyzed using inductive thematic analysis.

Main findings

Through the analysis of the data several themes emerged related to implementing a rural family medicine residency training program. Key predictors of success were physical resources, physician champions, physician teachers, educational support, administrative support, and other specialist support. Barriers to the development of a rural family medicine training site were differing priorities, lack of human resources, and lack of physical resources.

Conclusion

A project of this magnitude requires many people at different levels collaborating to be successful.     

Reduction of QTD - A Novel Marker of Successful Reperfusion in NSTEMI. Pathophysiologic Insights by CMR

Background/Objectives: Non-ST segment elevation myocardial infarction (MI) poses similar detrimental long-term prognosis as ST-segment elevation MI. No marker on ECG is established to predict successful reperfusion in NSTEMI. QT dispersion is increased by myocardial ischemia and reduced by successful restoration of epicardial blood flow by PCI. Whether QT dispersion reduction translates to smaller infarcts and thus indicates successful reperfusion is unknown.We hypothesized that the relative reduction of QT dispersion (QTD-R_rel ) on a standard ECG in acutely reperfused NSTEMI is related to infarct size and infarct transmurality as assessed by delayed enhancement CMR (DE-CMR).Methods and Results: 69 patients with a first acute NSTEMI were included. QTD-R_rel was stratified according to LV function and volumes, infarct transmurality and size as assessed by DE-CMR. Extensive myocardial infarction was defined as above median infarct size.LV function and end-systolic volume were only mildly related to QTD-R_rel . QTD-R_rel was inversely related to infarct size (r=-0.506,p=0.001) and infarct transmurality (r=-0.415, p=0.001). QTD-R_rel was associated with extensive myocardial infarction in univariate analysis (odds ratio (OR) 0.958, CI 0.935-0.982; p=0.001). Compared to clinical and angiographic data QTD-R_rel remained the only independent predictor of non-transmural infarcts (OR 1.110, CI 1.055-1.167; p=0.049).Conclusion: In patients with acute Non-ST-Segment Myocardial infarction QTd-R_rel calculated on a surface ECG prior and post PCI for restoration of epicardial blood flow detects small, non-transmural infarcts as assessed by delayed enhancement CMR. Thus, QTd-R_rel can indicate successful reperfusion therapy.