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

Contribution à l'étude des robots parallèles légers, 3T-1R et 3T-2R, à forts débattements angulaires

MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Problématiques fréquemment rencontrées par l'adolescent (addiction, sexualité et troubles alimentaires)

CAEN-BU Médecine pharmacie (141182102) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Force Performance Indexes for Parallel Mechanisms with Actuation Redundancy, Especially for Parallel Wire-Driven Manipulators

International audienceForce Performance Indexes for Parallel Mechanisms with Actuation Redundancy, Especially for Parallel Wire-Driven Manipulator

A New 5-Degree-of-Freedom Redundant Parallel Mechanism with High Tilting Capabilities

International audienceThis paper introduces Eureka (see video), a new parallel mechanism providing five motions: three translations plus two rotations. This device is able to reach high tilting angles ( ±90° about a first given axis and a whole revolution about the following axis). This is due to actuation redundancy and to the specific traveling plate. Kinematic models are derived. Due to its particular shape the forward geometrical model is also derived easily. A plot of its well conditioned workspace is given. Practical designs, free of self-collisions, are shown

On PKM with Articulated Travelling-Plate and Large Tilting Angles

International audienceThis paper discusses some ways to achieve large tilting motions with PKM by resorting to articulated travelling plate. Different known options are firstly presented: remote actuation, hybrid architectures, redundancy, rotation amplification and translation-to-rotation transformation. Starting from two of those features, the aim of this paper is to go one step further and to propose two ideas: (1) It might be indeed possible to obtain a 4-dof design which compares directly with commercially available Delta-based robots (e.g. the FlexPicker, an ABB Robotics equipment) in terms of technology, workspace, and performance while avoiding the RUPUR kinematic chain. (2) It might be possible to design a 5-dof machine with large tilting angle about two axes

Modelling of a 4 Axis Parallel Machine for Heavy Parts Handling

International audienc

Les kystes du tractus thyréoglosse

Les kystes du tractus thyréoglosse sont une pathologie fréquente en ORL pédiatrique...PARIS7-Xavier Bichat (751182101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Velocity Performances Indexes for Parallel Mechanisms with Actuation Redundancy

International audienceThis paper analyses the velocity isotropy of Parallel mechanism with Actuation Redundancy. The limits of classical indexes based on the Jacobean matrix condition number are shown. Two new indexes are proposed, and the ways to compute them efficiently are given