Nanonization of megestrol acetate by laser fragmentation in aqueous milieu

Faculté de PharmacieNanonization is a simple and effective method to improve dissolution rate and oral bioavailability of drugs with poor water solubility. There is growing interest to downscale the nanocrystal production to enable early preclinical evaluation of new drug candidates when compound availability is scarce. The purpose of the present study was to investigate laser fragmentation to form nanosuspensions in aqueous solution of the insoluble model drug megestrol acetate (MA) using very little quantities of the drug. Laser fragmentation was obtained by focusing a femtosecond (fs) or nanosecond (ns) laser radiation on a magnetically stirred MA suspension in water or aqueous solution of a stabilizing agent. The size distribution and physicochemical properties of the drug nanoparticles were characterized, and the in vitro dissolution and in vivo oral pharmacokinetics of a laser fragmented formulation were evaluated. A MA nanosuspension was also prepared by media milling for comparison purpose. For both laser radiations, smaller particles were obtained as the laser power was increased, but at a cost of higher degradation. Significant nanonization was achieved after a 30-min fs laser treatment at 250 mW and a 1-h ns laser treatment at 2500 mW. The degradation induced by the laser process of the drug was primarily oxidative in nature. The crystal phase of the drug was maintained, although partial loss of crystallinity was observed. The in vitro dissolution rate and in vivo bioavailability of the laser fragmented formulation were similar to those obtained with the nanosuspension prepared by media milling, and significantly improved compared to the coarse drug powder. It follows that this laser nanonization method has potential to be used for the preclinical evaluation of new drug candidates.IRSC - CRNS

Molecular Responses to Photogenotoxic Stress Induced by the Antibiotic Lomefloxacin in Human Skin Cells: From DNA Damage to Apoptosis

Photo-unstable chemicals sometimes behave as phototoxins in skin, inducing untoward clinical side-effects when exposed to sunlight. Some drugs, such as psoralens or fluoroquinolones, can damage genomic DNA, thus increasing the risk of photocarcinogenesis. Here, lomefloxacin, an antibiotic from the fluoroquinolone family known to be involved in skin tumor development in photoexposed mice, was studied using normal human skin cells in culture: fibroblasts, keratinocytes, and Caucasian melanocytes. When treated cells were exposed to simulated solar ultraviolet A (320–400 nm), lomefloxacin induced damage such as strand breaks and pyrimidine dimers in genomic DNA. Lomefloxacin also triggered various stress responses: heme-oxygenase-1 expression in fibroblasts, changes in p53 status as shown by the accumulation of p53 and p21 proteins or the induction of MDM2 and GADD45 genes, and stimulation of melanogenesis by increasing the tyrosinase activity in melanocytes. Lomefloxacin could also lead to apoptosis in keratinocytes exposed to ultraviolet A: caspase-3 was activated and FAS-L gene was induced. Moreover, keratinocytes were shown to be the most sensitive cell type to lomefloxacin phototoxic effects, in spite of the well-established effectiveness of their antioxidant equipment. These data show that the phototoxicity of a given drug can be driven by different mechanisms and that its biologic impact varies according to cell type

Le diagnostic précoce des troubles du comportement externalisé est-il fiable ? Mise à l’épreuve d’une procédure multi informateurs et multi méthodes

peer reviewedCette contribution questionne la fiabilité du diagnostic précoce des troubles du comportement externalisé chez l’enfant. Les données concernant le comportement de 118 enfants ont été collectées par questionnaires et observation auprès de leurs parents, leurs enseignants et les cliniciens lors du recrutement et après 12 mois. Les résultats montrent des variations importantes dans le nombre d’enfants atteignant un seuil clinique selon l’informateur et la méthode considérés. Une méthode combinant les évaluations des informateurs pour obtenir un diagnostic valide est éprouvée. Les résultats plaident en faveur d’une procédure multi-informateurs et multiméthodes dont les implications sont discutées sur le plan clinique et de la recherche.H2M childre

The reciprocal relation between children’s attachment representations and their cognitive ability

This study explores reciprocal relations between children’s attachment representations and their cognitive ability. Previous literature has mainly focused on the prediction of cognitive abilities from attachment, rarely on the reverse prediction. This was explored in the current research. Attachment representations were assessed with the Attachment Story Completion Task (Bretherton, Ridgeway, & Cassidy, 1990); the IQ was measured with the WPPSI-III (Wechsler, 2004). Data were collected twice, at a two-year interval, from about 400 preschoolers. Reasoning IQ was found to influence the development of secure attachment representations, while attachment security and disorganization influenced later verbal IQ. The implications of the findings for both clinical and research purposes are discussed in the light of the interactions between cognitive abilities and attachment representations

Viral sequence variation in chronic carriers of hepatitis C virus has a low impact on liver steatosis.: HCV variability and steatosis

International audienceMost clinical studies suggest that the prevalence and severity of liver steatosis are higher in patients infected with hepatitis C virus (HCV) genotype 3 than in patients infected with other genotypes. This may reflect the diversity and specific intrinsic properties of genotype 3 virus proteins. We analyzed the possible association of particular residues of the HCV core and NS5A proteins known to dysregulate lipid metabolism with steatosis severity in the livers of patients chronically infected with HCV. We used transmission electron microscopy to quantify liver steatosis precisely in a group of 27 patients, 12 of whom were infected with a genotype 3 virus, the other 15 being infected with viruses of other genotypes. We determined the area covered by lipid droplets in liver tissues and analyzed the diversity of the core and NS5A regions encoded by the viral variants circulating in these patients. The area covered by lipid droplets did not differ significantly between patients infected with genotype 3 viruses and those infected with other genotypes. The core and NS5A protein sequences of the viral variants circulating in patients with mild or severe steatosis were evenly distributed throughout the phylogenic trees established from all the collected sequences. Thus, individual host factors seem to play a much greater role than viral factors in the development of severe steatosis in patients chronically infected with HCV, including those infected with genotype 3 viruses

