Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado-Joseph disease.

Machado-Joseph disease is the most frequently found dominantly-inherited cerebellar ataxia. Over-repetition of a CAG trinucleotide in the MJD1 gene translates into a polyglutamine tract within the ataxin 3 protein, which upon proteolysis may trigger Machado-Joseph disease. We investigated the role of calpains in the generation of toxic ataxin 3 fragments and pathogenesis of Machado-Joseph disease. For this purpose, we inhibited calpain activity in mouse models of Machado-Joseph disease by overexpressing the endogenous calpain-inhibitor calpastatin. Calpain blockage reduced the size and number of mutant ataxin 3 inclusions, neuronal dysfunction and neurodegeneration. By reducing fragmentation of ataxin 3, calpastatin overexpression modified the subcellular localization of mutant ataxin 3 restraining the protein in the cytoplasm, reducing aggregation and nuclear toxicity and overcoming calpastatin depletion observed upon mutant ataxin 3 expression. Our findings are the first in vivo proof that mutant ataxin 3 proteolysis by calpains mediates its translocation to the nucleus, aggregation and toxicity and that inhibition of calpains may provide an effective therapy for Machado-Joseph disease.

[Voyage en Italie : 1824-1830]. , Eglise du St Esprit : détail d'une Chapelle : [élévation intérieure, plan et vue perspective] : [dessin] / h. L. [Henri Labrouste]

Référence bibliographique : Weigert, 134

[Voyage en Italie : 1825-1830]. , Justice de Paix, via Maggiore ; palais sur la place du St Esprit : [deux plans] : [dessin] / h. L. [Henri Labrouste]

Référence bibliographique : Weigert, 151

Impact of medical practice guidelines on the assessment of patients with acute coronary syndrome without persistent ST segment elevation.

OBJECTIVE: To assess the impact of introducing clinical practice guidelines on acute coronary syndrome without persistent ST segment elevation (ACS) on patient initial assessment. DESIGN: Prospective before-after evaluation over a 3-month period. SETTING: The emergency ward of a tertiary teaching hospital. PATIENTS: All consecutive patients with ACS evaluated in the emergency ward over the two 3-month periods. INTERVENTION: Implementation of the practice guidelines, and the addition of a cardiology consultant to the emergency team. MAIN OUTCOME MEASURES: Diagnosis, electrocardiogram interpretation, and risk stratification after the initial evaluation. RESULTS: The clinical characteristics of the 328 and 364 patients evaluated in the emergency ward for suspicion of ACS before and after guideline implementation were similar. Significantly more patients were classified as suffering from atypical chest pain (39.6% versus 47.0%; P = 0.006) after guideline implementation. Guidelines availability was associated with significantly more formal diagnoses (79.9% versus 92.9%; P < 0.0001) and risk stratification (53.7% versus 65.4%, P < 0.0001) at the end of initial assessment. CONCLUSION: Guidelines implementation, along with availability of a cardiology consultant in the emergency room had a positive impact on initial assessment of patients evaluated for suspicion of ACS. It led to increased confidence in diagnosis and stratification by risk, which are the first steps in initiating effective treatment for this common condition.

[Voyage en Italie : 1824-1830]. , Chapelle souterraine de St Janvier : [plan, coupe transversale] : [dessin] / h. L. [Henri Labrouste]

Référence bibliographique : Weigert, 226

[Voyage en Italie : 1824-1830]. , Chapelle souterraine de St Janvier, sur une échelle de 002 P.M. : [coupe longitudinale] : [dessin] / h. L. [Henri Labrouste]

Référence bibliographique : Weigert, 227

[Voyage en Italie : 1824-1830]. , BAPTISTERE, église de St Jean : [élévation toute hauteur d'une des faces intérieures du Baptistère] : [dessin] / h. L. [Henri Labrouste]

Référence bibliographique : Weigert, 145

[Voyage en Italie : 1824-1830]. , Baptistère. Eglise de St Jean, Sur une Echelle de 0,005 P.M. : [plan du rez-de-chaussée (partie gauche) et au niveau des tribunes (partie droite)] : [dessin] / h. L. [Henri Labrouste]

Référence bibliographique : Weigert, 143

[Voyage en Italie : 1824-1830]. , [La basilique et la place] St Pierre : [vue perspective] : [dessin] / h. L. [Henri Labrouste]

Référence bibliographique : Weigert, 538

[Voyage en Italie : 1824-1830]. , [Préparatifs pour la fête des SS. Pierre et Paul ?] St Pierre de Rome, 28 juin : [face et deux profils d'une femme voilée, vue perspective d'une porte intérieure de la basilique ornée de guirlandes] : [dessin] / h. L. [Henri Labrouste]

Référence bibliographique : Weigert, 539

[Voyage en Italie : 1824-1830]. , Panoplia Manuscrit grec du Vatican XII[e] Siècle. St François d'Assise. XIII[e] Siècle : [sept motifs : cinq personnages (trois hommes nimbés, une Vierge à l'enfant et un personnage non identifé), une croix, détail ornemental d'un arc] : [dessin] / h. L. [Henri Labrouste]

Référence bibliographique : Weigert, 614