IL-6-Mediated Activation of Stat3α Prevents Trauma/Hemorrhagic Shock-Induced Liver Inflammation

Trauma complicated by hemorrhagic shock (T/HS) is the leading cause of morbidity and mortality in the United States for individuals under the age of 44 years. Initial survivors are susceptible to developing multiple organ failure (MOF), which is thought to be caused, at least in part, by excessive or maladaptive activation of inflammatory pathways. We previously demonstrated in rodents that T/HS results in liver injury that can be prevented by IL-6 administration at the start of resuscitation; however, the contribution of the severity of HS to the extent of liver injury, whether or not resuscitation is required, and the mechanism(s) for the IL-6 protective effect have not been reported. In the experiments described here, we demonstrated that the extent of liver inflammation induced by T/HS depends on the duration of hypotension and requires resuscitation. We established that IL-6 administration at the start of resuscitation is capable of completely reversing liver inflammation and is associated with increased Stat3 activation. Global assessment of the livers showed that the main effect of IL-6 was to normalize the T/HS-induced inflammation transcriptome. Pharmacological inhibition of Stat3 activity within the liver blocked the ability of IL-6 to prevent liver inflammation and to normalize the T/HS-induced liver inflammation transcriptome. Genetic deletion of a Stat3β, a naturally occurring, dominant-negative isoform of the Stat3, attenuated T/HS-induced liver inflammation, confirming a role for Stat3, especially Stat3α, in preventing T/HS-mediated liver inflammation. Thus, T/HS-induced liver inflammation depends on the duration of hypotension and requires resuscitation; IL-6 administration at the start of resuscitation reverses T/HS-induced liver inflammation, through activation of Stat3α, which normalized the T/HS-induced liver inflammation transcriptome

Quantifying the improvement of surrogate indices of hepatic insulin resistance using complex measurement techniques

We evaluated the ability of simple and complex surrogate-indices to identify individuals from an overweight/obese cohort with hepatic insulin-resistance (HEP-IR). Five indices, one previously defined and four newly generated through step-wise linear regression, were created against a single-cohort sample of 77 extensively characterised participants with the metabolic syndrome (age 55.6±1.0 years, BMI 31.5±0.4 kg/m2; 30 males). HEP-IR was defined by measuring endogenous-glucose-production (EGP) with [6–62H2] glucose during fasting and euglycemic-hyperinsulinemic clamps and expressed as EGP*fasting plasma insulin. Complex measures were incorporated into the model, including various non-standard biomarkers and the measurement of body-fat distribution and liver-fat, to further improve the predictive capability of the index. Validation was performed against a data set of the same subjects after an isoenergetic dietary intervention (4 arms, diets varying in protein and fiber content versus control). All five indices produced comparable prediction of HEP-IR, explaining 39–56% of the variance, depending on regression variable combination. The validation of the regression equations showed little variation between the different proposed indices (r2 = 27–32%) on a matched dataset. New complex indices encompassing advanced measurement techniques offered an improved correlation (r = 0.75, P<0.001). However, when validated against the alternative dataset all indices performed comparably with the standard homeostasis model assessment for insulin resistance (HOMA-IR) (r = 0.54, P<0.001). Thus, simple estimates of HEP-IR performed comparable to more complex indices and could be an efficient and cost effective approach in large epidemiological investigations

Correlates of condom use in a sample of MSM in Ecuador

BACKGROUND: In Ecuador, the prevalence of HIV in the general population is approximately 0.3%. However, up to 17% prevalence has been reported among specific groups of homosexual and bisexual men. The objective of this study is to explore correlates of condom use among men who have sex with men (MSM) across eight cities in Ecuador. METHODS: A cross-sectional survey design was used. A questionnaire including variables on sexual behaviour, demographics, and socio-economic characteristics was distributed to a sample of MSM in eight Ecuadorian cities. RESULTS: Information was obtained for 2,594 MSM across the eight cities. The largest subcategory of self-identification was active bisexuals (35%), followed by those who described themselves as "hombrados" (masculine gays, 22%). The mean age was 25 years, and the majority were unmarried (78%), with a median of 10 years of schooling (IQR 7 – 12). Regarding condom use, 55% of those interviewed had unprotected penetrative sex with each of their last three partners, and almost 25% had never used a condom. The most important correlates of condom use were single status, high life-skills rating, and high socio-economic status (RP 5.45, 95% CI 4.26 – 6.37; RP 1.84, 95% CI 1.79 – 1.86, and RP 1.20, 95% CI 1.01 – 1.31, respectively). CONCLUSION: Our data illustrate the urgent need for targeted HIV-prevention programs for MSM populations in Ecuador. MSM have the highest HIV prevalence in the country, and condom use is extremely low. It is imperative that prevention strategies be re-evaluated and re-prioritized to more effectively respond to the Ecuadorian epidemic

Search for short baseline nu(e) disappearance with the T2K near detector

8 pages, 6 figures, submitted to PRD rapid communication8 pages, 6 figures, submitted to PRD rapid communicationWe thank the J-PARC staff for superb accelerator performance and the CERN NA61 collaboration for providing valuable particle production data. We acknowledge the support of MEXT, Japan; NSERC, NRC and CFI, Canada; Commissariat `a l’Energie Atomique and Centre National de la Recherche Scientifique–Institut National de Physique Nucle´aire et de Physique des Particules, France; DFG, Germany; INFN, Italy; National Science Centre (NCN), Poland; Russian Science Foundation, RFBR and Ministry of Education and Science, Russia; MINECO and European Regional Development Fund, Spain; Swiss National Science Foundation and State Secretariat for Education, Research and Innovation, Switzerland; STFC, UK; and DOE, USA. We also thank CERN for the UA1/NOMAD magnet, DESY for the HERA-B magnet mover system, NII for SINET4, the WestGrid and SciNet consortia in Compute Canada, GridPP, UK. In addition participation of individual researchers and institutions has been further supported by funds from ERC (FP7), EU; JSPS, Japan; Royal Society, UK; DOE Early Career program, USA

