Serum heparan sulfate levels are elevated in endotoxemia

<p>Abstract</p> <p>Background</p> <p>Increased vascular permeability is a characteristic feature of sepsis which, in the past, has been ascribed exclusively to a malfunction of endothelial cells. However, recently it has become evident that the endothelial glycocalyx is of considerable importance concerning various aspects of vascular physiology, e.g. the vascular barrier and inflammation. Heparan sulfate, one of its essential components is characteristically traceable in blood, in case the endothelial glycocalyx is damaged or destroyed.</p> <p>Methods</p> <p>In 15 pigs we investigated whether the administration of endotoxin from gram-negative bacteria (Escherichia coli) results in increased serum levels of heparan sulfate, signalizing a shedding of the glycocalyx. In addition, markers of inflammation (white blood cell count, platelet count, tumour necrosis factor-α and interleukin-6) were evaluated over an observation period of 6 hours.</p> <p>Results</p> <p>Serum heparan sulfate concentrations significantly increased over time in the endotoxin group and were significantly elevated in comparison to the control group 6 hours after administration of endotoxin (p < 0.001). In the endotoxin group all markers of inflammation significantly changed during the time course.</p> <p>Conclusions</p> <p>The administration of bacterial endotoxin induced a significant rise in degradation products of the endothelial glycocalyx.</p

Improved ventricular function during inhalation of PGI(2) aerosol partly relies on enhanced myocardial contractility

Inhaled prostacyclin (PGI(2)) aerosol induces selective pulmonary vasodilation. Further, it improves right ventricular ( RV) function, which may largely rely on pulmonary vasodilation, but also on enhanced myocardial contractility. We investigated the effects of the inhaled PGI(2) analogs epoprostenol (EPO) and iloprost (ILO) on RV function and myocardial contractility in 9 anesthetized pigs receiving aerosolized EPO (25 and 50 ng center dot kg(-1) center dot min(-1)) and, consecutively, ILO (60 ng center dot kg(-1) center dot min(-1)) for 20 min each. We measured pulmonary artery pressure ( PAP), RV ejection fraction (RVEF) and RV end-diastolic-volume (RV-EDV), and left ventricular end-systolic pressure-volume-relation (end-systolic elastance, E-es). EPO and ILO reduced PAP, increased RVEF and reduced RVEDV. E-es was enhanced during all doses tested, which reached statistical significance during EPO25ng and ILO, but not during EPO50ng. PGI(2) aerosol enhances myocardial contractility in healthy pigs, contributing to improve RV function. Copyright (C) 2005 S. Karger AG, Basel

Kinetic modelling of competition and depletion of shared miRNAs by competing endogenous RNAs

Non-conding RNAs play a key role in the post-transcriptional regulation of mRNA translation and turnover in eukaryotes. miRNAs, in particular, interact with their target RNAs through protein-mediated, sequence-specific binding, giving rise to extended and highly heterogeneous miRNA-RNA interaction networks. Within such networks, competition to bind miRNAs can generate an effective positive coupling between their targets. Competing endogenous RNAs (ceRNAs) can in turn regulate each other through miRNA-mediated crosstalk. Albeit potentially weak, ceRNA interactions can occur both dynamically, affecting e.g. the regulatory clock, and at stationarity, in which case ceRNA networks as a whole can be implicated in the composition of the cell's proteome. Many features of ceRNA interactions, including the conditions under which they become significant, can be unraveled by mathematical and in silico models. We review the understanding of the ceRNA effect obtained within such frameworks, focusing on the methods employed to quantify it, its role in the processing of gene expression noise, and how network topology can determine its reach.Comment: review article, 29 pages, 7 figure

The Volatile Anesthetic Isoflurane Increases Endothelial Adenosine Generation via Microparticle Ecto-5′-Nucleotidase (CD73) Release

Endothelial dysfunction is common in acute and chronic organ injury. Isoflurane is a widely used halogenated volatile anesthetic during the perioperative period and protects against endothelial cell death and inflammation. In this study, we tested whether isoflurane induces endothelial ecto-5′-nucleotidase (CD73) and cytoprotective adenosine generation to protect against endothelial cell injury. Clinically relevant concentrations of isoflurane induced CD73 activity and increased adenosine generation in cultured human umbilical vein or mouse glomerular endothelial cells. Surprisingly, isoflurane-mediated induction of endothelial CD73 activity occurred within 1 hr and without synthesizing new CD73. We determined that isoflurane rapidly increased CD73 containing endothelial microparticles into the cell culture media. Indeed, microparticles isolated from isoflurane-treated endothelial cells had significantly higher CD73 activity as well as increased CD73 protein. In vivo, plasma from mice anesthetized with isoflurane had significantly higher endothelial cell-derived CD144+ CD73+ microparticles and had increased microparticle CD73 activity compared to plasma from pentobarbital-anesthetized mice. Supporting a critical role of CD73 in isoflurane-mediated endothelial protection, a selective CD73 inhibitor (APCP) prevented isoflurane-induced protection against human endothelial cell inflammation and apoptosis. In addition, isoflurane activated endothelial cells Rho kinase evidenced by myosin phosphatase target subunit-1 and myosin light chain phosphorylation. Furthermore, isoflurane-induced release of CD73 containing microparticles was significantly attenuated by a selective Rho kinase inhibitor (Y27632). Taken together, we conclude that the volatile anesthetic isoflurane causes Rho kinase-mediated release of endothelial microparticles containing preformed CD73 and increase adenosine generation to protect against endothelial apoptosis and inflammation

Congruence and trajectories of device-measured and self-reported physical activity during therapy for early breast cancer

Purpose: This study examines congruence between self-reported and device-measured physical activity data in women with early breast cancer and compares trajectories under different treatments. Methods: Women with non-metastatic breast cancer were recruited before primary therapy. In four weeks distributed over six months after treatment start, patients reported time spent on work, transport, chores and sports via diary and wore Garmin super R vivofit 3 accelerometers to assess steps taken. Associations between these measures and agreement regarding guideline adherence were tested with Spearman's Correlation Coefficient and Weighted Kappa statistic. Effects of time and treatment were evaluated using mixed analyses of variance. Results: Ninety-nine participants (median age = 50) were treated with adjuvant (N= 23), neoadjuvant (N= 21) or without chemotherapy (N= 55). Coherence between self-report and device data was strong (r = 0.566). Agreement about reaching recommendations was only 'fair' (kappa coefficient = 0.321 and 0.249, resp.). Neither treatment or week nor their interaction had effects on step counts (all p &amp;gt; 0.05). Self-reported activity time was lower for patients with chemotherapy than for those without (adjuvant: increment = 69min, p= 0.006, neoadjuvant: increment = 45min, p= 0.038) and lower in week 18 than in week 3 ( increment = 43min, p= 0.010). Conclusion: Results show that consumer-grade activity monitors and self-reports correlate but show different perspectives on physical activity in breast cancer patients. In general, patients perceive some decline regardless of primary treatment regimen. Those affected should be offered assistance to gain the benefits of activity. Accelerometers may help professionals to identify these individuals and patients to verify appraisal of their activity levels