LE NANNOPLANCTON CALCAIRE ET LA FORMATION DES ALTERNANCES CALCAIRES-MARNES DANS LE LIAS DES BASSINS DE MARCHES-OMBRIE (ITALIE)

In the classical sections of Sentino-Valdorbia, Bosso and the Marne di Monte Serrone type-section the rhythmic, limestone/marl sedimentation of the following formations were studied: the Corniola (Late Sinemurian to Earliest Toarcian) and the Marne di Monte Serrone (Early Toarcian). The geological framework is drawn from the numerous and significant published papers which give a good stratigraphical scheme and a precise paleogeographic setting. The limestones have been studied in thin sections (texture, occurrence and abundance of schizospheres, other fauna, etc.) and with SEM (structure, occurrence, abundance and diagenetic state of schizospheres; coccoliths). Marly interbeds have been studied in light microscopy on smear slides of raw sediment to find out coccoliths and schizospheres and with SEM, both on washed and centrifuged sediments (for a better definition of the nannofloras) and on freshly broken surfaces. The conclusions are based upon 69 SEM pictures of limestones and 94 SEM pictures of marls from the Corniola Formation; on 169 SEM pictures of limestones and 303 SEM pictures of marls from the Marne di Monte Serrone Formation. The observations show the importance of the nannofloral contrast between the Limestone beds with schizospheres and the marly interbeds with coccoliths. The contrast is thought to portray rhe original difference between the components which generated the two different types of sediments. The lithogenetic role of the nannoplankton was strongly differentiated and was linked to an alternation of clay-poor, sea-warer phases when stable, calcareous nannoplankton (schizospheres) dominated and did not evolve and of clay-richer, sea-water phases when coccolithophorids expanded and evolved

Influence of drug safety advisories on drug utilisation: an international interrupted time series and meta-analysis

OBJECTIVE: To evaluate the association between regulatory drug safety advisories and changes in drug utilisation. DESIGN: We conducted controlled, interrupted times series analyses with administrative prescription claims data to estimate changes in drug utilisation following advisories. We used random-effects meta-analysis with inverse-variance weighting to estimate the average postadvisory change in drug utilisation across advisories. STUDY POPULATION: We included advisories issued in Canada, Denmark, the UK and the USA during 2009-2015, mainly concerning drugs in common use in primary care. We excluded advisories related to over-the-counter drugs, drug-drug interactions, vaccines, drugs used primarily in hospital and advisories with co-interventions within ±6 months. MAIN OUTCOME MEASURES: Change in drug utilisation, defined as actual versus predicted percentage change in the number of prescriptions (for advisories without dose-related advice), or in the number of defined daily doses (for dose-related advisories), per 100 000 population. RESULTS: Among advisories without dose-related advice (n=20), the average change in drug utilisation was -5.83% (95% CI -10.93 to -0.73; p=0.03). Advisories with dose-related advice (n=4) were not associated with a statistically significant change in drug utilisation (-1.93%; 95% CI -17.10 to 13.23; p=0.80). In a post hoc subgroup analysis of advisories without dose-related advice, we observed no statistically significant difference between the change in drug utilisation following advisories with explicit prescribing advice, such as a recommendation to consider the risk of a drug when prescribing, and the change in drug utilisation following advisories without such advice. CONCLUSIONS: Among safety advisories issued on a wide range of drugs during 2009-2015 in 4 countries (Canada, Denmark, the UK and the USA), the association of advisories with changes in drug utilisation was variable, and the average association was modest

Hydroxyzine Initiation Following Drug Safety Advisories on Cardiac Arrhythmias in the UK and Canada: A Longitudinal Cohort Study

