6,282 research outputs found
Delayed Resolution of Acute Inflammation in Ulcerative Colitis Is Associated with Elevated Cytokine Release Downstream of TLR4
Background: Ulcerative colitis (UC) is widely viewed as a leukocyte-mediated disorder. Although strong evidence implicates an exuberant response to microbial components in its pathogenesis, no intrinsic immune defect has been identified and the underlying pathogenic mechanisms remain obscure.Methodology/Principal Findings: The acute immune response to bacterial injection was determined in UC patients with quiescent disease and directly compared to healthy control subjects. Monocyte-derived macrophages were used to investigate bacterial recognition mechanisms in vitro. An exuberant and protracted acute inflammatory response to bacteria was evident in patients with UC, which coincides with increased systemic levels of CXCL10. Macrophages stimulated with bacteria and Toll-like receptor (TLR) ligands revealed a specific defect in the TLR4 response in UC. The defect resulted in the over-expression of a number of pro-inflammatory molecules under transcriptional control of the adaptor TIR-domain containing adaptor inducing interferon-b (TRIF).Conclusion: These findings highlight a dysregulated innate immune response with over-expression of molecules associated with leukocyte recruitment and activation that may eventuate in the hallmark chronic immune-mediated inflammation of UC
METRIC-EF: magnetic resonance enterography to predict disabling disease in newly diagnosed Crohn's disease-protocol for a multicentre, non-randomised, single-arm, prospective study
INTRODUCTION: Crohn's disease (CD) is characterised by discontinuous, relapsing enteric inflammation. Instituting advanced therapies at an early stage to suppress inflammation aims to prevent future complications such as stricturing or penetrating disease, and subsequent surgical resection. Therapeutics are effective but associated with certain side-effects and relatively expensive. There is therefore an urgent need for robust methods to predict which newly diagnosed patients will develop disabling disease, to identify patients who are most likely to benefit from early, advanced therapies. We aim to determine if magnetic resonance enterography (MRE) features at diagnosis improve prediction of disabling CD within 5 years of diagnosis. METHODS AND ANALYSIS: We describe the protocol for a multicentre, non-randomised, single-arm, prospective study of adult patients with newly diagnosed CD. We will use patients already recruited to the METRIC study and extend their clinical follow-up, as well as a separate group of newly diagnosed patients who were not part of the METRIC trial (MRE within 3 months of diagnosis), to ensure an adequate sample size. Follow-up will extend for at least 4 years. The primary outcome is to evaluate the comparative predictive ability of prognostic models incorporating MRE severity scores (Magnetic resonance Enterography Global Score (MEGS), simplified MAgnetic Resonance Index of Activity (sMaRIA) and Lémann Index) versus models using standard characteristics alone to predict disabling CD (modified Beaugerie definition) within 5 years of new diagnosis. ETHICS AND DISSEMINATION: This study protocol achieved National Health Service Research Ethics Committee (NHS REC), London-Hampstead Research Ethics Committee approval (IRAS 217422). Our findings will be disseminated via conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN76899103
Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease
The cause of Crohn's disease (CD) remains poorly understood. Counterintuitively, these patients possess an impaired acute inflammatory response, which could result in delayed clearance of bacteria penetrating the lining of the bowel and predispose to granuloma formation and chronicity. We tested this hypothesis in human subjects by monitoring responses to killed Escherichia coli injected subcutaneously into the forearm. Accumulation of 111In-labeled neutrophils at these sites and clearance of 32P-labeled bacteria from them were markedly impaired in CD. Locally increased blood flow and bacterial clearance were dependent on the numbers of bacteria injected. Secretion of proinflammatory cytokines by CD macrophages was grossly impaired in response to E. coli or specific Toll-like receptor agonists. Despite normal levels and stability of cytokine messenger RNA, intracellular levels of tumor necrosis factor (TNF) were abnormally low in CD macrophages. Coupled with reduced secretion, these findings indicate accelerated intracellular breakdown. Differential transcription profiles identified disease-specific genes, notably including those encoding proteins involved in vesicle trafficking. Intracellular destruction of TNF was decreased by inhibitors of lysosomal function. Together, our findings suggest that in CD macrophages, an abnormal proportion of cytokines are routed to lysosomes and degraded rather than being released through the normal secretory pathway
VAST: An ASKAP Survey for Variables and Slow Transients
The Australian Square Kilometre Array Pathfinder (ASKAP) will give us an
unprecedented opportunity to investigate the transient sky at radio
wavelengths. In this paper we present VAST, an ASKAP survey for Variables and
Slow Transients. VAST will exploit the wide-field survey capabilities of ASKAP
to enable the discovery and investigation of variable and transient phenomena
from the local to the cosmological, including flare stars, intermittent
pulsars, X-ray binaries, magnetars, extreme scattering events, interstellar
scintillation, radio supernovae and orphan afterglows of gamma ray bursts. In
addition, it will allow us to probe unexplored regions of parameter space where
new classes of transient sources may be detected. In this paper we review the
known radio transient and variable populations and the current results from
blind radio surveys. We outline a comprehensive program based on a multi-tiered
survey strategy to characterise the radio transient sky through detection and
monitoring of transient and variable sources on the ASKAP imaging timescales of
five seconds and greater. We also present an analysis of the expected source
populations that we will be able to detect with VAST.Comment: 29 pages, 8 figures. Submitted for publication in Pub. Astron. Soc.
