Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

L’empathie des chercheurs et formateurs confrontés à la question des vulnérabilités. D’un champ de recherche à son expérimentation émotionnelle

International audienc

L’empathie des chercheurs et formateurs confrontés à la question des vulnérabilités. D’un champ de recherche à son expérimentation émotionnelle

International audienc

Place des savoirs scientifiques dans l’enseignement des gestes techniques en formation infirmière initiale ::une étude qualitative descriptive

Contexte : l’universitarisation et le référentiel de la formation infirmière favorisent l’utilisation de savoirs scientifiques et l’intégration des données probantes dans la pratique clinique. Les étudiants en formation initiale sont formés aux gestes techniques. Sur quels savoirs se basent-ils ? Objectif : l’objectif principal de cette étude est d’identifier les savoirs mobilisés par les infirmiers et les formateurs pour enseigner les gestes techniques infirmiers. Méthode : une étude qualitative descriptive a été menée à l’aide d’entretiens semi-dirigés auprès de 16 participants. Résultats : les enseignements des gestes techniques se basent principalement sur des savoirs locaux ou issus de l’autorité. Les formateurs et les infirmières qui mobilisent les savoirs scientifiques réactualisent plus facilement leurs pratiques et leurs enseignements. Comme dans les services de soins, le manque de connaissance et de formation concernant les données probantes et l’utilisation des bases de données ainsi que la maîtrise de l’anglais sont les freins majeurs à l’enseignement des gestes techniques à partir de savoirs scientifiques. Discussion : la mobilisation de données scientifiques dans l’apprentissage des gestes techniques en formation initiale pourrait légitimer les savoirs enseignés, développer la pensée critique des étudiants, et favoriser leur autonomie face aux injonctions protocolaires et aux habitudes de service.Context : Universitarization and the nursing education reference system encourage the use of scientific knowledge and the integration of evidence into clinical practice. Students in initial training are trained in technical gestures. On what knowledge are they based ? Objective : The main objective of this study is to identify the knowledge utilised by nurses and trainers to teach technical nursing procedures. Method : A descriptive qualitative study was carried out using semi-directed interviews with 16 participants. Results : The teaching of nursing skills is mainly based on local or authoritative knowledge. Trainers and nurses who display scientific knowledge update their practices and education more easily. As in health care services, the lack of knowledge and training in evidence-based medicine and the use databases, as well as the lack of English language skills, are the major obstacles to teaching technical procedures based on scientific knowledge. Discussion : The use of scientific data in the learning of technical procedures during initial training could legitimate the knowledge taught, develop the students’ critical thinking and encourage their autonomy in the face of protocol injunctions and service habit

Dégradation de schistes argileux fossilifères (Bassin d’Autun, France, Permien), partie III : pyrite framboïdale et soufre identifiés comme cause principale des efflorescences

International audienceFossil-bearing shale specimens that include sulfides are chemically reactive and sometimes also mechanically fragile. This decay is provoked by iron sulfate efflorescence resulting from the oxidation of sulfide compounds. The processes underlying these degradations are poorly known, thus impeding the elaboration of curative or preventive treatments. The present contribution aims to identify the origin of museum specimen alterations. It focuses on the Flouest collection housed at the Muséum national d'Histoire naturelle (MNHN, Paris, France) and originating from the Autun Basin (Saône-et-Loire, France; Permian). To evaluate the alteration of MNHN specimens, it appeared necessary to compare their composition with that of unaltered shale so as to identify chemical changes occurring during ageing. Therefore new material was collected in the Autun Basin, among others on the locality of Muse that corresponds to the same lithostratigraphic unit than that of the MNHN specimens. This work is divided in three parts. The two first, presented elsewhere, deal with the composition of the shale matrices and led to the conclusion that these matrices could not account for the large iron(II) sulfate efflorescence provoking damage on the MNHN specimens. The last part of this work, presented here, focus on artificial age-ing experiments performed on new shale material. Most of the alterations observed on artificially aged samples correspond to dispersed crystals of calcium sulfate (gypsum). Similar crystals may be found on MNHN specimens, but they are relatively few and sporadically distributed. They are thus considered as damage of secondary importance with respect to iron sulfate efflorescence. These latter could be reproduced on three samples only (upon the 142 aged samples). They were also found on a copro-lite and on a wood remain that had got severely damaged in ambient conditions within a few months after their excavation. On all these samples iron sulfate had grown on brownish layers consisting in crystals of framboidal pyrite (1 to 3 m) and eventually sulfur (20 to 50 m). These brownish layers are associated to thin maceral layers probably because of bacterial activity: during fossil diagenesis, bacteria need organic matter for their metabolism to produce hydrogen sulfide, a precursor of sedi-mentary pyrite formation. Most of the damaged specimens of the Flouest collection show as well a thin maceral layer nearby iron(II) sulfate efflorescence. On one of them, this layer is particularly thick. It corresponds to vitrinite and shows in some areas a brownish aspect. The topology of this surface (observed with scanning electron microscopy) shows numerous small holes (< 2 m) and large holes (10–20 m). This morphology is compatible with a former occurrence of isolated grains and aggregates of framboidal pyrite. These observations suggest that iron sulfate efflorescence was provoked by th

