460 research outputs found
Effect of Narrow Spectrum Versus Selective Kinase Inhibitors on the Intestinal Proinflammatory Immune Response in Ulcerative Colitis
Background: Kinases are key mediators of inflammation, highlighting the potential of kinase inhibitors as treatments for inflammatory disorders. Selective kinase inhibitors, however, have proved disappointing, particularly in the treatment of rheumatoid arthritis and inflammatory bowel disease. Consequently, to improve efficacy, attention has turned to multikinase inhibition. Methods: The activity of a narrow spectrum kinase inhibitor, TOP1210, has been compared with selective kinase inhibitors (BIRB-796, dasatinib and BAY-61-3606) in a range of kinase assays, inflammatory cell assays, and in inflamed biopsies from patients with ulcerative colitis (UC). Effects on recombinant P38α, Src, and Syk kinase activities were assessed using Z-lyte assays (Invitrogen, Paisley, United Kingdom). Anti-inflammatory effects were assessed by measurement of proinflammatory cytokine release from peripheral blood mononuclear cells, primary macrophages, HT29 cells, inflamed colonic UC biopsies, and myofibroblasts isolated from inflamed colonic UC mucosa. Results: TOP1210 potently inhibits P38α, Src, and Syk kinase activities. Similarly, TOP1210 demonstrates potent inhibitory activity against proinflammatory cytokine release in each of the cellular assays and the inflamed colonic UC biopsies and myofibroblasts isolated from inflamed colonic UC mucosa. Generally, the selective kinase inhibitors showed limited and weaker activity in the cellular assays compared with the broad inhibitory profile of TOP1210. However, combination of the selective inhibitors led to improved efficacy and potency in both cellular and UC biopsy assays. Conclusions: Targeted, multikinase inhibition with TOP1210 leads to a broad efficacy profile in both the innate and adaptive immune responses, with significant advantages over existing selective kinase approaches, and potentially offers a much improved therapeutic benefit in inflammatory bowel disease
Rationale, design and methods of the Study of Work and Pain (SWAP): a cluster randomised controlled trial testing the addition of a vocational advice service to best current primary care for patients with musculoskeletal pain (ISRCTN 52269669)
Background
Musculoskeletal pain is a major contributor to short and long term work absence. Patients
seek care from their general practitioner (GP) and yet GPs often feel ill-equipped to deal with
work issues. Providing a vocational case management service in primary care, to support
patients with musculoskeletal problems to remain at or return to work, is one potential
solution but requires robust evaluation to test clinical and cost-effectiveness.
Methods/Design
This protocol describes a cluster randomised controlled trial, with linked qualitative
interviews, to investigate the effect of introducing a vocational advice service into general
practice, to provide a structured approach to managing work related issues in primary care
patients with musculoskeletal pain who are absent from work or struggling to remain in work.
General practices (n = 6) will be randomised to offer best current care or best current care
plus a vocational advice service. Adults of working age who are absent from or struggling to
remain in work due to a musculoskeletal pain problem will be invited to participate and 330
participants will be recruited. Data collection will be through patient completed
questionnaires at baseline, 4 and 12 months. The primary outcome is self-reported work
absence at 4 months. Incremental cost-utility analysis will be undertaken to calculate the cost
per additional QALY gained and incremental net benefits. A linked interview study will
explore the experiences of the vocational advice service from the perspectives of GPs, nurse
practitioners (NPs), patients and vocational advisors.
Discussion
This paper presents the rationale, design, and methods of the Study of Work And Pain
(SWAP) trial. The results of this trial will provide evidence to inform primary care practice
and guide the development of services to provide support for musculoskeletal pain patients
with work-related issues.
Trial registration
Current Controlled Trials ISRCTN52269669
Multiplicity Structure of the Hadronic Final State in Diffractive Deep-Inelastic Scattering at HERA
The multiplicity structure of the hadronic system X produced in
deep-inelastic processes at HERA of the type ep -> eXY, where Y is a hadronic
system with mass M_Y< 1.6 GeV and where the squared momentum transfer at the pY
vertex, t, is limited to |t|<1 GeV^2, is studied as a function of the invariant
mass M_X of the system X. Results are presented on multiplicity distributions
and multiplicity moments, rapidity spectra and forward-backward correlations in
the centre-of-mass system of X. The data are compared to results in e+e-
annihilation, fixed-target lepton-nucleon collisions, hadro-produced
diffractive final states and to non-diffractive hadron-hadron collisions. The
comparison suggests a production mechanism of virtual photon dissociation which
involves a mixture of partonic states and a significant gluon content. The data
are well described by a model, based on a QCD-Regge analysis of the diffractive
structure function, which assumes a large hard gluonic component of the
colourless exchange at low Q^2. A model with soft colour interactions is also
successful.Comment: 22 pages, 4 figures, submitted to Eur. Phys. J., error in first
submission - omitted bibliograph
Differential (2+1) Jet Event Rates and Determination of alpha_s in Deep Inelastic Scattering at HERA
Events with a (2+1) jet topology in deep-inelastic scattering at HERA are
studied in the kinematic range 200 < Q^2< 10,000 GeV^2. The rate of (2+1) jet
events has been determined with the modified JADE jet algorithm as a function
of the jet resolution parameter and is compared with the predictions of Monte
Carlo models. In addition, the event rate is corrected for both hadronization
and detector effects and is compared with next-to-leading order QCD
calculations. A value of the strong coupling constant of alpha_s(M_Z^2)=
0.118+- 0.002 (stat.)^(+0.007)_(-0.008) (syst.)^(+0.007)_(-0.006) (theory) is
extracted. The systematic error includes uncertainties in the calorimeter
energy calibration, in the description of the data by current Monte Carlo
models, and in the knowledge of the parton densities. The theoretical error is
dominated by the renormalization scale ambiguity.Comment: 25 pages, 6 figures, 3 tables, submitted to Eur. Phys.
