KIF1C Variants Are Associated with Hypomyelination, Ataxia, Tremor, and Dystonia in Fraternal Twins

Background: KIF1C (Kinesin Family Member 1C) variants have been associated with hereditary spastic paraplegia and spastic ataxia. Case report: We report fraternal twins presenting with cerebellar ataxia and dystonic tremor. Their brain MRI showed a hypomyelinating leukoencephalopathy. Whole exome sequencing identified a homozygous KIF1C variant in both patients. Discussion: KIF1C variants can manifest as a complex movement disorder with cerebellar ataxia and dystonic tremor. KIF1C variants may also cause a hypomyelinating leukoencephalopathy

Abnormal Functional Integration of Thalamic Low Frequency Oscillation in the BOLD Signal After Acute Heroin Treatment

Heroin addiction is a severe relapsing brain disorder associated with impaired cognitive control, including deficits in attention allocation. The thalamus has a high density of opiate receptors and is critically involved in orchestrating cortical activity during cognitive control. However, there have been no studies on how acute heroin treatment modulates thalamic activity. In a cross-over, double-blind, vehicle-controlled study, 29 heroin-maintained outpatients were studied after heroin and placebo administration, while 20 healthy controls were included for the placebo condition only. Resting-state functional magnetic resonance imaging was used to analyze functional integration of the thalamus by three different resting state analysis techniques. Thalamocortical functional connectivity (FC) was analyzed by seed-based correlation, while intrinsic thalamic oscillation was assessed by analysis of regional homogeneity (ReHo) and the fractional amplitude of low frequency fluctuations (fALFF). Relative to the placebo treatment and healthy controls, acute heroin administration reduced thalamocortical FC to cortical regions, including the frontal cortex, while the reductions in FC to the mediofrontal cortex, orbitofrontal cortex, and frontal pole were positively correlated with the plasma level of morphine, the main psychoactive metabolite of heroin. Furthermore, heroin treatment was associated with increased thalamic ReHo and fALFF values, whereas fALFF following heroin exposure correlated negatively with scores of attentional control. The heroin-associated increase in fALFF was mainly dominated by slow-4 (0.027-0.073 Hz) oscillations. Our findings show that there are acute effects of heroin within the thalamocortical system and may shed new light on the role of the thalamus in cognitive control in heroin addiction. Future research is needed to determine the underlying physiological mechanisms and their role in heroin addiction

Improving the deterministic skill of air quality ensembles

<p><strong>Abstract.</strong> Forecasts from chemical weather models are subject to uncertainties in the input data (e.g. emission inventory, initial and boundary conditions) as well as the model itself (e.g. physical parameterization, chemical mechanism). Multi-model ensemble forecasts can improve the forecast skill provided that certain mathematical conditions are fulfilled. We demonstrate through an intercomparison of two dissimilar air quality ensembles that unconditional raw forecast averaging, although generally successful, is far from optimum. One way to achieve an optimum ensemble is also presented. The basic idea is to either add optimum weights to members or constrain the ensemble to those members that meet certain conditions in time or frequency domain. The methods are evaluated against ground level observations collected from the EMEP and Airbase databases.<br><br> The two ensembles were created for the first and second phase of the Air Quality Model Evaluation International Initiative (AQMEII). Verification statistics shows that the deterministic models simulate better O<sub>3</sub> than NO<sub>2</sub> and PM<sub>10</sub>, linked to different levels of complexity in the represented processes. The ensemble mean achieves higher skill compared to each station's best deterministic model at 39 %–63 % of the sites. The skill gained from the favourable ensemble averaging has at least double the forecast skill compared to using the full ensemble. The method proved robust for the 3-monthly examined time-series if the training phase comprises 60 days. Further development of the method is discussed in the conclusion.</p&gt

Emergency department triage: an ethical analysis

<p>Abstract</p> <p>Background</p> <p>Emergency departments across the globe follow a triage system in order to cope with overcrowding. The intention behind triage is to improve the emergency care and to prioritize cases in terms of clinical urgency.</p> <p>Discussion</p> <p>In emergency department triage, medical care might lead to adverse consequences like delay in providing care, compromise in privacy and confidentiality, poor physician-patient communication, failing to provide the necessary care altogether, or even having to decide whose life to save when not everyone can be saved. These consequences challenge the ethical quality of emergency care. This article provides an ethical analysis of "routine" emergency department triage. The four principles of biomedical ethics - viz. respect for autonomy, beneficence, nonmaleficence and justice provide the starting point and help us to identify the ethical challenges of emergency department triage. However, they do not offer a <it>comprehensive </it>ethical view. To address the ethical issues of emergency department triage from a more comprehensive ethical view, the care ethics perspective offers additional insights.</p> <p>Summary</p> <p>We integrate the results from the analysis using four principles of biomedical ethics into care ethics perspective on triage and propose an integrated clinically and ethically based framework of emergency department triage planning, as seen from a comprehensive ethics perspective that incorporates both the principles-based and care-oriented approach.</p