Australi
Relativistic Hydrodynamic Evolutions with Black Hole Excision
We present a numerical code designed to study astrophysical phenomena
involving dynamical spacetimes containing black holes in the presence of
relativistic hydrodynamic matter. We present evolutions of the collapse of a
fluid star from the onset of collapse to the settling of the resulting black
hole to a final stationary state. In order to evolve stably after the black
hole forms, we excise a region inside the hole before a singularity is
encountered. This excision region is introduced after the appearance of an
apparent horizon, but while a significant amount of matter remains outside the
hole. We test our code by evolving accurately a vacuum Schwarzschild black
hole, a relativistic Bondi accretion flow onto a black hole, Oppenheimer-Snyder
dust collapse, and the collapse of nonrotating and rotating stars. These
systems are tracked reliably for hundreds of M following excision, where M is
the mass of the black hole. We perform these tests both in axisymmetry and in
full 3+1 dimensions. We then apply our code to study the effect of the stellar
spin parameter J/M^2 on the final outcome of gravitational collapse of rapidly
rotating n = 1 polytropes. We find that a black hole forms only if J/M^2<1, in
agreement with previous simulations. When J/M^2>1, the collapsing star forms a
torus which fragments into nonaxisymmetric clumps, capable of generating
appreciable ``splash'' gravitational radiation.Comment: 17 pages, 14 figures, submitted to PR
Measurement of Rapidity Distribution for High Mass Drell-Yan ee Pairs at CDF
We report on the first measurement of the rapidity distribution dsigma/dy
over nearly the entire kinematic region of rapidity for e^+e^- pairs in the
Z-boson region of 66116 GeV/c^2.
The data sample consists of 108 pb^{-1} of ppbar collisions at \sqrt{s}=1.8 TeV
taken by the Collider Detector at Fermilab during 1992--1995. The total cross
section in the -boson region is measured to be 252 +- 11 pb. The measured
total cross section and d\sigma/dy are compared with quantum chromodynamics
calculations in leading and higher orders.Comment: 7 pages, 3 figures. Submitted to Physical Review Letter
Inclusive Search for Anomalous Production of High-pT Like-Sign Lepton Pairs in Proton-Antiproton Collisions at sqrt{s}=1.8 TeV
We report on a search for anomalous production of events with at least two
charged, isolated, like-sign leptons with pT > 11 GeV/c using a 107 pb^-1
sample of 1.8 TeV ppbar collisions collected by the CDF detector. We define a
signal region containing low background from Standard Model processes. To avoid
bias, we fix the final cuts before examining the event yield in the signal
region using control regions to test the Monte Carlo predictions. We observe no
events in the signal region, consistent with an expectation of
0.63^(+0.84)_(-0.07) events. We present 95% confidence level limits on new
physics processes in both a signature-based context as well as within a
representative minimal supergravity (tanbeta = 3) model.Comment: 15 pages, 4 figures. Minor textual changes, cosmetic improvements to
figures and updated and expanded reference
Search for Narrow Diphoton Resonances and for gamma-gamma+W/Z Signatures in p\bar p Collisions at sqrt(s)=1.8 TeV
We present results of searches for diphoton resonances produced both
inclusively and also in association with a vector boson (W or Z) using 100
pb^{-1} of p\bar p collisions using the CDF detector. We set upper limits on
the product of cross section times branching ratio for both p\bar
p\to\gamma\gamma + X and p\bar p\to\gamma\gamma + W/Z. Comparing the inclusive
production to the expectations from heavy sgoldstinos we derive limits on the
supersymmetry-breaking scale sqrt{F} in the TeV range, depending on the
sgoldstino mass and the choice of other parameters. Also, using a NLO
prediction for the associated production of a Higgs boson with a W or Z boson,
we set an upper limit on the branching ratio for H\to\gamma\gamma. Finally, we
set a lower limit on the mass of a `bosophilic' Higgs boson (e.g. one which
couples only to \gamma, W, and Z$ bosons with standard model couplings) of 82
GeV/c^2 at 95% confidence level.Comment: 30 pages, 11 figure
Measurement of the Helicity of W Bosons in Top Quark Decays
We use the transverse momentum spectrum of leptons in the decay chain t-->bW
with W-->l nu to measure the helicity of the W bosons in the top quark rest
frame. Our measurement uses a ttbar sample isolated in 106 +/- 4 inverse
picobarns of data collected in ppbar collisions at sqrt(s)=1.8 TeV with the CDF
detector at the Fermilab Tevatron. Assuming a standard V--A weak decay, we find
that the fraction of W's with zero helicity in the top rest frame is F_0 = 0.91
+/- 0.37 (stat) +/- 0.13 (syst), consistent with the standard model prediction
of F_0=0.70 for a top mass of 175 GeV/c**2.Comment: Submitted to PRL. 8 pages, 2 figure
Limits on Gravitino Production and New Processes with Large Missing Transverse Energy in p-pbar Collisions at sqrt(s)=1.8 TeV
Events collected by the Collider Detector at Fermilab (CDF) with an energetic
jet plus large missing transverse energy can be used to search for physics
beyond the Standard Model. We see no deviations from the expected background
and set upper limits on the production of new processes. We consider in
addition the production of light gravitinos within the framework of the Gauge
Mediated Supersymmetry Breaking models and set a limit at 95% confidence level
on the breaking scale sqrt(F) >= 217 GeV, which excludes gravitino masses
smaller than 1.1x10^-5 eV/c^2.Comment: 13 pages, 4 figures. Submitted to Physical Review Letter
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