FGF signaling controls caudal hindbrain specification through Ras-ERK1/2 pathway

Background: During early steps of embryonic development the hindbrain undergoes a regionalization process along the anterior-posterior (AP) axis that leads to a metameric organization in a series of rhombomeres (r). Refinement of the AP identities within the hindbrain requires the establishment of local signaling centers, which emit signals that pattern territories in their vicinity. Previous results demonstrated that the transcription factor vHnf1 confers caudal identity to the hindbrain inducing Krox20 in r5 and MafB/Kreisler in r5 and r6, through FGF signaling [1].Results: We show that in the chick hindbrain, Fgf3 is transcriptionally activated as early as 30 min after mvHnf1 electroporation, suggesting that it is a direct target of this transcription factor. We also analyzed the expression profiles of FGF activity readouts, such as MKP3 and Pea3, and showed that both are expressed within the hindbrain at early stages of embryonic development. In addition, MKP3 is induced upon overexpression of mFgf3 or mvHnf1 in the hindbrain, confirming vHnf1 is upstream FGF signaling. Finally, we addressed the question of which of the FGF-responding intracellular pathways were active and involved in the regulation of Krox20 and MafB in the hindbrain. While Ras-ERK1/2 activity is necessary for MKP3, Krox20 and MafB induction, PI3K-Akt is not involved in that process.Conclusion: Based on these observations we propose that vHnf1 acts directly through FGF3, and promotes caudal hindbrain identity by activating MafB and Krox20 via the Ras-ERK1/2 intracellular pathway.

Population pharmacokinetic analysis and pharmacogenetics of raltegravir in HIV-positive and healthy individuals.

The objectives of this study were to characterize raltegravir (RAL) population pharmacokinetics in HIV-positive (HIV(+)) and healthy individuals, identify influential factors, and search for new candidate genes involved in UDP glucuronosyltransferase (UGT)-mediated glucuronidation. The pharmacokinetic analysis was performed with NONMEM. Genetic association analysis was performed with PLINK using the relative bioavailability as the phenotype. Simulations were performed to compare once- and twice-daily regimens. A 2-compartment model with first-order absorption adequately described the data. Atazanavir, gender, and bilirubin levels influenced RAL relative bioavailability, which was 30% lower in HIV(+) than in healthy individuals. UGT1A9*3 was the only genetic variant possibly influencing RAL pharmacokinetics. The majority of RAL pharmacokinetic variability remains unexplained by genetic and nongenetic factors. Owing to the very large variability, trough drug levels might be very low under the standard dosing regimen, raising the question of a potential relevance of therapeutic drug monitoring of RAL in some situations.

Flow-R, a model for susceptibility mapping of debris flows and other gravitational hazards at a regional scale

The development of susceptibility maps for debris flows is of primary importance due to population pressure in hazardous zones. However, hazard assessment by processbased modelling at a regional scale is difficult due to the complex nature of the phenomenon, the variability of local controlling factors, and the uncertainty in modelling parameters. A regional assessment must consider a simplified approach that is not highly parameter dependant and that can provide zonation with minimum data requirements. A distributed empirical model has thus been developed for regional susceptibility assessments using essentially a digital elevation model (DEM). The model is called Flow-R for Flow path assessment of gravitational hazards at a Regional scale (available free of charge under www.flow-r.org) and has been successfully applied to different case studies in various countries with variable data quality. It provides a substantial basis for a preliminary susceptibility assessment at a regional scale. The model was also found relevant to assess other natural hazards such as rockfall, snow avalanches and floods. The model allows for automatic source area delineation, given user criteria, and for the assessment of the propagation extent based on various spreading algorithms and simple frictional laws.We developed a new spreading algorithm, an improved version of Holmgren's direction algorithm, that is less sensitive to small variations of the DEM and that is avoiding over-channelization, and so produces more realistic extents. The choices of the datasets and the algorithms are open to the user, which makes it compliant for various applications and dataset availability. Amongst the possible datasets, the DEM is the only one that is really needed for both the source area delineation and the propagation assessment; its quality is of major importance for the results accuracy. We consider a 10m DEM resolution as a good compromise between processing time and quality of results. However, valuable results have still been obtained on the basis of lower quality DEMs with 25m resolution.

[Archives de la Parole]. , [Munḍārī songs] / [Sir George Grierson], éd. ; Linguistic survey of India ; Choeur mixte, chant ; accompagnement de percussions

[Traditions. Asie. Inde. Chotā Nāgpur]

Mechanical ventilation and clinical practice heterogeneity in intensive care units: a multicenter case-vignette study.

BACKGROUND: Observational studies on mechanical ventilation (MV) show practice variations across ICUs. We sought to determine, with a case-vignette study, the heterogeneity of processes of care in ICUs focusing on mechanical ventilation procedures, and whether organizational patterns or physician characteristics influence practice variations. METHODS: We conducted a cross-sectional multicenter study using the case-vignette methodology. Descriptive analyses were calculated for each organizational pattern and respondent characteristics. An Index of Qualitative Variation (IQV, from 0, no heterogeneity, to a maximum of 1) was calculated. RESULTS: Forty ICUs from France (N = 33) and Switzerland (N = 7) participated; 396 physicians answered our case-vignettes. There was major heterogeneity of management processes related to MV within and across centers (mean IQV per center 0.51, SD 0.09). We observed the lowest variability (mean IQV per question < 0.4) for questions related to intubation procedure, ventilation of acute respiratory distress syndrome and the use of the semirecumbent position. We observed a high variability (mean IQV per question > 0.6) for questions related to management of endotracheal tube or suctioning, management of sedation and analgesia, and respect of autonomy. Heterogeneity was independent of respondent characteristics and of the presence of written procedures. There was a correlation between the processes associated with the highest variability (mean IQV per question > 0.6) and the annual volume of ICU admission (r = 0.32 (0.01 to 0.58)) and MV (r = 0.38 (0.07 to 0.63)). Within ICUs there was a large heterogeneity regarding knowledge of a local written procedure. CONCLUSIONS: Large clinical practice variations were found among ICUs. High volume centers were more likely to have heterogeneous practices. The presence of a local written procedure or respondent characteristics did not influence practice variation.

Teaching motivational interviewing to medical students : a pre-post test pilot study

Objective: To test the efficacy of teaching motivational interviewing (MI) to medical students. Methods: Thirteen 4th year medical students volunteered to participate. Seven days before and 7 days after an 8-hour interactive training MI workshop, each student performed a videorecorded interview with two standardized patients: a 60 year old alcohol dependent woman and a 50 year old cigarette smoking man. Students' counseling skills were coded by two blinded clinicians using the Motivational Interviewing Treatment Integrity 3.0 (MITI). Inter-rater reliability was calculated for all interviews and a test-retest was completed in a sub-sample of 10 consecutive interviews three days apart. Difference between MITI scores before and after training were calculated and tested using non-parametric tests. Effect size was approximated by calculating the probability that posttest scores are greater than pretest scores (P*=P(Pre<Post)+1/2P(Pre=Post)), P*>1/2 indicating greater scores in posttest, P*=1/2 no effect, and P*<1/2 smaller scores in posttest. Results: Median differences between MITI scores before and after MI training indicated a general progression in MI skills: MI spirit global score (median difference=1.5, Inter quartile range=1.5, p<0.001, P*=0.90); Empathy global score (med diff=1, IQR=0.5, p<0.001, P*=0.85); Percentage of MI adherent skills (med diff=36.6, IQR=50.5, p<0.001, P*=0.85); Percentage of open questions (med diff=18.6, IQR=21.6, p<0.001, P*=0.96); reflections/ questions ratio (med diff=0.2, IQR=0.4, p<0.001, P*=0.81). Only Direction global score and the percentage of complex reflections were not significantly improved (med diff=0, IQR=1, p=0.53, P*=0.44, and med diff=4.3, IQR=24.8, p=0.48, P*=0.62, respectively). Inter-rater reliability indicated weighted kappa ranged between 0.14 for Direction to 0.51 for Collaboration and ICC ranged between 0.28 for Simple reflection to 0.95 for Closed question. Test-retests indicated weighted kappa ranged between 0.27 for Direction to 0.80 for Empathy and ICC ranged between 0.87 for Complex reflection to 0.98 for Closed question. Conclusion: This pilot study indicated that an 8-hour training in MI for voluntary 4th year medical students resulted in significant improvement of MI skills. Larger sample of unselected medical students should be studied to generalize the benefit of MI training to medical students. Interrater reliability and test-retests suggested that coders' training should be intensified.

Eager for fairness or revenge: psychological altruism in economics

To understand the human capacity for psychological altruism, one requires a proper understanding of how people actually think and feel. This paper addresses the possible relevance of recent findings in experimental economics and neuroeconomics to the philosophical controversy over altruism and egoism. After briefly sketching and contextualizing the controversy, we survey and discuss the results of various studies on behaviourally altruistic helping and punishing behaviour, which provide stimulating clues for the debate over psychological altruism. On closer analysis, these studies prove less relevant than originally expected because the data obtained admit competing interpretations such as people seeking fairness versus people seeking revenge. However, this mitigated conclusion does not preclude the possibility of more fruitful research in the area in the future. Throughout our analysis, we provide hints for the direction of future research on the question.

Théâtre itinéraire de la Guerre actuelle entre les Turcs, d'une part, les Russes et les Impériaux, d'autre part : carte relative aussi au partage éventuel d'une partie de l'Empire Othoman / par M[onsieur Louis] Brion de la Tour, Ing[énieu]r Géographe du Roi

Échelle(s) : [1:3 400 000 ca] Échelle de Lieues d'une heure, ou de 20 au Degré 80 = [10,4 cm] (d'après échelles graphiques).

Théâtre itinéraire de la Guerre actuelle entre les Turcs, d'une part, les Russes et les Impériaux, d'autre part : carte relative aussi au partage éventuel d'une partie de l'Empire Othoman / par M[onsieur Louis] Brion de la Tour, Ing[énieu]r Géographe du Roi

Échelle(s) : [1:3 400 000 ca] Échelle de Lieues d'une heure, ou de 20 au Degré 80 = [10,4 cm] (d'après échelles graphiques).