24 research outputs found
Ocular Application of the Kinin B1 Receptor Antagonist LF22-0542 Inhibits Retinal Inflammation and Oxidative Stress in Streptozotocin-Diabetic Rats
Purpose: Kinin B1 receptor (B1R) is upregulated in retina of Streptozotocin (STZ)-diabetic rats and contributes to vasodilation of retinal microvessels and breakdown of the blood-retinal barrier. Systemic treatment with B 1R antagonists reversed the increased retinal plasma extravasation in STZ rats. The present study aims at determining whether ocular application of a water soluble B1R antagonist could reverse diabetes-induced retinal inflammation and oxidative stress. Methods: Wistar rats were made diabetic with STZ (65 mg/kg, i.p.) and 7 days later, they received one eye drop application of LF22-0542 (1 % in saline) twice a day for a 7 day-period. The impact was determined on retinal vascular permeability (Evans blue exudation), leukostasis (leukocyte infiltration using Fluorescein-isothiocyanate (FITC)-coupled Concanavalin A lectin), retinal mRNA levels (by qRT-PCR) of inflammatory (B1R, iNOS, COX-2, ICAM-1, VEGF-A, VEGF receptor type 2, IL-1b and HIF-1a) and anti-inflammatory (B2R, eNOS) markers and retinal level of superoxide anion (dihydroethidium staining). Results: Retinal plasma extravasation, leukostasis and mRNA levels of B 1R, iNOS, COX-2, VEGF receptor type 2, IL-1b and HIF-1a were significantly increased in diabetic retinae compared to control rats. All these abnormalities were reversed to control values in diabetic rats treated with LF22-0542. B1R antagonist also significantly inhibited the increased production of superoxide anion in diabetic retinae. Conclusion: B1R displays a pathological role in the early stage of diabetes by increasing oxidative stress and proinflammator
Improving our understanding of the in vivo modelling of psychotic disorders: a systematic review and meta-analysis
Psychotic disorders represent a severe category of mental disorders affecting about one
percent of the population. Individuals experience a loss or distortion of contact with reality
alongside other symptoms, many of which are still not adequately managed using existing
treatments. While animal models of these disorders could offer insights into these disorders
and potential new treatments, translation of this knowledge has so far been poor in terms of
informing clinical trials and practice. The aim of this project was to improve our
understanding of these pre-clinical studies and identify potential weaknesses underlying
translational failure.
I carried out a systematic search of the literature to provide an unbiased summary of
publications reporting animal models of schizophrenia and other psychotic disorders. From
these publications, data were extracted to quantify aspects of the field including reported
quality of studies, study characteristics and behavioural outcome data. The latter of these
data were then used to calculate estimates of efficacy using random-effects meta-analysis.
Having identified 3847 publications of relevance, including 852 different methods used to
induce the model, over 359 different outcomes tested in them and almost 946 different
treatments reported to be administered. I show that a large proportion of studies use simple
pharmacological interventions to induce their models of these disorders, despite the
availability of models using other interventions that are arguably of higher translational
relevance. I also show that the reported quality of these studies is low, and only 22% of
studies report taking measures to reduce the risk of biases such as randomisation and
blinding, which has been shown to affect the reliability of results drawn.
Through this work it becomes apparent that the literature is incredibly vast for studies looking
at animal models of psychotic disorders and that some of the relevant work potentially
overlaps with studies describing other conditions. This means that drawing reliable
conclusions from these data is affected by what is made available in the literature, how it is
reported and identified in a search and the time that it takes to reach these conclusions. I
introduce the idea of using computer-assisted tools to overcome one of these problems in
the long term.
Translation of results from studies looking at animals modelling uniquely-human psychotic
disorders to clinical successes might be improved by better reporting of studies including
publishing of all work carried out, labelling of studies more uniformly so that it is identifiable,
better reporting of study design including improving on reporting of measures taken to
reduce the risk of bias and focusing on models with greater validity to the human condition
Search for lepton flavour violating decays of the Higgs boson to eτand eμin proton–proton collisions at √s=8TeV
A direct search for lepton flavour violating decays of the Higgs boson (H) in the H →eτand H →eμchannels is described. The data sample used in the search was collected in proton–proton collisions at √s=8TeVwith the CMS detector at the LHC and corresponds to an integrated luminosity of 19.7fb−1. No evidence is found for lepton flavour violating decays in either final state. Upper limits on the branching fractions, B(H →eτ) <0.69%and B(H →eμ) <0.035%, are set at the 95% confidence level. The constraint set on B(H →eτ)is an order of magnitude more stringent than the existing indirect limits. The limits are used to constrain the corresponding flavour violating Yukawa couplings, absent in the standard model
Search for neutral resonances decaying into a Z boson and a pair of b jets or tau leptons
Peer reviewe