Modeling the world oceans with TELEMAC

Hydrodynamic

Modelling historical global tsunamis with TELEMAC

Hydrodynamic

Metocean regional models using TELEMAC

Hydrodynamic

Validation of TELEMAC for tsunami inundation modelling in compliance with the NOAA-NTHMP benchmark test cases

Hydrodynamic

Physiopathologie des malformations du développement cortical associées à des mutations du gène tubuline b3

D une organisation très complexe, le cortex résulte de différents processus coordonnés qui comprennent la neurogenèse, la migration et la différenciation neuronales. L altération d un ou plusieurs de ces processus peut entrainer chez l homme l apparition de malformations du développement cortical (MDC).L identification de mutations chez des patients présentant des MDC dans les gènes DCX et LIS1 codant des protéines s associant directement ou indirectement aux microtubules a montré le rôle primordial du cytosquelette dans le développement cortical. Ce constat fut renforcé par la découverte de mutations dans des gènes codant des sous-unités tubulines elles-mêmes (TUBA1A, TUBB2B et TUBB5), unités structurelles et fonctionnelles des microtubules.Notre étude apporte des contributions à cette observation importante. En effet, nous avons tout d abord identifié l'existence de six mutations faux-sens dans le gène TUBB3, chez douze patients, incluant un cas fœtal. Les mutations ont été trouvées principalement à l'état hétérozygote et peuvent être de novo ou transmises selon un mode autosomique dominant. Tous les patients ont en commun des anomalies complexes du développement du cortex, évocatrices de polymicrogyries frontales ou de désorganisations et simplifications gyrales en combinaison avec des anomalies du corps calleux et de la capsule interne des ganglions de la base ainsi qu'une hypoplasie du pont et du cervelet. La deuxième partie de ce travail s intéresse à l effet de la perte d expression de la tubuline b3 et des mutations responsables de MDC sur les processus de la migration radiaire des neurones pyramidaux par une approche d électroporation in utero chez la souris. L inactivation de Tubb3 entraine un défaut de migration drastique : la majorité des cellules électroporées sont présentes dans la zone sous ventriculaire et la zone intermédiaire. Des explorations montrent une diminution du nombre de cellules multipolaires présentant des processus multiples et bien élongés, et une augmentation du nombre de cellules rondes ne présentant pas ou peu de processus. Ces résultats laissent penser que la diminution de Tubb3 entraine des défauts du contrôle des étapes de multipolarisation et rebipolarisation des neurones pyramidaux lors de la migration radiale. Nous avons également mis en évidence une augmentation de la population de progéniteurs intermédiaires électroporés avec l ARNsh anti-Tubb3. Cette augmentation est accompagnée d une forte diminution de leur division cellulaire. Ce résultat soulève de nombreuses questions sur le rôle potentiel de Tubb3 dans cette population. Enfin, nous avons pu constater que l arrêt de migration observé peut être sauvé par une surexpression du transcrit de TUBB3 alors que les tubulines TUBB1, TUBB2B et TUBB4A sont dans l incapacité de restaurer pleinement la migration radiaire des neurones sous exprimant Tubb3. Ces observations tendent à étayer l hypothèse selon laquelle les sous unités tubulines possèdent des spécificités fonctionnelles.Dans l ensemble, nos travaux montrent donc que des mutations de TUBB3 sont liées à des formes de MDC et que Tubb3 joue un rôle important dans la migration des neurones pyramidaux chez la souris, notamment par le contrôle des changements morphologiques qui interviennent dans la phase multipolaire. Enfin, nous apportons une nouvelle proposition d interdépendance entre l arrêt de migration neuronale et la division des progéniteurs neuronaux dans le développement cortical.Over the last years, the critical role of the cytoskeletal network in the proper cortical development has been established. The importance of microtubules was further emphasized with the association of mutations in gene encoding for alpha-tubulin (TUBA1A, TUBA8), beta-tubulin (TUBB2B) in malformations of cortical development (MCD) including lissencephalies and polymicrogyria (Keays 2007, Poirier 2007, Jaglin 2009, Abdollahi 2009) and TUBB5 in microcephaly with cortical gyration abnormalities. We report the implication of TUBB3 missense mutations in polymicrogyria and cortical simplifications in 6 different families including a foetal case harboring a severe micerolissencephaly.We investigated the properties of MT network in patients' fibroblasts and revealed that MCD-related mutations can alter the resistance of microtubules to depolymerisation. These results led us to hypothesise that either microtubule dynamics or their interactions with various MT interacting proteins could be differently affected by TUBB3 variations, thus resulting in distinct alteration of downstream processes and therefore explaining the phenotypic diversity of the TUBB3-related spectrum. In a second time, we investigate further the association between TUBB3 mutations and MCDs by analyzing the consequences of Tubb3 knockdown on cortical development in mice. Using the in utero electroporation approach, we demonstrate that Tubb3 knockdown leads to delayed bipolar morphology and radial migration with evidence suggesting that the neuronal arrest is a transient phenomenon overcome after birth. Silenced blocked cells display a round shape and decreased number of processes and a delay in the acquisition of the bipolar morphology. Also, more Tbr2 positive cells are observed, although less cells express the proliferation marker Ki67, suggesting that Tubb3 inactivation might have an indirect effect on intermediate progenitor proliferation. Furthermore, we show by rescue experiments the non interchangeability of other beta-tubulins which are unable to rescue the phenotype. Our study highlights the critical and specific role of Tubb3 on the stereotyped morphological changes and polarization processes that are required for initiating radial migration to the cortical plate.PARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF

Patient Experience Shows Little Relationship with Hospital Quality Management Strategies.

