In vitro prediction of stop-codon suppression by intravenous gentamicin in patients with cystic fibrosis: a pilot study

BACKGROUND: Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which acts as a chloride channel activated by cyclic AMP (cAMP). The most frequent mutation found in 70% of CF patients is F508del, while premature stop mutations are found in about 10% of patients. In vitro aminoglycoside antibiotics (e.g. gentamicin) suppress nonsense mutations located in CFTR permitting translation to continue to the natural termination codon. Pharmacologic suppression of stop mutations within the CFTR may be of benefit to a significant number of patients. Our pilot study was conducted to determine whether intravenous gentamicin suppresses stop codons in CF patients and whether it has clinical benefits. METHODS: A dual gene reporter system was used to determine the gentamicin-induced readthrough level of the most frequent stop mutations within the CFTR in the French population. We investigated readthrough efficiency in response to 10 mg/kg once-daily intravenous gentamicin perfusions in patients with and without stop mutations. Respiratory function, sweat chloride concentration, nasal potential difference (NPD) and CFTR expression in nasal epithelial cells were measured at baseline and after 15 days of treatment. RESULTS: After in vitro gentamicin incubation, the readthrough efficiency for the Y122X mutation was at least five times higher than that for G542X, R1162X, and W1282X. In six of the nine patients with the Y122X mutation, CFTR immunodetection showed protein at the membrane of the nasal epithelial cells and the CFTR-dependent Cl(- )secretion in NPD measurements increased significantly. Respiratory status also improved in these patients, irrespective of the gentamicin sensitivity of the bacteria present in the sputum. Mean sweat chloride concentration decreased significantly and normalised in two patients. Clinical status, NPD and sweat Cl(- )values did not change in the Y122X patients with no protein expression, in patients with the other stop mutations investigated in vitro and those without stop mutations. CONCLUSION: Suppression of stop mutations in the CFTR gene with parenteral gentamicin can be predicted in vitro and is associated with clinical benefit and significant modification of the CFTR-mediated Cl(- )transport in nasal and sweat gland epithelium

Croyances et pratiques populaires ( à propos de la santé de l'enfant à l'ile de la Réunion)

FORT-DE-FRANCE-CHRU-BU (972332102) / SudocBORDEAUX2-BU Santé (330632101) / SudocSAINT DENIS/REUNION-Droit Lettre (974112101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

<i>Pierre de Ronsard et Marc-Antoine Muret, Les Amours, leurs Commentaires (1553)</i>

Index des Commentaires de Muret et Index des Amours de Ronsard en collaboration avec P. Martin. Préface de Michel Simonin. Postface de Jean Céard. Contient : François Lesure, "Ronsard et ses musiciens"; et le Cahier musical constitué et annoté par Pierre Laumonier.International audienc

Cystic fibrosis at the Reunion Island (France): spectrum of mutations and genotype-phenotype for the Y122X mutation

Background: The Reunion Island is a French administrative department located in the Indian Ocean between the islands of Madagascar and Mauritius. Its population is known to be at a high risk of cystic fibrosis (CF). Methods: Data concerning all CF patients born at the Reunion Island was extracted from the French CF Registry. Twenty-eight DF508/DF508, 17 Y122X/DF508, and 11 Y122X/Y122X were included in a genotype – phenotype study. Results: The detection rate of the CFTR mutations was 83% among the CF patients born at the Reunion Island. Three CFTR mutations accounted for 75% of the detected CF alleles at the Reunion Island (DF508, Y122X, and 3120 + 1G→A.). The DF508/DF508, DF508/Y122X, and Y122X/Y122X genotypes accounted for 60.2% of the CF patients. Patients carrying at least one Y122X mutation were pancreatic insufficient, had high sweat chloride values and significantly lower anthropometric measures. The mean anthropometric values in all three groups were lower that in the whole CF population followed in ‘‘continental’’ France. This may reflect the poor compliance and even the refusal of treatment noted by the clinicians. Conclusions: The distribution of CFTR mutations could be explained by the history of the Reunion Island: admixture of French settlers, African and Asian populations, founder effect and isolation followed by genetic drift. The Y122X allele appears to be associated with a severe phenotype

Maurice Ravel : [exposition], Bibliothèque nationale, [Paris, 26 mars-fin juillet] 1975 / [catalogue par François Lesure et Jean-Michel Nectoux] ; [préface par Étienne Dennery]

[Exposition. Paris, Bibliothèque nationale. 1975][Exposition. Ravel, Maurice. 1975]Contient une table des matièresAvec mode texteCatalogues d'expositio