Inhibiting ERK Activation with CI-1040 Leads to Compensatory Upregulation of Alternate MAPKs and Plasminogen Activator Inhibitor-1 following Subtotal Nephrectomy with No Impact on Kidney Fibrosis

Extracellular-signal regulated kinase (ERK) activation by MEK plays a key role in many of the cellular processes that underlie progressive kidney fibrosis including cell proliferation, apoptosis and transforming growth factor β1-mediated epithelial to mesenchymal transition. We therefore assessed the therapeutic impact of ERK1/2 inhibition using a MEK inhibitor in the rat 5/6 subtotal nephrectomy (SNx) model of kidney fibrosis. There was a twentyfold upregulation in phospho-ERK1/2 expression in the kidney after SNx in Male Wistar rats. Rats undergoing SNx became hypertensive, proteinuric and developed progressive kidney failure with reduced creatinine clearance. Treatment with the MEK inhibitor, CI-1040 abolished phospho- ERK1/2 expression in kidney tissue and prevented phospho-ERK1/2 expression in peripheral lymphocytes during the entire course of therapy. CI-1040 had no impact on creatinine clearance, proteinuria, glomerular and tubular fibrosis, and α-smooth muscle actin expression. However, inhibition of ERK1/2 activation led to significant compensatory upregulation of the MAP kinases, p38 and JNK in kidney tissue. CI-1040 also increased the expression of plasminogen activator inhibitor-1 (PAI-1), a key inhibitor of plasmin-dependent matrix metalloproteinases. Thus inhibition of ERK1/2 activation has no therapeutic effect on kidney fibrosis in SNx possibly due to increased compensatory activation of the p38 and JNK signalling pathways with subsequent upregulation of PAI-1

Modelling optimal location for pre-hospital helicopter emergency medical services

<p>Abstract</p> <p>Background</p> <p>Increasing the range and scope of early activation/auto launch helicopter emergency medical services (HEMS) may alleviate unnecessary injury mortality that disproportionately affects rural populations. To date, attempts to develop a quantitative framework for the optimal location of HEMS facilities have been absent.</p> <p>Methods</p> <p>Our analysis used five years of critical care data from tertiary health care facilities, spatial data on origin of transport and accurate road travel time catchments for tertiary centres. A location optimization model was developed to identify where the expansion of HEMS would cover the greatest population among those currently underserved. The protocol was developed using geographic information systems (GIS) to measure populations, distances and accessibility to services.</p> <p>Results</p> <p>Our model determined Royal Inland Hospital (RIH) was the optimal site for an expanded HEMS – based on denominator population, distance to services and historical usage patterns.</p> <p>Conclusion</p> <p>GIS based protocols for location of emergency medical resources can provide supportive evidence for allocation decisions – especially when resources are limited. In this study, we were able to demonstrate conclusively that a logical choice exists for location of additional HEMS. This protocol could be extended to location analysis for other emergency and health services.</p

The impact of glucose-insulin-potassium infusion in acute myocardial infarction on infarct size and left ventricular ejection fraction [ISRCTN56720616]

BACKGROUND: Favorable clinical outcomes have been observed with glucose-insulin-potassium infusion (GIK) in acute myocardial infarction (MI). The mechanisms of this beneficial effect have not been delineated clearly. GIK has metabolic, anti-inflammatory and profibrinolytic effects and it may preserve the ischemic myocardium. We sought to assess the effect of GIK infusion on infarct size and left ventricular function, as part of a randomized controlled trial. METHODS: Patients (n = 940) treated for acute MI by primary percutaneous coronary intervention (PCI) were randomized to GIK infusion or no infusion. Endpoints were the creatinine kinase MB-fraction (CK-MB) and left ventricular ejection fraction (LVEF). CK-MB levels were determined 0, 2, 4, 6, 24, 48, 72 and 96 hours after admission and the LVEF was measured before discharge. RESULTS: There were no differences between the two groups in the time course or magnitude of CK-MB release: the peak CK-MB level was 249 ± 228 U/L in the GIK group and 240 ± 200 U/L in the control group (NS). The mean LVEF was 43.7 ± 11.0 % in the GIK group and 42.4 ± 11.7% in the control group (P = 0.12). A LVEF ≤ 30% was observed in 18% in the controls and in 12% of the GIK group (P = 0.01). CONCLUSION: Treatment with GIK has no effect on myocardial function as determined by LVEF and by the pattern or magnitude of enzyme release. However, left ventricular function was preserved in GIK treated patients