OBJECTIVES: Patient-reported experience measures are increasingly being used to routinely monitor the quality of care. With the increasing attention on such measures, hospital managers seek ways to systematically improve patient experience across hospital departments, in particular where outcomes are used for public reporting or reimbursement. However, it is currently unclear whether hospitals with more mature quality management systems or stronger focus on patient involvement and patient-centered care strategies perform better on patient-reported experience. We assessed the effect of such strategies on a range of patient-reported experience measures. MATERIALS AND METHODS: We employed a cross-sectional, multi-level study design randomly recruiting hospitals from the Czech Republic, France, Germany, Poland, Portugal, Spain, and Turkey between May 2011 and January 2012. Each hospital contributed patient level data for four conditions/pathways: acute myocardial infarction, stroke, hip fracture and deliveries. The outcome variables in this study were a set of patient-reported experience measures including a generic 6-item measure of patient experience (NORPEQ), a 3-item measure of patient-perceived discharge preparation (Health Care Transition Measure) and two single item measures of perceived involvement in care and hospital recommendation. Predictor variables included three hospital management strategies: maturity of the hospital quality management system, patient involvement in quality management functions and patient-centered care strategies. We used directed acyclic graphs to detail and guide the modeling of the complex relationships between predictor variables and outcome variables, and fitted multivariable linear mixed models with random intercept by hospital, and adjusted for fixed effects at the country level, hospital level and patient level. RESULTS: Overall, 74 hospitals and 276 hospital departments contributed data on 6,536 patients to this study (acute myocardial infarction n = 1,379, hip fracture n = 1,503, deliveries n = 2,088, stroke n = 1,566). Patients admitted for hip fracture and stroke had the lowest scores across the four patient-reported experience measures throughout. Patients admitted after acute myocardial infarction reported highest scores on patient experience and hospital recommendation; women after delivery reported highest scores for patient involvement and health care transition. We found no substantial associations between hospital-wide quality management strategies, patient involvement in quality management, or patient-centered care strategies with any of the patient-reported experience measures. CONCLUSION: This is the largest study so far to assess the complex relationship between quality management strategies and patient experience with care. Our findings suggest absence of and wide variations in the institutionalization of strategies to engage patients in quality management, or implement strategies to improve patient-centeredness of care. Seemingly counterintuitive inverse associations could be capturing a scenario where hospitals with poorer quality management were beginning to improve their patient experience. The former suggests that patient-centered care is not yet sufficiently integrated in quality management, while the latter warrants a nuanced assessment of the motivation and impact of involving patients in the design and assessment of services

De novo TUBB2B mutation causes fetal akinesia deformation sequence with microlissencephaly: an unusual presentation of tubulinopathy

International audienceTubulinopathies are increasingly emerging major causes underlying complex cerebral malformations, particularly in case of microlissencephaly often associated with hypoplastic or absent corticospinal tracts. Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. We report on an early foetal case with FADS and microlissencephaly due to TUBB2B mutation. Neuropathological examination disclosed virtually absent cortical lamination, foci of neuronal overmigration into the leptomeningeal spaces, corpus callosum agenesis, cerebellar and brainstem hypoplasia and extremely severe hypoplasia of the spinal cord with no anterior and posterior horns and almost no motoneurons. At the cellular level, the p.Cys239Phe TUBB2B mutant leads to tubulin heterodimerization impairment, decreased ability to incorporate into the cytoskeleton, microtubule dynamics alteration, with an accelerated rate of depolymerization. To our knowledge, this is the first case of microlissencephaly to be reported presenting with a so severe and early form of FADS, highlighting the importance of tubulin mutation screening in the context of FADS with microlissencephaly

Review of multidrug-resistant and extensively drug-resistant TB: global perspectives with a focus on sub-Saharan Africa

Tuberculosis (TB) remains a global emergency and is responsible for 1.7 million deaths annually. Widespread global misuse of isoniazid and rifampicin over three decades has resulted in emergence of the ominous spread of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) globally. These difficult to treat resistant forms of TB are increasingly seen in Asia, Eastern Europe, South America and sub-Saharan Africa, disrupting TB and HIV control programmes. We review the latest available global epidemiological and clinical evidence on drug-resistant TB in HIV-infected and uninfected populations, with focus on Africa where data are scanty because of poor diagnostic and reporting facilities. The difficult management and infection control problems posed by drug-resistant TB in HIV-infected patients are discussed. Given the increasing current global trends in MDR-TB, aggressive preventive and management strategies are urgently required to avoid disruption of global TB control efforts. The data suggest that existing interventions, public health systems and TB and HIV programmes must be strengthened significantly. Political and funder commitment is essential to curb the spread of drug-resistant TB

MYOD1 involvement in myopathy

[Excerpt] Introduction Myogenic Differentiation 1 (MYOD1) encodes a transcription factor that plays an important role in myogenic determination into mature skeletal muscle [1]. The first loss-of-function mutation of MYOD1 in humans was described in three siblings with perinatal lethal fetal akinesia [2].[...]We thank the individual and family. Funding was provided by The Fonds de recherche du Québec - Santé (FRQS) and Canadian Institutes of Health Research (CIHR) to P.M.C., Fundação para a Ciência e Tecnologia (FCT) with the fellowship SFRH/BD/84650/2010 to F.L. and Groupe Pasteur Mutualité Foundation (GPM Foundation) to M.M.info:eu-repo/semantics/publishedVersio