Measurements of Transverse Energy Flow in Deep-Inelastic Scattering at HERA
Measurements of transverse energy flow are presented for neutral current
deep-inelastic scattering events produced in positron-proton collisions at
HERA. The kinematic range covers squared momentum transfers Q^2 from 3.2 to
2,200 GeV^2, the Bjorken scaling variable x from 8.10^{-5} to 0.11 and the
hadronic mass W from 66 to 233 GeV. The transverse energy flow is measured in
the hadronic centre of mass frame and is studied as a function of Q^2, x, W and
pseudorapidity. A comparison is made with QCD based models. The behaviour of
the mean transverse energy in the central pseudorapidity region and an interval
corresponding to the photon fragmentation region are analysed as a function of
Q^2 and W.Comment: 26 pages, 8 figures, submitted to Eur. Phys.
Searches at HERA for Squarks in R-Parity Violating Supersymmetry
A search for squarks in R-parity violating supersymmetry is performed in e^+p
collisions at HERA at a centre of mass energy of 300 GeV, using H1 data
corresponding to an integrated luminosity of 37 pb^(-1). The direct production
of single squarks of any generation in positron-quark fusion via a Yukawa
coupling lambda' is considered, taking into account R-parity violating and
conserving decays of the squarks. No significant deviation from the Standard
Model expectation is found. The results are interpreted in terms of constraints
within the Minimal Supersymmetric Standard Model (MSSM), the constrained MSSM
and the minimal Supergravity model, and their sensitivity to the model
parameters is studied in detail. For a Yukawa coupling of electromagnetic
strength, squark masses below 260 GeV are excluded at 95% confidence level in a
large part of the parameter space. For a 100 times smaller coupling strength
masses up to 182 GeV are excluded.Comment: 32 pages, 14 figures, 3 table
Multi-Jet Event Rates in Deep Inelastic Scattering and Determination of the Strong Coupling Constant
Jet event rates in deep inelastic ep scattering at HERA are investigated
applying the modified JADE jet algorithm. The analysis uses data taken with the
H1 detector in 1994 and 1995. The data are corrected for detector and
hadronization effects and then compared with perturbative QCD predictions using
next-to-leading order calculations. The strong coupling constant alpha_S(M_Z^2)
is determined evaluating the jet event rates. Values of alpha_S(Q^2) are
extracted in four different bins of the negative squared momentum
transfer~\qq in the range from 40 GeV2 to 4000 GeV2. A combined fit of the
renormalization group equation to these several alpha_S(Q^2) values results in
alpha_S(M_Z^2) = 0.117+-0.003(stat)+0.009-0.013(syst)+0.006(jet algorithm).Comment: 17 pages, 4 figures, 3 tables, this version to appear in Eur. Phys.
J.; it replaces first posted hep-ex/9807019 which had incorrect figure 4
Deep-Inelastic Inclusive ep Scattering at Low x and a Determination of alpha_s
A precise measurement of the inclusive deep-inelastic e^+p scattering cross
section is reported in the kinematic range 1.5<= Q^2 <=150 GeV^2 and
3*10^(-5)<= x <=0.2. The data were recorded with the H1 detector at HERA in
1996 and 1997, and correspond to an integrated luminosity of 20 pb^(-1). The
double differential cross section, from which the proton structure function
F_2(x,Q^2) and the longitudinal structure function F_L(x,Q^2) are extracted, is
measured with typically 1% statistical and 3% systematic uncertainties. The
measured partial derivative (dF_2(x,Q^2)/dln Q^2)_x is observed to rise
continuously towards small x for fixed Q^2. The cross section data are combined
with published H1 measurements at high Q^2 for a next-to-leading order DGLAP
QCD analysis.The H1 data determine the gluon momentum distribution in the range
3*10^(-4)<= x <=0.1 to within an experimental accuracy of about 3% for Q^2 =20
GeV^2. A fit of the H1 measurements and the mu p data of the BCDMS
collaboration allows the strong coupling constant alpha_s and the gluon
distribution to be simultaneously determined. A value of alpha
_s(M_Z^2)=0.1150+-0.0017 (exp) +0.0009-0.0005 (model) is obtained in NLO, with
an additional theoretical uncertainty of about +-0.005, mainly due to the
uncertainty of the renormalisation scale.Comment: 68 pages, 24 figures and 18 table
Hadron Production in Diffractive Deep-Inelastic Scattering
Characteristics of hadron production in diffractive deep-inelastic
positron-proton scattering are studied using data collected in 1994 by the H1
experiment at HERA. The following distributions are measured in the
centre-of-mass frame of the photon dissociation system: the hadronic energy
flow, the Feynman-x (x_F) variable for charged particles, the squared
transverse momentum of charged particles (p_T^{*2}), and the mean p_T^{*2} as a
function of x_F. These distributions are compared with results in the gamma^* p
centre-of-mass frame from inclusive deep-inelastic scattering in the
fixed-target experiment EMC, and also with the predictions of several Monte
Carlo calculations. The data are consistent with a picture in which the
partonic structure of the diffractive exchange is dominated at low Q^2 by hard
gluons.Comment: 16 pages, 6 figures, submitted to Phys. Lett.
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