244 research outputs found

    GM1 as adjuvant of innovative therapies for cystic fibrosis disease

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    Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein is expressed at the apical plasma membrane (PM) of different epithelial cells. The most common mutation responsible for the onset of cystic fibrosis (CF), F508del, inhibits the biosynthesis and transport of the protein at PM, and also presents gating and stability defects of the membrane anion channel upon its rescue by the use of correctors and potentiators. This prompted a multiple drug strategy for F508delCFTR aimed simultaneously at its rescue, functional potentiation and PM stabilization. Since ganglioside GM1 is involved in the functional stabilization of transmembrane proteins, we investigated its role as an adjuvant to increase the effectiveness of CFTR modulators. According to our results, we found that GM1 resides in the same PM microenvironment as CFTR. In CF cells, the expression of the mutated channel is accompanied by a decrease in the PM GM1 content. Interestingly, by the exogenous administration of GM1, it becomes a component of the PM, reducing the destabilizing effect of the potentiator VX-770 on rescued CFTR protein expression/function and improving its stabilization. This evidence could represent a starting point for developing innovative therapeutic strategies based on the co-administration of GM1, correctors and potentiators, with the aim of improving F508del CFTR function

    Rationale and design of an independent randomised controlled trial evaluating the effectiveness of aripiprazole or haloperidol in combination with clozapine for treatment-resistant schizophrenia

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    <p>Abstract</p> <p>Background</p> <p>One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers has progressively increased the occurrence of antipsychotic polypharmacy, despite the lack of robust evidence of its efficacy, we sought to implement a pre-planned protocol where two alternative therapeutic answers are systematically provided and evaluated within the context of a pragmatic, multicentre, independent randomised study.</p> <p>Methods/Design</p> <p>The principal clinical question to be answered by the present project is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared with combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. This project is a prospective, multicentre, randomized, parallel-group, superiority trial that follow patients over a period of 12 months. Withdrawal from allocated treatment within 3 months is the primary outcome.</p> <p>Discussion</p> <p>The implementation of the protocol presented here shows that it is possible to create a network of community psychiatric services that accept the idea of using their everyday clinical practice to produce randomised knowledge. The employed pragmatic attitude allowed to randomly allocate more than 100 individuals, which means that this study is the largest antipsychotic combination trial conducted so far in Western countries. We expect that the current project, by generating evidence on whether it is clinically useful to combine clozapine with aripiprazole rather than with haloperidol, provides physicians with a solid evidence base to be directly applied in the routine care of patients with schizophrenia.</p> <p>Trial Registration</p> <p><b>Clincaltrials.gov Identifier</b>: NCT00395915</p

    Les droits disciplinaires des fonctions publiques : « unification », « harmonisation » ou « distanciation ». A propos de la loi du 26 avril 2016 relative à la déontologie et aux droits et obligations des fonctionnaires

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    The production of tt‾ , W+bb‾ and W+cc‾ is studied in the forward region of proton–proton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98±0.02 fb−1 . The W bosons are reconstructed in the decays W→ℓν , where ℓ denotes muon or electron, while the b and c quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions.The production of ttt\overline{t}, W+bbW+b\overline{b} and W+ccW+c\overline{c} is studied in the forward region of proton-proton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98 ±\pm 0.02 \mbox{fb}^{-1}. The WW bosons are reconstructed in the decays WνW\rightarrow\ell\nu, where \ell denotes muon or electron, while the bb and cc quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions

    Understanding Factors Associated With Psychomotor Subtypes of Delirium in Older Inpatients With Dementia

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    Research and Development for Near Detector Systems Towards Long Term Evolution of Ultra-precise Long-baseline Neutrino Experiments

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    With the discovery of non-zero value of θ13\theta_{13} mixing angle, the next generation of long-baseline neutrino (LBN) experiments offers the possibility of obtaining statistically significant samples of muon and electron neutrinos and anti-neutrinos with large oscillation effects. In this document we intend to highlight the importance of Near Detector facilities in LBN experiments to both constrain the systematic uncertainties affecting oscillation analyses but also to perform, thanks to their close location, measurements of broad benefit for LBN physics goals. A strong European contribution to these efforts is possible