Evidence for νμ→ντ\nu_\mu \to \nu_\tau appearance in the CNGS neutrino beam with the OPERA experiment

The OPERA experiment is designed to search for $\nu_{\mu} \rightarrow \nu_{\tau}$ oscillations in appearance mode i.e. through the direct observation of the $\tau$ lepton in $\nu_{\tau}$ charged current interactions. The experiment has taken data for five years, since 2008, with the CERN Neutrino to Gran Sasso beam. Previously, two $\nu_{\tau}$ candidates with a $\tau$ decaying into hadrons were observed in a sub-sample of data of the 2008-2011 runs. Here we report the observation of a third $\nu_\tau$ candidate in the $\tau^-\to\mu^-$ decay channel coming from the analysis of a sub-sample of the 2012 run. Taking into account the estimated background, the absence of $\nu_{\mu} \rightarrow \nu_{\tau}$ oscillations is excluded at the 3.4 $\sigma$ level.Comment: 9 pages, 5 figures, 1 table

Emulsion sheet doublets as interface trackers for the OPERA experiment

New methods for efficient and unambiguous interconnection between electronic counters and target units based on nuclear photographic emulsion films have been developed. The application to the OPERA experiment, that aims at detecting oscillations between mu neutrino and tau neutrino in the CNGS neutrino beam, is reported in this paper. In order to reduce background due to latent tracks collected before installation in the detector, on-site large-scale treatments of the emulsions ("refreshing") have been applied. Changeable Sheet (CSd) packages, each made of a doublet of emulsion films, have been designed, assembled and coupled to the OPERA target units ("ECC bricks"). A device has been built to print X-ray spots for accurate interconnection both within the CSd and between the CSd and the related ECC brick. Sample emulsion films have been extensively scanned with state-of-the-art automated optical microscopes. Efficient track-matching and powerful background rejection have been achieved in tests with electronically tagged penetrating muons. Further improvement of in-doublet film alignment was obtained by matching the pattern of low-energy electron tracks. The commissioning of the overall OPERA alignment procedure is in progress.Comment: 19 pages, 19 figure

Measurement of the atmospheric muon charge ratio with the OPERA detector

The OPERA detector at the Gran Sasso underground laboratory (LNGS) was used to measure the atmospheric muon charge ratio in the TeV energy region. We analyzed 403069 atmospheric muons corresponding to 113.4 days of livetime during the 2008 CNGS run. We computed separately the muon charge ratio for single and for multiple muon events in order to select different energy regions of the primary cosmic ray spectrum and to test the charge ratio dependence on the primary composition. The measured charge ratio values were corrected taking into account the charge-misidentification errors. Data have also been grouped in five bins of the "vertical surface energy". A fit to a simplified model of muon production in the atmosphere allowed the determination of the pion and kaon charge ratios weighted by the cosmic ray energy spectrum.Comment: 14 pages, 10 figure

Trauma Hemorrhagic Shock-Induced Lung Injury Involves a Gut-Lymph-Induced TLR4 Pathway in Mice

Injurious non-microbial factors released from the stressed gut during shocked states contribute to the development of acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS). Since Toll-like receptors (TLR) act as sensors of tissue injury as well as microbial invasion and TLR4 signaling occurs in both sepsis and noninfectious models of ischemia/reperfusion (I/R) injury, we hypothesized that factors in the intestinal mesenteric lymph after trauma hemorrhagic shock (T/HS) mediate gut-induced lung injury via TLR4 activation.The concept that factors in T/HS lymph exiting the gut recreates ALI is evidenced by our findings that the infusion of porcine lymph, collected from animals subjected to global T/HS injury, into naïve wildtype (WT) mice induced lung injury. Using C3H/HeJ mice that harbor a TLR4 mutation, we found that TLR4 activation was necessary for the development of T/HS porcine lymph-induced lung injury as determined by Evan's blue dye (EBD) lung permeability and myeloperoxidase (MPO) levels as well as the induction of the injurious pulmonary iNOS response. TRIF and Myd88 deficiency fully and partially attenuated T/HS lymph-induced increases in lung permeability respectively. Additional studies in TLR2 deficient mice showed that TLR2 activation was not involved in the pathology of T/HS lymph-induced lung injury. Lastly, the lymph samples were devoid of bacteria, endotoxin and bacterial DNA and passage of lymph through an endotoxin removal column did not abrogate the ability of T/HS lymph to cause lung injury in naïve mice.Our findings suggest that non-microbial factors in the intestinal mesenteric lymph after T/HS are capable of recreating T/HS-induced lung injury via TLR4 activation

The detection of neutrino interactions in the emulsion/lead target of the OPERA experiment

The OPERA neutrino detector in the underground Gran Sasso Laboratory (LNGS) was designed to perform the first detection of neutrino oscillations in appearance mode through the study of $\nu_\mu\to\nu_\tau$ oscillations. The apparatus consists of an emulsion/lead target complemented by electronic detectors and it is placed in the high energy long-baseline CERN to LNGS beam (CNGS) 730 km away from the neutrino source. Runs with CNGS neutrinos were successfully carried out in 2007 and 2008 with the detector fully operational with its related facilities for the emulsion handling and analysis. After a brief description of the beam and of the experimental setup we report on the collection, reconstruction and analysis procedures of first samples of neutrino interaction events