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

Salvage Liver Transplantation Is a Reasonable Option for Selected Patients Who Have Recurrent Hepatocellular Carcinoma after Liver Resection

Background: Salvage liver transplantation (SLT) has been reported as being feasible for patients who develop recurrent hepatocellular carcinoma (HCC) after primary liver resection, but this finding remains controversial. We retrospectively studied the clinical characteristics of SLT recipients and conducted a comparison between SLT recipients and primary liver transplantation (PLT) recipients. Methodology and Principal Findings: A retrospective study examined data from the China Liver Transplant Registry (CLTR) for 6,975 transplants performed from January 1999 to December 2009. A total of 6,087 patients underwent PLT and 888 patients underwent SLT for recurrence. Living donor liver transplantation (LDLT) was performed in 389 patients, while 6,586 patients underwent deceased donor liver transplantation (DDLT). Kaplan-Meier curves were used to compare survival rates. The 1-year, 3-year, and 5-year overall survival of SLT recipients was similar to that of PLT recipients: 73.00%, 51.77%, and 45.84 % vs. 74.49%, 55.10%, and 48.81%, respectively (P = 0.260). The 1-year, 3-year and 5-year disease-free survival of SLT recipients was inferior to that of PLT recipients: 64.79%, 45.57%, and 37.78 % vs. 66.39%, 50.39%, and 43.50%, respectively (P = 0.048). Similar survival results were observed for SLT and PLT within both the LDLT and DDLT recipients. Within the SLT group, the 1-year, 3-year, and 5-year overall survival for LDLT and DDLT recipients was similar: 93.33%, 74.67%, and 74.67 % vs. 80.13%, 62.10%, and 54.18 % (P = 0.281), as was the disease-free survival: 84.85%, 62.85%, an

Mitchell-Riley Syndrome : Improving Clinical Outcomes and Searching for Functional Impact of RFX-6 Mutations

Aims/HypothesisCaused by biallelic mutations of the gene encoding the transcription factor RFX6, the rare Mitchell-Riley syndrome (MRS) comprises neonatal diabetes, pancreatic hypoplasia, gallbladder agenesis or hypoplasia, duodenal atresia, and severe chronic diarrhea. So far, sixteen cases have been reported, all with a poor prognosis. This study discusses the multidisciplinary intensive clinical management of 4 new cases of MRS that survived over the first 2 years of life. Moreover, it demonstrates how the mutations impair the RFX6 function. MethodsClinical records were analyzed and described in detail. The functional impact of two RFX6(R181W) and RFX6(V506G) variants was assessed by measuring their ability to transactivate insulin transcription and genes that encode the L-type calcium channels required for normal pancreatic beta-cell function. ResultsAll four patients were small for gestational age (SGA) and prenatally diagnosed with duodenal atresia. They presented with neonatal diabetes early in life and were treated with intravenous insulin therapy before switching to subcutaneous insulin pump therapy. All patients faced recurrent hypoglycemic episodes, exacerbated when parenteral nutrition (PN) was disconnected. A sensor-augmented insulin pump therapy with a predictive low-glucose suspension system was installed with good results. One patient had a homozygous c.1517T>G (p.Val506Gly) mutation, two patients had a homozygous p.Arg181Trp mutation, and one patient presented with new compound heterozygosity. The RFX6(V506G) and RFX6(R181W) mutations failed to transactivate the expression of insulin and genes that encode L-type calcium channel subunits required for normal pancreatic beta-cell function. Conclusions/InterpretationMultidisciplinary and intensive disease management improved the clinical outcomes in four patients with MRS, including adjustment of parenteral/oral nutrition progression and advanced diabetes technologies. A better understanding of RFX6 function, in both intestine and pancreas cells, may break ground in new therapies, particularly regarding the use of drugs that modulate the enteroendocrine system.Peer reviewe

Évaluation des compétences acquises par les internes de médecine générale à la fin du stage chez le praticien de niveau 1 (à partir d'une étude réalisée sur trois semestre de stage en Midi-Pyrénées)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Présentation et bilan d'activité sur un an de la régulation au centre 15 de la permanence des soins en médecine générale en Haute-Garonne

Contexte : la permanence des soins en médecine générale est reconnue comme mission d'intérêt général . Cette notion récente a nécessité des réformes progressives pour répondre aux appels des patients aux horaires de fermeture des cabinets libéraux. La régulation de la permanence des soins au centre 15 mise en place en Haute-Garonne joue un rôle fondamental dans cette réorganisation. Objectifs : Présenter la mise en place de la régulation de la permanence des soins au centre 15 en Haute-Garonne et établir un bilan d'activité de sa première année d'existence. Méthode : La présentation se base sur des données recueillies à l'aide de différents acteurs de la permanence des soins tout en l'intégrant dans le cadre légal et déontologique national. Le bilan d'activité est obtenu en utilisant les logiciels de recueil de données et d'évaluation disponibles au SAMU 31. Résultats : L'organisation et le bilan d'activité de la régulation de la permanence des soins en Haute-Garonne au centre 15 répond aux attentes des réformes nationalesTOULOUSE3-BU Santé-Centrale (315552105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

La consultation approfondie du patient en affection de longue durée (un outil pédagogique proposé aux internes en stage autonome en soins primaires ambulatoires supervisé (SASPAS) pour la prise en charge de patients relevant d'un suivi au long cours)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Quelle est la prise en charge des "petits maux" de la grossesse par les médecins généralistes de Midi-Pyrénées ? (enquête auprès de 169 médecins généralistes)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Etude de la relation médecin patient lors de l'introduction d'un médicament nouveau par le médecin généraliste

Nous étudions de manière qualitative la relation médecin patient lorsqu'il s'agit de prescrire un médicament nouveau au travers de l'expérience de vingt médecins généralistes de la région Midi-Pyrénées auprès desquels nous avons effectué une série d'interviews semi-dirigés. La situation de prescription d'un médicament nouveau, par son caractère novateur et la réflexion induite par son utilisation, fournit la possibilité d'un nouveau modèle de relation médecin patient ainsi qu'une interrogation du médecin généraliste sur sa pratique. Le modèle délibératif de relation médecin patient présente un avantage sur le modèle paternaliste même en cas de retrait du médicament nouveau car le patient est plus actif dans sa participation au processus de soin, qu'il conserve une autonomie décisionnelle et assume sa part de responsabilité, il serait donc à privilégier.TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Utilisation d'Internet en consultation de médecine générale (faisabilité, acceptabilité et validité)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Les entretiens motivationnels dans la prévention cardio-vasculaire (une revue systématique de la littérature)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF