Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice

OBJECTIVE OF THE STUDY: Diabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis. METHODOLOGY AND PRINCIPAL FINDINGS: Streptozotocin (STZ)-induced diabetes in apolipoprotein E(-/-) mice resulted in 2.2 fold increased aortic atherosclerosis and enhanced pro-inflammatory burden, as evidenced by elevated blood monocytes, endothelial activation- and inflammatory markers in aorta, and pro-inflammatory cytokines in plasma. In vivo treatment with the NFAT blocker A-285222 for 4 weeks completely inhibited the diabetes-induced aggravation of atherosclerosis, having no effect in non-diabetic mice. STZ-treated mice exhibited hyperglycemia and higher plasma cholesterol and triglycerides, but these were unaffected by A-285222. NFAT-dependent transcriptional activity was examined in aorta, spleen, thymus, brain, heart, liver and kidney, but only augmented in the aorta of diabetic mice. A-285222 completely blocked this diabetes-driven NFAT activation, but had no impact on the other organs or on splenocyte proliferation or cytokine secretion, ruling out systemic immunosuppression as the mechanism behind reduced atherosclerosis. Instead, NFAT inhibition effectively reduced IL-6, osteopontin, monocyte chemotactic protein 1, intercellular adhesion molecule 1, CD68 and tissue factor expression in the arterial wall and lowered plasma IL-6 in diabetic mice. CONCLUSIONS: Targeting NFAT signaling may be a novel and attractive approach for the treatment of diabetic macrovascular complications

A threshold imaging Cerenkov detector with CsI photocathodes

A Threshold Imaging Cherenkov (TIC) detector, in conjunction with a tracking device and a time-of-flight system, has been developed to allow pion, kaon and proton identification in the 3--8 GeV/$c$ range of momenta. The system allows spatial identification of the photons of particles above the Cherenkov threshold and their correlation to a particular track. The TIC detector uses a MWPC detector with a CsI coated photocathode for photon conversion. The results obtained in ultrarelativistic lead--lead collisions at the CERN SPS accelerator are presented

A four gap glass RPC time-of-flight array with 90 ps time resolution

In this work we describe the performance of a prototype developped in the context of the ALICE team-of-flight R&D system. The detector module consists of a 32-channel array of 3 x 3 cm2 glass-RPC cells, each of which has four accurately spaced gaps of 0.3. mm thickness arranged as a pair of double-gap resistive plate chambers. Operated with a non-flammable gas mixture at atmospheric pressure, the system achieved a time resolution of 90 ps at 90% efficiency with good uniformity and moderate crosstalk. This result shows the feasibility of large-area, high resolution time-of-flight systems based on RPCs at affordable cost

Paraphrases and summaries: A means of clarification or a vehicle for articulating a preferred version of student accounts?

The use of group discussions as a means to facilitate learning from experiences is well documented in adventure education literature. Priest and Naismith (1993) assert that the use of the circular discussion method, where the leader poses questions to the participants, is the most common form of facilitation in adventure education. This paper draws on transcripts of facilitation sessions to argue that the widely advocated practice of leader summaries or paraphrases of student responses in these sessions functions as a potential mechanism to control and sponsor particular knowledge(s). Using transcripts from recorded facilitation sessions the analysis focuses on how the leader paraphrases the students’ responses and how these paraphrases or ‘formulations’ function to modify or exclude particular aspects of the students’ responses. I assert that paraphrasing is not simply a neutral activity that merely functions to clarify a student response, it is a subtle means by which the leader of the session can, often inadvertently or unknowingly, alter the student’s reply with the consequence of favouring particular knowledge(s). Revealing the subtle work that leader paraphrases perform is of importance for educators who claim to provide genuine opportunities for students to learn from their experience

Dynamic Monitoring of Cellular Remodeling Induced by the Transforming Growth Factor-β1

The plasticity of differentiated adult cells could have a great therapeutic potential, but at the same time, it is characteristic of progression of serious pathological states such as cancer and fibrosis. In this study, we report on the application of a real-time noninvasive system for dynamic monitoring of cellular plasticity. Analysis of the cell impedance profile recorded as cell index using a real-time cell analyzer revealed its significant increase after the treatment of prostate epithelial cells with the transforming growth factor-β1. Changes in the cell index profile were paralleled with cytoskeleton rebuilding and induction of epithelial–mesenchymal transition and negatively correlated with cell proliferation. This novel application of such approach demonstrated a great potential of the impedance-based system for noninvasive and real-time monitoring of cellular fate

Two-Proton Correlations near Midrapidity in p+Pb and S+Pb Collisions at the CERN SPS

Correlations of two protons emitted near midrapidity in p+Pb collisions at 450 GeV/c and S+Pb collisions at 200A GeV/c are presented, as measured by the NA44 Experiment. The correlation effect, which arises as a result of final state interactions and Fermi-Dirac statistics, is related to the space-time characteristics of proton emission. The measured source sizes are smaller than the size of the target lead nucleus but larger than the sizes of the projectiles. A dependence on the collision centrality is observed; the source size increases with decreasing impact parameter. Proton source sizes near midrapidity appear to be smaller than those of pions in the same interactions. Quantitative agreement with the results of RQMD (v1.08) simulations is found for p+Pb collisions. For S+Pb collisions the measured correlation effect is somewhat weaker than that predicted by the model simulations, implying either a larger source size or larger contribution of protons from long-lived particle decays.Comment: 10 pages (LaTeX) text, 4 (EPS) figures; accepted for publication in Phys. Lett.

Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells

Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 β-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.Peer reviewe

The concept of "compartment allergy": prilocaine injected into different skin layers

We herein present a patient with delayed-type allergic hypersensitivity against prilocaine leading to spreading eczematous dermatitis after subcutaneous injections for local anesthesia with prilocaine. Prilocaine allergy was proven by positive skin testing and subcutaneous provocation, whereas the evaluation of other local anesthetics - among them lidocaine, articaine and mepivacaine - did not exhibit any evidence for cross-reactivity

Front-end electronics for the ALICE TPC-detector

The Front-End electronics for the Time Projection Chamber (TPC) for the ALICE experiment consists of 5x105 channels. A single readout channel is comprised of three basic units: a charge sensitive amplifier/shaper with a fast tail cancellation; a 10 bit 10 Msamples/sec low power ADC; a digital ASIC which contains the zero suppression circuit and a multiple-event buffer. Data from a number of channels (4096) are multiplexed into an optical link (DDL) by means of a local custom bus which can support a data throughput of 2 Mbyte/event at a trigger rate of 50 Hz. The construction of a prototype of this electronics is presented in this paper