Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency

Purpose Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved. Methods Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated. Results Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated. Conclusions This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features

La directive 2001/20/CE du 4 avril 2001 relative à l'application de bonnes pratiques cliniques dans la conduite d'essais cliniques de médicaments à usage humain (présentation, contenu et conséquences)

PARIS-BIUP (751062107) / SudocSudocFranceF

La pharmacovigilance et les essais cliniques de médicaments en Europe

La réglementation de la pharmacovigilance dans le cadre des essais cliniques s'est développée au plan international sous la forme de lignes directrices issues du Conseil des organisations Internationales des Sciences Médicales et des Conférences Internationales d'Harmonisation. En Europe, la directive 2001/20/CE a été transposée dans les 27 Etats membres et a ainsi permis une harmonisation des pratiques de pharmacovigilance lors des essais cliniques. Cette thèse expose la transposition de cette Directive concernant la pharmacovigilance dans les Etats membres, et plus particulièrement en France, ainsi qu'une nouvelle recommandation internationale à venir : le rapport actualisé de pharmacovigilance pour les produits en développement. Ces mesures doivent permettre de concilier le progrès thérapeutique tout en assurant la sécurité sanitaire des participants aux essais cliniques.CLERMONT FD-BCIU-Santé (631132104) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Les enjeux de la transposition de la Directive européenne 2001/20/CE dans les principaux Etats Membres

Depuis la publication de la Directive 2001/20/CE parue au Journal Officiel des communautés européennes le 1er mai 2001, les Etats Membres préparent sa transposition dans leurs réglementations nationales pour une application au plus tard en mai 2004. Il s'avère que les discussions portent essentiellement sur l'organisation des Comités d'éthique (CE) qui doivent désormais rendre un avis unique par Etat Membre, ainsi que sur les délais pour l'obtention de cet avis et de l'autorisation d'essai par l'Autorité compétente (AC). Les réflexions conduisent à des propositions de délais plus courts pour les études portant sur des produits en stade précoce de développement ou traitant certaines pathologies. Malgré une harmonisation des réglementations, la mise en application de la Directive ne supprimera pas toutes les spécificités nationales

Distal Lung Inflammation Assessed by Alveolar Concentration of Nitric Oxide Is an Individualised Biomarker of Severe COVID-19 Pneumonia

Pulmonary sequelae as assessed by pulmonary function tests (PFTs) are often reported in patients infected by SARS-CoV-2 during the post-COVID-19 period. Little is known, however, about the status of pulmonary inflammation during clinical recovery after patients’ discharge from the hospitals. We prospectively measured PFTs coupled with the exhaled nitric oxide (NO) stemming from the proximal airways (FeNO) and the distal lung (CaNO) in 169 consecutive patients with varying degrees of the severity of COVID-19 six weeks to one year after acute infection by SARS-CoV-2. The proportions of patients with abnormal PFTs, defined as the presence of either obstructive/restrictive patterns or impaired lung gas transfer, or both, increased with the severity of the initial lung disease (15, 30, and 52% in patients with mild, moderate, and severe COVID-19). FeNO values remained within normal ranges and did not differ between the three groups of patients. CaNO, however, was significantly higher in patients with severe or critical COVID-19, compared with patients with milder forms of the disease. There was also an inverse relationship between CaNO and DLCO. We conclude that the residual inflammation of the distal lung is still present in the post-COVID-19 follow-up period, in particular, in those patients with an initially severe form of COVID-19. This long-lasting alveolar inflammation might contribute to the long-term development of pulmonary fibrosis and warrants the regular monitoring of exhaled NO together with PFTs in patients with COVID-19