Dyclonine rescues frataxin deficiency in animal models and buccal cells of patients with Friedreich's ataxia.

Inherited deficiency in the mitochondrial protein frataxin (FXN) causes the rare disease Friedreich's ataxia (FA), for which there is no successful treatment. We identified a redox deficiency in FA cells and used this to model the disease. We screened a 1600-compound library to identify existing drugs, which could be of therapeutic benefit. We identified the topical anesthetic dyclonine as protective. Dyclonine increased FXN transcript and FXN protein dose-dependently in FA cells and brains of animal models. Dyclonine also rescued FXN-dependent enzyme deficiencies in the iron-sulfur enzymes, aconitase and succinate dehydrogenase. Dyclonine induces the Nrf2 [nuclear factor (erythroid-derived 2)-like 2] transcription factor, which we show binds an upstream response element in the FXN locus. Additionally, dyclonine also inhibited the activity of histone methyltransferase G9a, known to methylate histone H3K9 to silence FA chromatin. Chronic dosing in a FA mouse model prevented a performance decline in balance beam studies. A human clinical proof-of-concept study was completed in eight FA patients dosed twice daily using a 1% dyclonine rinse for 1 week. Six of the eight patients showed an increase in buccal cell FXN levels, and fold induction was significantly correlated with disease severity. Dyclonine represents a novel therapeutic strategy that can potentially be repurposed for the treatment of FA

Supramolecular layers and versatile packing modes: the solid state behavior of ortho, ortho-linked bisphenols

A series of ortho-ortho-linked bisphenols featuring electron-withdrawing groups (EWGs) attached to the phenolic rings is reported. Their respective molecular structures and packing behaviors have been studied by X-ray diffraction, comparatively discussed and put into relation with the unsubstituted mother compound. Except for the mother compound, the molecular structures of all bisphenols studied here exhibit distorted aromatic moieties. Hence, the substituents studied here prevent proximal positioning of phenolic units and the formation of strong O-H···O hydrogen bonds. In the packing of the underivatized bisphenol we found a strand-like molecular arrangement featuring strong O-H···O hydrogen bonds and extensive edge-to-face contacts (C-H···π) between the bisphenol molecules. The introduction of EWGs to the aromatic moieties changes these intermolecular interactions into face-to-face contacts resulting either in bisphenol stacks or handshake-like motifs between two bisphenol molecules. In both cases, the C-H···π interactions are more or less replaced by C-H···O contacts as the prevalent non-covalent interaction. In the packing of two nitro bisphenols in their DMSO inclusion compounds an exciting layered arrangement is observed, which also matches with the pronounced foliated habitus of their crystals. Additionally, proton NMR was used to establish the binding coefficients between the respective bisphenols and DMSO in solution

Galleria Aurora

exterior, view of the northeast facade, with the cathedral partially visible through the open central court, August 199

Galleria Aurora

exterior, southeast facade, August 199

Galleria Aurora

interior, view within open-air central court, looking to southwest corner, August 199

Étude comparative de vraie vie du traitement standard du Purpura Thrombotique Thrombocytopénique avec et sans caplacizumab dans un centre de référence des microangiopathies thrombotiques

Le Purpura Thrombotique Thrombocytopénique (PTT) est une pathologie rare mais potentiellement fatale en l’absence de prise en charge. Le caplacizumab est le premier médicament indiqué dans le traitement du PTT acquis. Il est intéressant d’étudier le coût de cette nouvelle molécule en tenant compte de l’efficacité et de la sécurité pour les patients dans des conditions de vraie vie d’autant plus que la Haute Autorité de Santé utilise de plus en plus les études de vraie vie dans le cadre de l’évaluation des médicaments. Ce travail est une étude rétrospective comparant deux groupes de patients, le groupe CAPLA+ traité par le traitement de référence (échanges plasmatiques, corticoïdes, rituximab) et par caplacizumab et le groupe CAPLA- traité par le traitement standard seulement. Les critères d’efficacité et de sécurité ont été relevés pour chaque patient. Le coût de l’hospitalisation et des traitements a été calculé pour chaque groupe et comparé au remboursement reçu par l’hôpital. Le délai de normalisation du taux de plaquettes était plus court dans le groupe CAPLA+, la durée d’hospitalisation (p=0,023) ainsi que le nombre d’échanges plasmatiques (p=0,009) sont également diminués. Le caplacizumab apporte un coût supplémentaire par rapport au traitement standard (89 845 € versus 31 249 €). Bien que son prix élevé soit un frein à son utilisation en première ligne de traitement, le caplacizumab permet une économie de ressources pour l’hôpital en réduisant le nombre d’échanges plasmatiques et la durée d’hospitalisation et génère une recette par la rétrocession. Il a également des bénéfices pour le patient avec notamment une diminution des rechutes et des exacerbations