Alteration of fossil-bearing shale (Autun Basin, France; Permian), part I: Characterizing iron speciation and its vulnerability to weathering by combined use of Mössbauer spectroscopy, X-ray diffraction, porosimetry and permeability measurements

Fossil-bearing shale specimens that include sulfides in their compositions are chemically reactive and sometimes also mechanically fragile. This decay is often related to iron sulfate efflorescence resulting from the oxidation of sulfide compounds. The processes underlying these degradations are poorly known, thus impeding the elaboration of curative or preventive treatments. The present contribution aims to identify the origin of museum specimen alterations. It focuses on the Flouest collection housed at the Muséum national d’Histoire naturelle (MNHN, Paris, France) and originating from the Autun Basin (Saône-et-Loire,France; Permian). To evaluate the alteration of MNHN specimens, it appeared necessary to compare their composition with that of unaltered shale so as to identify chemical changes occurring during ageing. Therefore new material was collected in the Autun Basin, among others on the locality of Muse that corresponds to the same lithostratigraphic unit than that of the MNHN specimens. The present article focuseson the combined use of X-ray diffraction and Mössbauer spectrometry for characterizing the speciation and reactivity of iron within the shale matrix. Crystalline pyrite was evidenced by X-ray diffraction (XRD) on one sample only and elemental analysis showed that iron is present in large excess with respect to sulfur. Iron sulfide, if present, involves a minor fraction of iron. A more complete characterization of iron-bearing phases was achieved with Mössbauer measurements, showing that a great part of iron, between approx. 25% and 65%, corresponds to iron(II) incorporated in clay minerals (illite and vermiculite weredetected by XRD). Similar percentages of these iron(II) signatures were found for MNHN specimens and new shale samples, suggesting that iron(II) present in clays is not affected by ageing. This point is complementary highlighted by porosity and permeability measurements showing that the pore size distribution of the samples originating from Muse is mostly unimodal and narrow (average radius below 10 nm). As a result, the shale is poorly permeable to water and almost fully impermeable to oxygen. This might explain the poor reactivity of iron(II) during ageing. Iron(III)-bearing phases were also identified. On new shale samples, they exclusively involve clay minerals. On MNHN specimens, poorly crystallized iron(III) sulfates are additionally observed. The presence of iron(III) oxyhydroxides appeared unlikely. The change of iron speciation provoked by the alteration of the matrix also mainly corresponds to the emergence of more or less crystallized iron(III) sulfates probably formed though iron sulfide oxidation. These phase show ever remain in the inner part of shale and cannot account for the large efflorescence of iron(II) sulfates observed nearby the fossil

Alteration of fossil-bearing shale (Autun Basin, France; Permian), part I: Characterizing iron speciation and its vulnerability to weathering by combined use of Mössbauer spectroscopy, X-ray diffraction, porosimetry and permeability measurements

