Étude de l'effet de l'antibiothérapie et de l'anticoagulothérapie sur le développement de la sclérodermie expérimentale chez la souris

La sclérose systémique (SSc) est une maladie auto-immune chronique incurable caractérisée par une présentation clinique complexe et hétérogène. Notre laboratoire a développé un modèle murin de fibrose pulmonaire et cutanée qui est induit par l’immunisation répétitive avec des cellules dendritiques chargées avec des peptides de la topoisomérase I, et qui partage de nombreuses caractéristiques avec la SSc humaine. Premièrement, nous avons caractérisé la maladie expérimentale quant à sa persistance à long terme (objectif 1) et son caractère progressif (objectif 2). Une cascade de coagulation dérégulée est impliquée dans le développement de la fibrose dans la SSc. La thrombine, un médiateur clé de la coagulation, semble contribuer à ce processus. Deuxièmement, nous avons étudié l’efficacité d’un inhibiteur de la thrombine, i.e. dabigatran, dans ce modèle (objectif 3). Le microbiote intestinal semble jouer un rôle déterminant dans plusieurs pathologies, y compris les maladies auto-immunes. Troisièmement, nous avons évalué l’effet de la manipulation du microbiote des souris par l’administration de streptomycine (objectif 4). Les souris immunisées développent une maladie persistante et la fibrose observée est précédée d’une phase inflammatoire. Le dabigatran aggrave la fibrose pulmonaire et cutanée lorsqu’administré durant la période inflammatoire et n’a aucun effet protecteur durant la phase fibrotique. La manipulation du microbiote par la streptomycine aggrave l’atteinte pulmonaire lorsque l’antibiothérapie est donnée en début de vie et exacerbe l’atteinte cutanée lorsqu’administrée à l’âge adulte. Notre modèle expérimental représente donc un outil important pour évaluer différentes approches thérapeutiques pour la SSc de par sa persistance et son caractère progressif. En se basant sur nos résultats, le dabigatran ne semble pas constituer un choix thérapeutique adéquat pour traiter la fibrose chez les patients atteints de SSc. L’exposition à la streptomycine à certaines périodes de la vie affecte différentiellement le développement et les manifestations cliniques de la maladie expérimentale.Systemic sclerosis (SSc) is an incurable and chronic autoimmune disease characterized by a complex and heterogeneous clinical presentation. Our laboratory has developed a mouse model of lung and skin fibrosis that shares many features with human SSc, and is induced by repeated immunization with dendritic cells loaded with peptides of topoisomerase I. First, the long term persistence (objective 1) and progressive nature (objective 2) of this experimental disease model was characterized. A dysregulated coagulation cascade is implicated in the development of fibrosis in SSc. Thrombin, a key mediator of coagulation, appears to contribute to this process. Next, the efficacy of dabigatran, a thrombin inhibitor, to ameliorate lung and skin fibrosis was studied in this model (objective 3). Intestinal microbiota appears to play a key role in several diseases including autoimmune diseases. Finally, the effect of manipulating gut microbiota by administration of streptomycin on disease pathogenesis was evaluated in this model (objective 4). Immunized mice developed persistent fibrosis that was preceded by an inflammatory phase. Dabigatran aggravated pulmonary and skin fibrosis when administered during the inflammatory period and was not protective when given during the fibrotic phase. Manipulation of intestinal microbiota by streptomycin aggravated lung fibrosis when it was given early in life and exacerbated skin disease when administered in adulthood. Our model of experimental SSc with progressive and persistent disease represents an important tool to evaluate different therapeutic approaches for SSc. Furthermore, our results caution against the use of dabigatran as a therapeutic option to treat fibrosis in patients with SSc. Exposure to streptomycin for certain periods of life differentially affects the development and clinical manifestations of experimental SSc

SCALES: An Original Model to Diagnose Soil Erosion Hazard and Assess the Impact of Climate Change on Its Evolution

International audienceSoil erosion is a major and growing cause of soil deterioration in many European countries. The main issue is that we must no longer consider soil as a renewable natural resource. Whatever the scale of intervention, the territorial structures need to have spatially spread information in order to overcome or prevent soil erosion. In this regard, maps of erosion hazard constitute essential documents. Our goal was multiple when we developed SCALES model. Firstly, the point was to prove that it was reasonable to foresee a regional scale model and map while we have detailed local scale data. Then, we wanted to limit the model applicability to the European oceanic areas which are marked by a mutual pedoclimatic situation and a territorial dividing into agricultural parcels. Besides, our idea was to consider the soil erosion hazard within these parcels which are area sources: assuming that in this geographic context the erosion is more controlled by agricultural units rather than the environment where they dwell. We eventually had to take into consideration the weight of agricultural practices through their temporality when we assessed this hazard. 250 After we proved SCALES was operational in Calvados, we contemplated editing the model in order to achieve an assessment of the erosion hazard within intra-annual time scales. SCALES progressive nature allows us to consider this model as spatially and temporally dynamic. However, the required investment for produce the data in order to decline the model at the monthly and seasonal scales does not allow us to establish a mapping of the soil erosion hazard on a regional level. Consequently, this fine temporal approach must be held for sectors with strong environmental stake. If SCALES can be used in a predictive approach, its structuring and its modularity also give opportunities within a prospective framework. It is what we did, in Basse-Normandie, concerning the topic of the impact of the climate change on the evolution of the cultivated soils susceptibility to erosion by water. In average year at horizon 2100, the results of this new application show that the levels of soil erosion hazard would be comparable with those currently obtained within the one year framework rainy of which the probability of return is once every 4 years. One would thus witness a reinforcement of the soil erosion hazard in average year. We now wish to look further into the prospective application of SCALES starting from the studies which present, in comparable areas, the scenarios of agricultural practices evolution in a near future and a future distance. Our first results and the aim which we propose are altogether in the spirit of the recommendations of the GIEC (2007b) and the European Environment Agency which reminds us the necessity to develop tools to assess the impact of climate change on soils

The incidence and types of physical contact associated with body checking regulation experience in 13–14 year old Ice Hockey players

Background: Ice hockey has one of the highest sport participation and injury rates in youth in Canada. Body checking (BC) is the predominant mechanism of injury in leagues in which it is permitted. The objectives of this study were to determine whether the incidence and types of physical contact differ for Bantam players (aged 13–14 years) who were exposed to BC at Pee Wee level (aged 11–12 years) in Calgary, Alberta versus Bantam players who were not exposed to BC at Pee Wee level in Québec City, Québec. All teams were exposed to BC at bantam level; Methods: A cohort study was conducted in Québec City and Calgary. Sixteen games for Calgary and 15 for Québec City were randomly selected and analysed with a validated observation system to quantify five intensities of physical contact and to observe different types of physical contact such as slashing and holding; Results: A total of 5610 incidences of physical contact with the trunk and 3429 other types of physical contact were observed. Very light intensity trunk contact was more frequent in Calgary (adjusted incidence RR (ARR): 1.71; 95% CI: 1.28–2.29). Holding (ARR: 1.04; 95% CI: 1.02–1.07) and slashing (ARR: 1.38; 95% CI: 1.07–1.77) were more frequent in Calgary; Conclusion: Results suggest that players’ physical contacts differ between Bantam leagues in which BC was permitted at Pee Wee level and leagues in which it was not permitted until Bantam level. View Full-Tex

La lecture des œuvres complètes en contexte scolaire au Québec

Au Québec, les récentes réformes curriculaires témoignent d’exigences élevées quant au nombre d’œuvres complètes à lire en formation pré-universitaire, mais accordent une grande liberté aux enseignants pour la sélection des titres. Les auteurs se fondent sur les résultats d’une vaste enquête pour dresser un état des lieux des exigences des enseignants en matière de lecture des œuvres, des finalités associées à cette pratique et des corpus choisis. Les enseignants du primaire et du secondaire ciblent le développement du plaisir de lire, ceux du collégial visent la constitution d’une culture littéraire de base : la première est centrée sur la littérature québécoise alors que la seconde prend en compte le patrimoine français.In Quebec, the recent curricular reforms are very demanding in terms of the number of whole works to be read in pre-university training, but give teachers free rein for choosing which books. The authors draw from the findings of an extensive study to review teachers’ requirements in terms of reading works, the aims of this practice and the texts chosen. Primary and secondary school teachers want to develop a liking for reading while high school teachers focus on fostering a basic literary culture: the first is based on Quebecker literature while the second embraces French heritage.En Quebec, las recientes reformas curriculares atestiguan unas elevadas exigencias en cuanto al número de obras completas que deben leerse durante la formación preuniversitaria, pero les conceden una gran libertad a los docentes a la hora de elegir los títulos. Los autores se basan en los resultados de una amplia encuesta para establecer un estado de la cuestión de las exigencias de los docentes en lo que toca a la lectura de las obras, finalidades asociadas a esta práctica y corpus seleccionados. Los docentes de primaria y de secundaria se proponen desarrollar el placer de la lectura, y los de postsecundaria se esmeran por cimentar una cultura literaria básica: la primera se centra en la cultura quebequesa, mientras que la segunda tiene en cuenta el patrimonio francés

The localisation of the apical Par/Cdc42 polarity module is specifically affected in microvillus inclusion disease

corrigéInternational audienceBACKGROUND INFORMATION: . Microvillus inclusion disease (MVID) is a genetic disorder affecting intestinal absorption. It is caused by mutations in MYO5B or syntaxin 3 (STX3) affecting apical membrane trafficking. Morphologically MVID is characterised by a depletion of apical microvilli and the formation of microvillus inclusions inside the cells, suggesting a loss of polarity. To investigate this hypothesis we examined the location of essential apical polarity determinants in five MVID patients. RESULTS: We found that the polarity determinants Cdc42, Par6B, PKCζ/ι and the structural proteins ezrin and phospho-ezrin were lost from the apical membrane and accumulated either in the cytoplasm or on the basal side of enterocytes in patients which suggests an inversion of cell polarity. Moreover microvilli-like structures were observed at the basal side in electron microscopy. We next performed Myo5B depletion in 3D-grown human Caco2 cells forming cysts and we found a direct link between the loss of Myo5B and the mislocalisation of the same apical proteins; furthermore we observed that a majority of cyst displayed an inverted polarity phenotype as seen in some patients. Finally we found that this loss of polarity was specific for MVID: tissue samples of patients with Myo5B independent absorption disorders showed normal polarity but we identified Cdc42 as a potentially essential biomarker for tricho-hepato-enteric syndrome. CONCLUSION: Our findings indicate that the loss of Myo5B induces a strong loss of enterocyte polarity, potentially leading to polarity inversion. SIGNIFICANCE: Our results show that polarity determinants could be useful markers to help establishing a diagnosis in patients. Furthermore they could be used to characterise other rare intestinal absorption diseases

Genetic analysis of Italian patients with congenital tufting enteropathy

BACKGROUND: Congenital tufting enteropathy (CTE), an inherited autosomal recessive rare disease, is a severe diarrhea of infancy which is clinically characterized by absence of infl ammation and presence of intestinal villous atrophy. Mutations in the EpCAM gene were identified to cause CTE. Recent cases of syndromic tufting enteropathy harboring the SPINT2 (19q13.2) mutation were described. METHODS: Four CTE Italian patients were clinically and immunohistochemically characterized. Direct DNA sequencing of EpCAM and SPINT2 genes was performed. RESULTS: All patients were of Italian origin. Three different mutations were detected (p.Asp219Metfs*15, Tyr186Phefs*6 and p.Ile146Asn) in the EpCAM gene; one of them is novel (p.Ile146Asn). Two patients (P1 and P2) showed compound heterozygosity revealing two mutations in separate alleles. A third patient (P3) was heterozygous for only one novel EpCAM missense mutation (p.Ile146Asn). In a syndromic patient (P4), no deleterious EpCAM mutation was found. Additional SPINT2 mutational analysis was performed. P4 showed a homozygous SPINT2 mutation (p.Y163C). No SPINT2 mutation was found in P3. CLDN7 was also evaluated as a candidate gene by mutational screening in P3 but no mutation was identifi ed. CONCLUSIONS: This study presented a molecular characterization of CTE Italian patients, and identified three mutations in the EpCAM gene and one in the SPINT2 gene. One of EpCAM mutations was novel, therefore increasing the mutational spectrum of allelic variants of the EpCAM gene. Molecular analysis of the SPINT2 gene also allowed us to identify a SPINT2 substitution mutation (c.488A>G) recentl

Catch-Up Growth in Infants and Young Children With Faltering Growth:Expert Opinion to Guide General Clinicians

Faltering growth (FG) is a problem regularly seen by clinicians in infants and young children (&lt;2 years of age). It can occur due to non-disease-related and disease-related causes and is associated with a wide range of adverse outcomes, including shorter-term effects such as impaired immune responses and increased length of hospital stay, and longer-term consequences, including an impact on schooling and cognitive achievements, short stature, and socioeconomic outcomes. It is essential to detect FG, address underlying causes and support catch-up growth where this is indicated. However, anecdotal reports suggest misplaced fear of promoting accelerated (too rapid) growth may deter some clinicians from adequately addressing FG. An invited international group of experts in pediatric nutrition and growth reviewed the available evidence and guidelines on FG resulting from disease-related and non-disease-related effects on nutritional status in healthy term and small for gestational age infants and children up to the age of 2 years in low-, middle-, and high-income countries. Using a modified Delphi process, we developed practical consensus recommendations to provide clarity and practical recommendations for general clinicians on how FG should be defined in different young child populations at risk, how FG should be assessed and managed, and the role of catch-up growth after a period of FG. We also suggested areas where further research is needed to answer remaining questions on this important issue.</p

Catch-up Growth in Infants and Young Children with Faltering Growth: Expert Opinion to Guide General Clinicians

Faltering growth (FG) is a problem regularly seen by clinicians in infants and young children (<2 years of age). It can occur due to non-disease related and disease-related causes and is associated with a wide range of adverse outcomes, including shorter-term effects such as impaired immune responses and increased length of hospital stay, and longer-term consequences, including an impact on schooling and cognitive achievements, short stature, and socioeconomic outcomes. It is essential to detect FG, address underlying causes and support catch-up growth where this is indicated. However, anecdotal reports suggest misplaced fear of promoting accelerated (too rapid) growth may deter some clinicians from adequately addressing faltering growth. An invited international group of experts in paediatric nutrition and growth reviewed the available evidence and guidelines on FG resulting from disease-related and non-disease-related effects on nutritional status in healthy term and small for gestational age (SGA) infants and children up to the age of two years in low-, middle- and high-income countries. Using a modified Delphi process, we developed practical consensus recommendations to provide clarity and practical recommendations for general clinicians on how faltering growth should be defined in different young child populations at risk, how faltering growth should be assessed and managed and the role of catch-up growth after a period of faltering growth. We also suggested areas where further research is needed to answer remaining questions on this important issue

Electric potential across epidermis and its role during wound healing can be studied by using an in vitro reconstructed human skin

Background : After human epidermis wounding, transepithelial potential (TEP) present in nonlesional epidermis decreases and induces an endogenous direct current epithelial electric field (EEF) that could be implicated in the wound re-epithelialization. Some studies suggest that exogenous electric stimulation of wounds can stimulate healing, although the mechanisms remain to be determined. The Problem : Little is known concerning the exact action of the EEF during healing. The mechanism responsible for TEP and EEF is unknown due to the lack of an in vitro model to study this phenomenon. Basic Science Advances : We carried out studies by using a wound created in a human tissue-engineered skin and determined that TEP undergoes ascending and decreasing phases during the epithelium formation. The in vitro TEP measurements over time in the wound were corroborated with histological changes and with in vivo TEP variations during porcine skin wound healing. The expression of a crucial element implicated in Na+ transport, Na+/K+ ATPase pumps, was also evaluated at the same time points during the re-epithelialization process. The ascending and decreasing TEP values were correlated with changes in the expression of these pumps. The distribution of Na+/K+ ATPase pumps also varied according to epidermal differentiation. Further, inhibition of the pump activity induced a significant decrease of the TEP and of the re-epithelization rate. Clinical Care Relevance : A better comprehension of the role of EEF could have important future medical applications regarding the treatment of chronic wound healing. Conclusion : This study brings a new perspective to understand the formation and restoration of TEP during the cutaneous wound healing process