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Intra-arterial delivery of triolein emulsion increases vascular permeability in skeletal muscles of rabbits

<p>Abstract</p> <p>Background</p> <p>To test the hypothesis that triolein emulsion will increase vascular permeability of skeletal muscle.</p> <p>Methods</p> <p>Triolein emulsion was infused into the superficial femoral artery in rabbits (triolein group, n = 12). As a control, saline was infused (saline group, n = 18). Pre- and post-contrast T1-weighted MR images were obtained two hours after infusion. The MR images were qualitatively and quantitatively evaluated by assessing the contrast enhancement of the ipsilateral muscles. Histologic examination was performed in all rabbits.</p> <p>Results</p> <p>The ipsilateral muscles of the rabbits in the triolein group showed contrast enhancement, as opposed to in the ipsilateral muscles of the rabbits in the saline group. The contrast enhancement of the lesions was statistically significant (p < 0.001). Histologic findings showed that most examination areas of the triolein and saline groups had a normal appearance.</p> <p>Conclusion</p> <p>Rabbit thigh muscle revealed significantly increased vascular permeability with triolein emulsion; this was clearly demonstrated on the postcontrast MR images.</p

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Measurement of the cross-section of high transverse momentum vector bosons reconstructed as single jets and studies of jet substructure in pp collisions at √s = 7 TeV with the ATLAS detector

This paper presents a measurement of the cross-section for high transverse momentum W and Z bosons produced in pp collisions and decaying to all-hadronic final states. The data used in the analysis were recorded by the ATLAS detector at the CERN Large Hadron Collider at a centre-of-mass energy of √s = 7 TeV;{\rm Te}{\rm V}$and correspond to an integrated luminosity of$4.6\;{\rm f}{{{\rm b}}^{-1}}$. The measurement is performed by reconstructing the boosted W or Z bosons in single jets. The reconstructed jet mass is used to identify the W and Z bosons, and a jet substructure method based on energy cluster information in the jet centre-of-mass frame is used to suppress the large multi-jet background. The cross-section for events with a hadronically decaying W or Z boson, with transverse momentum${{p}_{{\rm T}}}\gt 320\;{\rm Ge}{\rm V}$and pseudorapidity$|\eta |\lt 1.9$, is measured to be${{\sigma }_{W+Z}}=8.5\pm 1.7$ pb and is compared to next-to-leading-order calculations. The selected events are further used to study jet grooming techniques

Search for R-parity-violating supersymmetry in events with four or more leptons in sqrt(s) =7 TeV pp collisions with the ATLAS detector

A search for new phenomena in final states with four or more leptons (electrons or muons) is presented. The analysis is based on 4.7 fb−1 of $\sqrt{s}=7\;\mathrm{TeV}$ proton-proton collisions delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in two signal regions: one that requires moderate values of missing transverse momentum and another that requires large effective mass. The results are interpreted in a simplified model of R-parity-violating supersymmetry in which a 95% CL exclusion region is set for charged wino masses up to 540 GeV. In an R-parity-violating MSUGRA/CMSSM model, values of m 1/2 up to 820 GeV are excluded for 10 < tan β < 40

Search for high-mass resonances decaying to dilepton final states in pp collisions at s√=7 TeV with the ATLAS detector

The ATLAS detector at the Large Hadron Collider is used to search for high-mass resonances decaying to an electron-positron pair or a muon-antimuon pair. The search is sensitive to heavy neutral Z′ gauge bosons, Randall-Sundrum gravitons, Z * bosons, techni-mesons, Kaluza-Klein Z/γ bosons, and bosons predicted by Torsion models. Results are presented based on an analysis of pp collisions at a center-of-mass energy of 7 TeV corresponding to an integrated luminosity of 4.9 fb−1 in the e + e − channel and 5.0 fb−1 in the μ + μ −channel. A Z ′ boson with Standard Model-like couplings is excluded at 95 % confidence level for masses below 2.22 TeV. A Randall-Sundrum graviton with coupling k/MPl=0.1 is excluded at 95 % confidence level for masses below 2.16 TeV. Limits on the other models are also presented, including Technicolor and Minimal Z′ Models