Sélection des sites et des proies par les Barges à queue noire Limosa limosa islandica s’alimentant sur les herbiers de zoostères et les vasières du centre de la côte atlantique française

Characeae surveys and water physico-chemical studies have been performed during four years (2007-2011) on 41 wetlands of Numidia (NE Algeria). Among the 12 species inventoried in the region, four are rare in North Africa and one, Nitella batrachosperma, is new for Algeria. Comparison between Characeae communities and phosphate contents shows that (1) Characeae have nearly disappeared from habitats that contain high levels of orthophosphates (> 780 μg.l-1), (2) three species of Chara (C. globularis, C. gymnophylla and C. vulgaris) characterize medium-polluted habitats (213-780 μg.l-1), where they are often present as discontinuous populations, and (3) the Nitella (N. opaca and N. translucens) are good indicators of low water pollution (< 70 μg.l-1). In addition to the sole presence of a given species, the physiological appearance of the plants has to be taken into consideration as a sign of a healthy population.Dans une population en expansion, certains individus sont voués à explorer et exploiter de nouveaux habitats de moindre qualité. Sur la façade ouest européenne, la Barge à queue noire Limosa limosa islandica, qui se reproduit exclusivement en Islande, est l’une des rares espèces de limicoles avec une tendance démographique positive. Les côtes françaises accueillent 28 % de la population au milieu de l’hiver, le reste se distribuant sur les îles britanniques et la péninsule ibérique. Contrairement à la Grande Bretagne et l’Irlande, la population française se concentre sur un nombre restreint de sites mais avec de fortes concentrations. Les Pertuis Charentais accueillent plus de 65 % de la population nationale (ca 18 000 individus). Dans cette étude, nous décrivons comment la sélection des proies et les stratégies d’alimentation en milieux intertidaux sont liées à la sélection des sites à l’échelle locale and peuvent expliquer la distribution des oiseaux en période de non reproduction. La sélection des sites et des espèces-proies par les barges a été étudiée par la description du régime alimentaire et de la ressource trophique sur six zones d’alimentation sur les quatre principaux sites hivernages. Dans les Pertuis Charentais, il a été confirmé que ces barges occupent une niche écologique herbivore sur le nouveau site d’hivernage de l’île de Ré, où elles s’alimentent de Zostères naines Zostera noltii. La barge garde un régime carnivore sur les sites continentaux, où elle s’alimente principalement du bivalve Macoma balthica. Sur ces sites, les barges ciblent la proie la plus rentable. À l’exception du dérangement humain, la distribution des individus dans les Pertuis Charentais semble être déterminée par la distribution, l’abondance et l’accessibilité de seulement deux espèces-proies parmi un large éventail d’espèces benthiques

Physical and psychological consequences of serious road traffic injuries, deliverable 7.2 of the H2020 project SafetyCube

SafetyCube aims to develop an innovative road safety Decision Support System (DSS) that will enable policy-makers and stakeholders to select the most appropriate strategies, measures and cost-effective approaches to reduce casualties of all road user types and all severities. Work Package 7 of SafetyCube is dedicated to serious road traffic injuries, their health impacts and their costs. This Deliverable discusses health impacts of (serious) road traffic injuries

High precision astrometry mission for the detection and characterization of nearby habitable planetary systems with the Nearby Earth Astrometric Telescope (NEAT)

(abridged) A complete census of planetary systems around a volume-limited sample of solar-type stars (FGK dwarfs) in the Solar neighborhood with uniform sensitivity down to Earth-mass planets within their Habitable Zones out to several AUs would be a major milestone in extrasolar planets astrophysics. This fundamental goal can be achieved with a mission concept such as NEAT - the Nearby Earth Astrometric Telescope. NEAT is designed to carry out space-borne extremely-high-precision astrometric measurements sufficient to detect dynamical effects due to orbiting planets of mass even lower than Earth's around the nearest stars. Such a survey mission would provide the actual planetary masses and the full orbital geometry for all the components of the detected planetary systems down to the Earth-mass limit. The NEAT performance limits can be achieved by carrying out differential astrometry between the targets and a set of suitable reference stars in the field. The NEAT instrument design consists of an off-axis parabola single-mirror telescope, a detector with a large field of view made of small movable CCDs located around a fixed central CCD, and an interferometric calibration system originating from metrology fibers located at the primary mirror. The proposed mission architecture relies on the use of two satellites operating at L2 for 5 years, flying in formation and offering a capability of more than 20,000 reconfigurations (alternative option uses deployable boom). The NEAT primary science program will encompass an astrometric survey of our 200 closest F-, G- and K-type stellar neighbors, with an average of 50 visits. The remaining time might be allocated to improve the characterization of the architecture of selected planetary systems around nearby targets of specific interest (low-mass stars, young stars, etc.) discovered by Gaia, ground-based high-precision radial-velocity surveys.Comment: Accepted for publication in Experimental Astronomy. The full member list of the NEAT proposal and the news about the project are available at http://neat.obs.ujf-grenoble.fr. The final publication is available at http://www.springerlink.co