1,222 research outputs found

    Implanted reuptake-deficient or wild-type dopaminergic neurons improve ON l-dopa dyskinesias without OFF-dyskinesias in a rat model of Parkinson's disease

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    OFF-l-dopa dyskinesias have been a surprising side-effect of intrastriatal foetal ventral mesencephalic transplantation in patients with Parkinson's disease. It has been proposed that excessive and unregulated dopaminergic stimulation of host post-synaptic striatal neurons by the grafts could be responsible for these dyskinesias. To address this issue we transplanted foetal dopaminergic neurons from mice lacking the dopamine transporter (DATKO) or from wild-type mice, into a rat model of Parkinson's disease and l-dopa-induced dyskinesias. Both wild-type and DATKO grafts reinnervated the host striatum to a similar extent, but DATKO grafts produced a greater and more diffuse increase in extra-cellular striatal dopamine levels. Interestingly, grafts containing wild-type dopaminergic neurons improved parkinsonian signs to a similar extent as DATKO grafts, but provided a more complete reduction of l-dopa induced dyskinesias. Neither DATKO nor wild-type grafts induced OFF-l-dopa dyskinesias. Behavioural and receptor autoradiography analyses demonstrated that DATKO grafts induced a greater normalization of striatal dopaminergic receptor supersensitivity than wild-type grafts. Both graft types induced a similar downregulation and normalization of PEnk and fosb/Δfosb in striatal neurons. In summary, DATKO grafts causing high and diffuse extra-cellular dompamine levels do not per se alter graft-induced recovery or produce OFF-l-dopa dyskinesias. Wild-type dopaminergic neurons appear to be the most effective neuronal type to restore function and reduce l-dopa-induced dyskinesias

    Variability in prescription drug expenditures explained by adjusted clinical groups (ACG) case-mix: A cross-sectional study of patient electronic records in primary care

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    <p>Abstract</p> <p>Background</p> <p>In view of rapidly increasing prescription costs, case-mix adjustment should be considered for effective control of costs. We have estimated the variability in pharmacy costs explained by ACG in centers using patient electronic records, profiled centers and physicians and analyzed the correlation between cost and quality of prescription.</p> <p>Methods</p> <p>We analyzed 65,630 patient records attending five primary care centers in Spain during 2005. Variables explored were age, gender, registered diagnosed episodes of care during 2005, total cost of prescriptions, physician and center. One ACG was assigned to each patient with ACG case-mix software version 7.1. In a two-part model, logistic regression was used to explain the incurrence of drug expenditure at the first stage and a linear mixed model that considered the multilevel structure of data modeled the cost, conditional upon incurring any expense. Risk and efficiency indexes in pharmacy cost adjusted for ACG were obtained for centers and physicians. Spearman rank correlation between physician expenditure, adjusted for ACG, and a prescription quality index was also obtained. Pediatric and adult data were analyzed separately.</p> <p>Results</p> <p>No prescription was recorded for 13% of adults and 39.6% of children. The proportion of variance of the incurrence of expenditure explained by ACGs was 0.29 in adults and 0.21 in children. For adults with prescriptions, the variance of cost explained by ACGs was 35.4%, by physician-center was 1.8% and age 10.5% (residual 52.3%). For children, ACGs explained 22.4% of cost and physician-center 10.9% (residual 66.7%). Center efficiency index for adults ranged 0.58 to 1.22 and for children 0.32 to 2.36.</p> <p>Spearman correlation between expenditure and prescription quality index was -0.36 in family physicians (p = 0.019, N = 41) and -0.52 in pediatricians (p = 0.08, N = 12).</p> <p>Conclusion</p> <p>In our setting, ACG is the variable studied that explains more variability in pharmacy cost in adults compared to physician and center. In children there is greater variability among physicians and centers not related to case-mix. In our sites, ACG is useful to profile physicians and centers using electronic records in real practical conditions. Physicians with lower pharmaceutical expenditure have higher scores for a prescription quality index.</p

    An analysis of returned medicines in primary care

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    Objective: The number of pharmaceutical items issued on prescription is continually rising and contributing to spiralling healthcare costs. Although there is some data highlighting the quantity, in terms of weight of medicines returned specifically to community pharmacies, little is known about the specific details of such returns or other destinations for wasted medications. This pilot study has been designed to investigate the types and amounts of medicines returned to both general practices (GPs) and associated local community pharmacies determining the reasons why these medicines have been returned. Method: The study was conducted in eight community pharmacies and five GP surgeries within East Birmingham over a 4-week period. Main outcome Measure: Reason for return and details of returned medication. Results: A total of 114 returns were made during the study: 24 (21.1) to GP surgeries and 90 (78.9) to community pharmacies. The total returns comprised 340 items, of which 42 (12.4) were returned to GPs and 298 (87.6) to pharmacies, with the mean number of items per return being 1.8 and 3.3, respectively. Half of the returns in the study were attributed to the doctor changing or stopping the medicine; 23.7 of returns were recorded as excess supplies or clearout often associated with patients' death and 3.5 of returns were related to adverse drug reactions. Cardiovascular drugs were most commonly returned, amounting to 28.5 of the total drugs returned during the study. Conclusions: The results from this pilot study indicate that unused medicines impose a significant financial burden on the National Health Service as well as a social burden on the United Kingdom population. Further studies are examining the precise nature of returned medicines and possible solutions to these issues. © Springer 2005

    Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

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    This paper presents measurements of the W+μ+νW^+ \rightarrow \mu^+\nu and WμνW^- \rightarrow \mu^-\nu cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

    Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

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    A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

    Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

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    Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

    Oct4-Induced Reprogramming Is Required for Adult Brain Neural Stem Cell Differentiation into Midbrain Dopaminergic Neurons

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    Neural stem cells (NSCs) lose their competency to generate region-specific neuronal populations at an early stage during embryonic brain development. Here we investigated whether epigenetic modifications can reverse the regional restriction of mouse adult brain subventricular zone (SVZ) NSCs. Using a variety of chemicals that interfere with DNA methylation and histone acetylation, we showed that such epigenetic modifications increased neuronal differentiation but did not enable specific regional patterning, such as midbrain dopaminergic (DA) neuron generation. Only after Oct-4 overexpression did adult NSCs acquire a pluripotent state that allowed differentiation into midbrain DA neurons. DA neurons derived from Oct4-reprogrammed NSCs improved behavioural motor deficits in a rat model of Parkinson's disease (PD) upon intrastriatal transplantation. Here we report for the first time the successful differentiation of SVZ adult NSCs into functional region-specific midbrain DA neurons, by means of Oct-4 induced pluripotency
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