INTRODUCTION: Regulatory advisories on hydroxyzine and risk of QT prolongation and Torsade de pointes (TdP) were issued in the UK in April 2015 and Canada in June 2016. We hypothesized patients with risk factors for QT prolongation and TdP, compared with those without risk factors, would be less likely to initiate hydroxyzine in the UK and in British Columbia (BC), Canada, following advisories. METHODS: We conducted a longitudinal study with repeated measures, and evaluated hydroxyzine initiation in a UK cohort and a concurrent BC control cohort (April 2013-March 2016) as well as in a BC advisory cohort (June 2014-May 2017). RESULTS: This study included 247,665 patients in the UK cohort, 297,147 patients in the BC control cohort, and 303,653 patients in the BC advisory cohort. Over a 12-month post-advisory period, hydroxyzine initiation decreased by 21% in the UK (rate ratio 0.79, 95% confidence interval 0.66-0.96) relative to the expected level of initiation based on the pre-advisory trend. Hydroxyzine initiation did not change in the BC control cohort or following the Canadian advisory in the BC advisory cohort. The decrease in hydroxyzine initiation in the UK in the 12 months after the advisories was not significantly different for patients with risk factors compared with those without risk factors. CONCLUSION: Hydroxyzine initiation decreased in the UK, but not in BC, in the 12 months following safety advisories. The decrease in hydroxyzine initiation in the UK was not significantly different for patients with versus without risk factors for QT prolongation and TdP

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Agir humain et détachement chez Maître Eckhart

Le détachement (abegescheidenheit) est un terme forgé par Eckhart et constitue l'axe principal de sa prédication en moyen-haut-allemand. Il s'agit d'un travail de libération par rapport à toutes choses et à soi-même, mais aussi d'une expérience de la grâce conduisant à une réalisation de l'homme dans son être propre. A ce titre, le détachement n'est pas une fuite du monde, mais bien au contraire la condition et le fondement d'un agir proprement humain comme le manifeste tout particulièrement l'acte de la parole. La pensée eckhartienne s'inscrit ainsi dans la tradition théologique et reprend un certain nombre de thèmes classiques comme par exemple celui de l'Incarnation du Verbe et de la divinisation de l'homme, ou encore le schème augustinien de la liberté et de la grâce. Cette articulation entre détachement et agir doit également être située par rapport au contexte historique. A la fin du Moyen Age, on assiste en effet à un renouveau de la vie spirituelle et en particulier à un essor des pratiques ascétiques et pénitentielles. Les gens veulent savoir ce qu'il faut faire pour être en " bons termes " avec Dieu. Par-delà les considérations morales de bien et de mal, de péché et de vertu, Eckhart répond à ces préoccupations en montrant le fondement mystique de l'agir humain. En même temps, la dimension pratique du détachement lui permet de dénoncer les faux spirituels et les thèses développées par les disciples du Libre esprit qui envisagent la perfection comme une forme d'indifférence par rapport à la pratique des œuvres. Nourri de la tradition et enraciné dans les polémiques de son temps. Eckhart interroge également notre époque et l'étude de sa pensée s'avère féconde pour comprendre aujourd'hui certains auteurs comme Maurice Zundel, ce qui explique en partie l'engouement contemporain pour celui qui est peut-être encore un maître de vie (lebemeister).STRASBOURG-B.N.U.S. (674821001) / SudocSTRASBOURG-Théologie Catho. (674822201) / SudocSTRASBOURG-Théologie Protest. (674822202) / SudocSudocFranceF

Les neuf cases de l'architecture

Une histoire de la villa, de Palladio au 16e siècle à la villa des Five au 20e siècle, à travers l'étude d'une variation sur un même thème : le plan carré divisé en 9 cases (très nombreux plans de villas). En conclusion, quelques notes étymologiques sur le mot structur

Acetylcholine Controls GABA-, Glutamate-, and Glycine-Dependent Giant Depolarizing Potentials that Govern Spontaneous Motoneuron Activity at the Onset of Synaptogenesis in the Mouse Embryonic Spinal Cord

International audienceA remarkable feature of early neuronal networks is their endogenous ability to generate spontaneous rhythmic electrical activity independently of any external stimuli. In the mouse embryonic SC, this activity starts at an embryonic age of similar to 12 d and is characterized by bursts of action potentials recurring every 2-3 min. Although these bursts have been extensively studied using extracellular recordings and are known to play an important role in motoneuron (MN) maturation, the mechanisms driving MN activity at the onset of synaptogenesis are still poorly understood. Because only cholinergic antagonists are known to abolish early spontaneous activity, it has long been assumed that spinal cord (SC) activity relies on a core network of MNs synchronized via direct cholinergic collaterals. Using a combination of whole-cell patch-clamp recordings and extracellular recordings in E12.5 isolated mouse SC preparations, we found that spontaneous MN activity is driven by recurrent giant depolarizing potentials. Our analysis reveals that these giant depolarizing potentials are mediated by the activation of GABA, glutamate, and glycine receptors. We did not detect direct nAChR activation evoked by ACh application on MNs, indicating that cholinergic inputs between MNs are not functional at this age. However, we obtained evidence that the cholinergic dependency of early SC activity reflects a presynaptic facilitation of GABA and glutamate synaptic release via nicotinic AChRs. Our study demonstrates that, even in its earliest form, the activity of spinal MNs relies on a refined poly-synaptic network and involves a tight presynaptic cholinergic regulation of both GABAergic and glutamatergic inputs

Breeding for sunflower hybrids adapted to climate change: the SUNRISE collaborative and multi-disciplinary project

International audienceIn the context of climate change, an increased variability is expected in timing and amount of water available for crop production. For sunflower crop, yield losses of 10 to 30 % have been predicted at 2030 horizon in Europe. During the past 10 years, genetic progress was lower than expected to improve yield, which imposes to the sunflower community to re-invest current breeding resources and methodologies. To reach high and stable yields across a wide range of environments a French project of 8 years, named 'SUNRISE' (SUNflower Resources to Improve yield Stability in a changing Environment) and supported by the French National Research Agency, is gathering 9 public and 7 private partners since 2012. It associates several approaches: (i) the sequencing and genotyping of the genetic diversity among cultivated and wild sunflowers, (ii) the development of appropriate and high-throughput phenotyping strategies to characterize the molecular, physiological and agronomical responses to variation of the abiotic environment, (iii) the discovery through genome-wide association, linkage mapping and genomic selection of the genetic factors involved in those responses, (iv) the integration of this genetic knowledge into a crop mode! (SUNFLO) to test in silico G by E interactions and design promising ideotypes in future environments, and finally (v) the evaluation of the outputs for the breeding sector and the transfer ofknowledge to agriculture. This partnership will ensure that the developed knowledge, resources and methods will be translated into products and varieties supporting the adaptation of the agriculture to societal and ecological challenges

Identification of pea lines resistant to Aphanomyces euteiches and related root architecture traits

International audienceCommon root rot caused by Aphanomyces euteiches, is a major soil borne disease of pea in many countries. Genetic resistance is considered to be the main way to control the disease. The role of plant root architecture in Aphanomyces root rot resistance is not well known. This study aimed at identifying pea lines with high levels of resistance in a collection of 175 accessions enriched with sources of resistance and root architectural traits harbored by resistant lines. The collection was assessed for resistance to A. euteiches on the roots and on the aerial plant parts, both in controlled conditions and in a four-year and multi-location field disease network. The collection was also described for root architectural traits on healthy and infested plants in controlled conditions at young plant stage. Lines with higher levels of resistance than partially resistant controls were identified. Susceptible and partially resistant plants mostly showed a decrease of lateral root density and dry weight when compared to healthy controls. However, some resistant lines maintained both root density and dry weight, suggesting their ability to preserve the root system in response to infection. These results will be confirmed in the field using a set of contrasted genotypes. Genome wide association analysis will be performed to compare the genetic control of Aphanomyces root rot resistance and of root architecture traits in response to infection