Les Neuropathies des Mitochondriopathies (étude de 18 cas et revue de la littérature)

Les maladies mitochondriales sont un groupe hétérogène de maladies dont le spectre évolue avec les connaissances médicales. L atteinte neuro-musculaire, myopathie ou neuropathie sensitive, en est un trait classique. L objectif de ce travail est de décrire la variabilité des atteintes du nerf périphérique en rapport avec une mitochondriopathie.Les patients ont été inclus rétrospectivement, parmi les consultant entre 1998 et 2012 au Centre de Références Maladies Rares du CHU Bicêtre, pour une neuropathie et ayant eu une biopsie musculaire +/- nerveuse avec étude de la chaîne respiratoire et de l ADN mitochondrial. Les patients inclus avaient un diagnostic prouvé, probable ou possible de mitochondriopathie. Dix-huit patients remplissaient les critères d inclusion, 7 ont une mitochondriopathie prouvée (2 MNGIE par mutation thymidine phosphorylase, 2 pseudo MNGIE par mutation POLG, 2 neuropathies, l une axonale, l autre mixte, associées à une atrophie optique, avec mutation Mitofusine 2, une ganglionopathie associée à un syndrome extrapyramidal avec mutation Twinkle), 4 une mitochondriopathie probable avec des phénotypes évocateurs et des anomalies histologiques, biochimiques et/ou moléculaires, 7 une mitochondriopathie possible dont 5 avec neuropathie démyélinisante. Ces résultats concordent avec certaines données de la littérature, notamment concernant les MNGIE et pseudo MNGIE, offrent un éclairage intéressant sur la Mitofusine 2 en tant que cytopathie mitochondriale, et permettent de discuter la pathogénicité de certaines mutations. Par ailleurs, ils offrent un regard nouveau sur l atteinte neurologique périphérique des mitochondriopathies, qu il conviendra de confirmer par des études prospectives. Un arbre diagnostique est donc proposé pour la prise en charge des neuropathies des mitochondriopathies, qui pourra être modifié en fonction des données ultérieures. Une fiche clinique à introduire dans les dossiers est également élaborée, destinée à favoriser un suivi prospectif efficace.Mitochondrial Diseases constitute a broad spectrum of phenotypes. Myopathies and sensitive neuropathies are typical features of neuro-muscular involvement. The aim of this study is to describe the various patterns of peripheral neuropathies in mitochondrial cytopathies. Patients were included retrospectively among patients referred to the Reference Centre of Rare Diseases (CRMR) of Bicêtre Hospital between 1998 and 2012 for symptoms of neuropathy and having undergone a muscle (and nerve) biopsy, including analysis of the respiratory chain and mitochondrial DNA. Patients with proven, probable or possible mitochondrial cytopathies were included in the study. Eighteen patients matched inclusion criteria, seven have a proven mutation: two have a heterozygote thymidine phosphorylase mutation accounting for the MNGIE syndrom, two have a POLG mutation accounting for the pseudo MNGIE phenotype, two more have a Mitofusine 2 mutation, associated with an axonal neuropathy or mixed neuropathy with optic atrophy. The last one has a Twinkle mutation with sensitive neuronopathy and parkinsonism. Four more patients presented a strong suspicion of mitochondriopathy with compatible phenotypes and histological, biochemical or molecular abnormalities. The last seven are light suspicions with some analyses still running. Our results exhibit good match with literature on MNGIE and pseudo MNGIE. They shine a new light on Mitofusine 2 as a mitochondrial cytopathy and give us the occasion of a debate on mutations pathogenicity. We propose a diagnostic tree from symptoms to genetic findings that will probably change with the future medical progress, and a clinical data-sheet to be included in the medical file to help physicians in the follow-up of patients.ST QUENTIN EN YVELINES-BU (782972101) / SudocSudocFranceF

Bases moléculaires des angiomes caverneux héréditaires

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF