Sectional Analysis of Engineered Cementitious Composite Beams

A procedure to predict the flexural response of an engineered cementitious composite (ECC) prismatic beam specimen subjected to four-point bending and its implementation into an Excel spreadsheet are described. It utilises the layered sectional analysis approach and nonlinear ECC constitutive models, allowing for the calculation of the moment–curvature relationship for any selected section of the beam specimen at various stages of loading. Further, the curvature–area method is employed to integrate the sectional response and determine the overall beam deflection profile. To this end, predictions by the proposed method are compared against three series of experiments available in the literature, to provide a better understanding of the relation between the tensile properties of ECC and the corresponding flexural response. It is shown that due to flexural cracking, the beam curvature over the shear span varies nonlinearly from the support and is found to influence the prediction of beam deflection. A series of empirical equations are presented to allow for the quick calculation of tensile strain capacity and tensile strength of ECC based upon flexural test data. </jats:p

Size distribution and number concentration of the 10nm-20um aerosol at an urban background site, Gennevilliers, Paris area

International audienceThe purpose of this study is to quantify the exposure of people to the submicronic particles, and especially ultrafine/nanoparticules (< 100 nm) at an urban background site in the Paris area. Since 2003, two particle sizers have been used every year for a winter five weeks campaign

Lung transplantation after allogeneic stem cell transplantation : a pan-European experience

Late-onset noninfectious pulmonary complications (LONIPCs) affect 6% of allogeneic stem cell transplantation (SCT) recipients within 5 years, conferring subsequent 5-year survival of 50%. Lung transplantation is rarely performed in this setting due to concomitant extrapulmonary morbidity, excessive immunosuppression and concerns about recurring malignancy being considered contraindications. This study assesses survival in highly selected patients undergoing lung transplantation for LONIPCs after SCT. SCT patients undergoing lung transplantation at 20 European centres between 1996 and 2014 were included. Clinical data pre- and post-lung transplantation were reviewed. Propensity score-matched controls were generated from the Eurotransplant and Scandiatransplant registries. Kaplan-Meier survival analysis and Cox proportional hazard regression models evaluating predictors of graft loss were performed. Graft survival at 1, 3 and 5 years of 84%, 72% and 67%, respectively, among the 105 SCT patients proved comparable to controls (p=0.75). Sepsis accounted for 15 out of 37 deaths (41%), with prior mechanical ventilation (HR 6.9, 95% CI 1.0-46.7; p Lung transplantation outcomes following SCT were comparable to other end-stage diseases. Lung transplantation should be considered feasible in selected candidates. No SCT-specific factors influencing outcome were identified within this carefully selected patient cohort.Peer reviewe

Genetic regulation of pituitary gland development in human and mouse

Normal hypothalamopituitary development is closely related to that of the forebrain and is dependent upon a complex genetic cascade of transcription factors and signaling molecules that may be either intrinsic or extrinsic to the developing Rathke’s pouch. These factors dictate organ commitment, cell differentiation, and cell proliferation within the anterior pituitary. Abnormalities in these processes are associated with congenital hypopituitarism, a spectrum of disorders that includes syndromic disorders such as septo-optic dysplasia, combined pituitary hormone deficiencies, and isolated hormone deficiencies, of which the commonest is GH deficiency. The highly variable clinical phenotypes can now in part be explained due to research performed over the last 20 yr, based mainly on naturally occurring and transgenic animal models. Mutations in genes encoding both signaling molecules and transcription factors have been implicated in the etiology of hypopituitarism, with or without other syndromic features, in mice and humans. To date, mutations in known genes account for a small proportion of cases of hypopituitarism in humans. However, these mutations have led to a greater understanding of the genetic interactions that lead to normal pituitary development. This review attempts to describe the complexity of pituitary development in the rodent, with particular emphasis on those factors that, when mutated, are associated with hypopituitarism in humans

Développement de nouvelles stratégies de thérapie génique pour le syndrome de Leigh

Mutations in mitochondrial DNA or in nuclear genes involved in the mitochondrial respiratory chain complexes are responsible for mitochondrial disorders. Mutations affecting mitochondrial complex I are responsible for a broad spectrum of disorders among which Leigh syndrome (LS) is the most common in infancy. This condition is fatal during the first years of life and no treatment is currently available. Brain pathology is critical in LS and one the challenges of gene therapy is the limited transfer of genes to the central nervous system due to the impermeability of the blood-brain barrier (BBB). Our hypothesis is that the development of new strategies to improve the cerebral transduction of viral vectors would provide a therapeutic benefit for LS. We first showed that the pathology does not cause anatomical or functional changes of the BBB in Ndufs4 KO mice, a standard model of LS. This result confirms the necessity to overcome the BBB. To this end, we first used an AAV-PHP.B vector, a new variant able to cross the BBB. Gene replacement with this viral vector improved the phenotype and increased the lifespan in Ndufs4 KO mice. This approach provides a proof of concept that widespread restoration of gene expression can alleviate the pathology in a model of severe mitochondrial diseases. Our second method was to combine the injection of an AAV9 vector with the application of focused ultrasound enabling the BBB opening. We first set up ultrasonic parameters affording an efficient and safe increase in BBB permeability. We then showed that this strategy extend the survival of Ndufs4 KO mice. This approach combines two technologies currently used in clinic and therefore represents an interesting prospect for the treatment of LS. Finally, we developed a new genetic construct to study whether the intercellular transfer of mitochondria contributes to the effect of gene therapy. This tool represents a new way of studying mitochondrial transfer both in vitro and in vivo. Overall, my thesis work demonstrates that strategies improving gene delivery to the brain offers new therapeutic perspectives for LS and other conditons affecting the nervous system.Des mutations de l'ADN mitochondrial ou des gènes nucléaires impliqués dans le fonctionnement de chaîne respiratoire mitochondriale sont à l’origine des maladies mitochondriales. Le syndrome de Leigh (SL) est la maladie mitochondriale infantile la plus commune. Cette pathologie est principalement caractérisée par une atteinte cérébrale. Elle est fatale durant les premières années de vie et aucun traitement n’est actuellement disponible. Un des challenges de la thérapie génique pour cette pathologie concerne le transfert d’un gène dans le système nerveux central du fait de l’imperméabilité de la barrière hémato-encéphalique (BHE). Notre hypothèse est que le développement de nouvelles stratégies permettant d’améliorer la transduction cérébrale des vecteurs viraux permettrait d’obtenir un bénéfice thérapeutique dans le cas du SL. Nous avons tout d’abord montré que la pathologie n’impactait pas l’anatomie et la fonction de la BHE chez les souris Ndufs4 KO, un modèle standard du SL. Ce résultat confirme la nécessité d'utiliser des stratégies permettant de contourner la BHE. Pour cela nous avons tout abord utilisé un vecteur AAV-PHP.B. qui est un nouveau variant traversant la BHE. Le remplacement du gène Ndufs4 avec ce vecteur viral a permis d’améliorer le phénotype et de prolonger la survie des animaux. Cette approche apporte une preuve de concept qu'une restauration généralisée de l'expression du gène permet d’obtenir un effet thérapeutique dans un modèle de maladie mitochondriale sévère. Notre deuxième approche a consisté en la combinaison de l’injection d’un vecteur AAV9 et de l’application d’ultrasons focalisés destinés à perméabiliser la BHE. Après avoir défini des paramètres ultrasonores permettant d’augmenter efficacement et sans danger la perméabilité de BHE sur une large partie du cerveau, nous avons montré que cette stratégie permettait de prolonger la survie des souris Ndufs4 KO. Cette approche expérimentale combine deux technologies déjà utilisées en clinique et pourrait donc représenter une perspective intéressante pour le traitement su SL. Enfin, nous avons mis au point une nouvelle construction génétique permettant d’étudier si le transfert intercellulaire de mitochondries participe à l’effet de la thérapie génique. Cet outil représente un nouveau moyen d’étudier le transfert des mitochondries à la fois in vitro et in vivo. Ce travail de thèse apporte la démonstration que des stratégies permettant d’améliorer le transfert de gènes vers le cerveau offre de nouvelles perspectives thérapeutiques pour le SL ainsi que pour d’autres pathologies affectant le système nerveux