Fossil-bearing shale specimens that include sulfides in their compositions are chemically reactive and sometimes also mechanically fragile. This decay is often related to iron sulfate efflorescence resulting from the oxidation of sulfide compounds. The processes underlying these degradations are poorly known, thus impeding the elaboration of curative or preventive treatments. The present contribution aims to identify the origin of museum specimen alterations. It focuses on the Flouest collection housed at the Muséum national d’Histoire naturelle (MNHN, Paris, France) and originating from the Autun Basin (Saône-et-Loire,France; Permian). To evaluate the alteration of MNHN specimens, it appeared necessary to compare their composition with that of unaltered shale so as to identify chemical changes occurring during ageing. Therefore new material was collected in the Autun Basin, among others on the locality of Muse that corresponds to the same lithostratigraphic unit than that of the MNHN specimens. The present article focuseson the combined use of X-ray diffraction and Mössbauer spectrometry for characterizing the speciation and reactivity of iron within the shale matrix. Crystalline pyrite was evidenced by X-ray diffraction (XRD) on one sample only and elemental analysis showed that iron is present in large excess with respect to sulfur. Iron sulfide, if present, involves a minor fraction of iron. A more complete characterization of iron-bearing phases was achieved with Mössbauer measurements, showing that a great part of iron, between approx. 25% and 65%, corresponds to iron(II) incorporated in clay minerals (illite and vermiculite weredetected by XRD). Similar percentages of these iron(II) signatures were found for MNHN specimens and new shale samples, suggesting that iron(II) present in clays is not affected by ageing. This point is complementary highlighted by porosity and permeability measurements showing that the pore size distribution of the samples originating from Muse is mostly unimodal and narrow (average radius below 10 nm). As a result, the shale is poorly permeable to water and almost fully impermeable to oxygen. This might explain the poor reactivity of iron(II) during ageing. Iron(III)-bearing phases were also identified. On new shale samples, they exclusively involve clay minerals. On MNHN specimens, poorly crystallized iron(III) sulfates are additionally observed. The presence of iron(III) oxyhydroxides appeared unlikely. The change of iron speciation provoked by the alteration of the matrix also mainly corresponds to the emergence of more or less crystallized iron(III) sulfates probably formed though iron sulfide oxidation. These phase show ever remain in the inner part of shale and cannot account for the large efflorescence of iron(II) sulfates observed nearby the fossil

Prognostic value of ERM gene expression in human primary breast cancers

We measured the expression of ERM gene, a nuclear transcription factor belonging to the ets family, in a series of 364 unselected primary breast cancers from patients who underwent locoregional surgery in the Centre Oscar Lambret between May 1989 and December 1991. The expression of ERM was quantified with a real-time one-step reverse transcription-PCR assay based on the 5′-nuclease activity of the TaqDNA polymerase and with an Abi Prism 7700 Sequence Detector System (Applied Biosystems, Courtaboeuf, France). ERM was positively correlated (Spearman test) to epidermal growth factor receptor (EGFR; P < 0.001, r = 0.296) and to histoprognostic grading (P = 0.044, r = 0.112), whereas it was negatively correlated to estradiol receptors (P = 0.019, r = -0.124), HER3 (c-erbB-3; P = 0.01, r = -0.135), and HER4 (c-erbB-4; P = 0.003, r = -0.154). Using the χ2 test, a positive relationship was found between the expression of ERM and EGFR (χ2 = 7.795, P = 0.007). In overall survival studies, Cox univariate analyses demonstrated a prognostic value of ERM (P = 0.006; risk ratio, 2.95) besides the classical prognostic factors histoprognostic grading, node involvement, tumor size, estradiol receptors, progesterone receptors, EGFR, HER3, and HER4. In multivariate analyses, ERM preserved its prognostic value (P = 0.004; risk ratio, 3.779) together with histoprognostic grading, tumor size, estradiol receptors, and progesterone receptors. In relapse-free survival studies, univariate analyses demonstrated that histoprognostic grading, node involvement, tumor size, and HER4 were prognostic factors. These parameters, except histoprognostic grading, retained their prognostic value in multivariate analyses. This study demonstrates for the first time that ERM gene expression is an independent adverse prognostic factor for overall survival in breast cancer patients.SCOPUS: ar.jinfo:eu-repo/semantics/publishe