    Measurement of CP violation parameters and polarisation fractions in Bs0J/ψK0 {\mathrm{B}}_{\mathrm{s}}^0\to \mathrm{J}/\psi {\overline{\mathrm{K}}}^{\ast 0} decays

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    The first measurement of C ⁣P{C\!P} asymmetries in the decay Bs0J/ψK(892)0{B_s^0\to J/\psi \overline{K}^{*}(892)^{0}} and an updated measurement of its branching fraction and polarisation fractions are presented. The results are obtained using data corresponding to an integrated luminosity of 3.0fb13.0\,fb^{-1} of proton-proton collisions recorded with the LHCb detector at centre-of-mass energies of 77 and 8TeV8\,\mathrm{TeV}. Together with constraints from B0J/ψρ0{B^0\to J/\psi \rho^0}, the results are used to constrain additional contributions due to penguin diagrams in the C ⁣P{C\!P}-violating phase ϕs{{\phi}_{s}}, measured through Bs0{B_s^0} decays to charmonium.The first measurement of CP asymmetries in the decay Bs0J/ψK(892)0 {B}_s^0\to J/\psi {\overline{\mathrm{K}}}^{\ast }{(892)}^0 and an updated measurement of its branching fraction and polarisation fractions are presented. The results are obtained using data corresponding to an integrated luminosity of 3.0 fb^{−}^{1} of proton-proton collisions recorded with the LHCb detector at centre-of-mass energies of 7 and 8 TeV. Together with constraints from B0^{0} → J/ψ ρ0^{0}, the results are used to constrain additional contributions due to penguin diagrams in the CP -violating phase ϕs_{s} , measured through Bs0_{s}^{0} decays to charmonium.The first measurement of C ⁣P{C\!P} asymmetries in the decay Bs0J/ψK(892)0{B_s^0\to J/\psi \overline{K}^{*}(892)^{0}} and an updated measurement of its branching fraction and polarisation fractions are presented. The results are obtained using data corresponding to an integrated luminosity of 3.0fb13.0\,fb^{-1} of proton-proton collisions recorded with the LHCb detector at centre-of-mass energies of 77 and 8TeV8\,\mathrm{TeV}. Together with constraints from B0J/ψρ0{B^0\to J/\psi \rho^0}, the results are used to constrain additional contributions due to penguin diagrams in the C ⁣P{C\!P}-violating phase ϕs{{\phi}_{s}}, measured through Bs0{B_s^0} decays to charmonium

    Measurement of the J/ψ pair production cross-section in pp collisions at s=13 \sqrt{s}=13 TeV

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    The production cross-section of J/ψ pairs is measured using a data sample of pp collisions collected by the LHCb experiment at a centre-of-mass energy of s=13 \sqrt{s}=13 TeV, corresponding to an integrated luminosity of 279 ±11 pb1^{−1}. The measurement is performed for J/ψ mesons with a transverse momentum of less than 10 GeV/c in the rapidity range 2.0 < y < 4.5. The production cross-section is measured to be 15.2 ± 1.0 ± 0.9 nb. The first uncertainty is statistical, and the second is systematic. The differential cross-sections as functions of several kinematic variables of the J/ψ pair are measured and compared to theoretical predictions.The production cross-section of J/ψJ/\psi pairs is measured using a data sample of pppp collisions collected by the LHCb experiment at a centre-of-mass energy of s=13TeV\sqrt{s} = 13 \,{\mathrm{TeV}}, corresponding to an integrated luminosity of 279±11pb1279 \pm 11 \,{\mathrm{pb^{-1}}}. The measurement is performed for J/ψJ/\psi mesons with a transverse momentum of less than 10GeV/c10 \,{\mathrm{GeV}}/c in the rapidity range 2.0<y<4.52.0<y<4.5