Les canicules de l’été 2003 : un événement météorologique exceptionnel dans le quart nord-est de la France

L’été 2003 restera dans les annales climatiques comme un événement météorologique exceptionnel de par son ampleur et sa durée. 22 postes synoptiques situés dans le quart Nord-Est de la France, ont été sélectionnés pour faire ressortir les principales caractéristiques de cet été. Plusieurs paramètres (températures, précipitations, insolation) ont été comparés aux normales climatiques de la période 1971-2000. Au vu des écarts thermiques observés, trois périodes de canicule ont pu être mises en évidence. Elles sont d’ampleur inégale selon la latitude et la région considérées. Une analyse détaillée des conditions synoptiques a été réalisée afin de connaître les facteurs à l’origine de la canicule. L’épisode du 3 au 14 août 2003 a fait l’objet d’une attention particulière.Owing to its magnitude and duration, the summer of 2003 will be remembered as an outstanding meteorological event. 22 synoptical weather stations located in northeastern France have been selected in view of analysing the main features of this summer. Three meteorological parameters (air temperature, rainfall, sunshine duration) have been compared to their 1971-2000 climate normals. Air temperature anomalies allow identifying three heat waves during summer 2003 with different magnitudes according to the latitude and the considered region. A detailed analysis of synoptical weather conditions has been performed in order to identify heat wave explanatory factors, especially for the 3rd to 14th of August 2003 episod.Der Sommer 2003 wird in den Klimatologischen Annalen als einem besonderen météorologische Ereignis, an Intensität und Dauer, bezeichnet. Mit Hilfe, 22 synoptische Klimastationen im Nord-Osten von Frankreich, wurden die hauptsächlichen Charakteristiken dieses Sommers analysiert. Mehrere Parameter (Temperatur, Niederschlag, Sonnenscheindauer) wurden mit den Normalen vom Zeitraum 1971-2000 verglichen. In Betrachtung der verschiedenen Abweichungen, wurden drei Hitzewellen deutlich Identifiziert. Von dem Breitengrad und der Regionen abgesehen, sind sie von verschiedener Intensität. Mit Hilfe von synoptischen Daten und Karten wurden die Ursachen der Hitzewelle analysiert. Der Zeitraum vom 3. bis 14. August wurde aufmerksam untersucht

Dose-finding study of valspodar (PSC 833) with daunorubicin and cytarabine to reverse multidrug resistance in elderly patients with previously untreated acute myeloid leukemia

Introduction: This trial was designed to determine the maximum tolerated dose of intravenous daunorubicin (DNR) in combination with valspodar and to test the feasibility of P-glycoprotein modulation using valspodar in elderly patients with previously untreated acute myelogenous leukemia receiving standard induction chemotherapy. Methods: Patients ≥60 years of age with previously untreated AML received valspodar (10 mg/kg/24 h by continuous intravenous infusion [CIV] on days 1-4 with a 2-mg/kg loading dose on day 1) in conjunction with two cycles of induction chemotherapy consisting of cytarabine (200 mg/m2 CIV on days 1-7), and DNR (35 mg/m2 [cohort 1] or 45 mg/m2 [cohort 2] on days 1-3, intravenous bolus). Patients were assessed for dose-limiting toxicities (DLT), response rate, event-free and overall survival, and pharmacokinetics of valspodar and DNR. Results: Valspodar was well tolerated at the lower DNR dose level (ie, 35 mg/m2) resulting in a 21% rate of DLT and only three toxic deaths. Treatment-related mortality was unacceptably high at the 45 mg/m2 DNR dose level. The complete response rate was 49% overall and similar in both cohorts. The median overall survival of patients was 333 days in cohort 1 compared to 98 days in cohort 2. At baseline, 70% of assessable patients were P-glycoprotein positive. Conclusion: Substantial inhibition of P-glycoprotein activity can be achieved in this patient population at clinically tolerable doses of valspodar and DNR. The maximum tolerated dose of DNR was established as 35 mg/m2. This regimen is being further evaluated in phase III trials.</p

Clinically practical pharmacometrics computer model to evaluate and personalize pharmacotherapy in pediatric rare diseases: application to Graves' disease

ObjectivesGraves' disease (GD) with onset in childhood or adolescence is a rare disease (ORPHA:525731). Current pharmacotherapeutic approaches use antithyroid drugs, such as carbimazole, as monotherapy or in combination with thyroxine hormone substitutes, such as levothyroxine, as block-and-replace therapy to normalize thyroid function and improve patients' quality of life. However, in the context of fluctuating disease activity, especially during puberty, a considerable proportion of pediatric patients with GD is suffering from thyroid hormone concentrations outside the therapeutic reference ranges. Our main goal was to develop a clinically practical pharmacometrics computer model that characterizes and predicts individual disease activity in children with various severity of GD under pharmacotherapy.MethodsRetrospectively collected clinical data from children and adolescents with GD under up to two years of treatment at four different pediatric hospitals in Switzerland were analyzed. Development of the pharmacometrics computer model is based on the non-linear mixed effects approach accounting for inter-individual variability and incorporating individual patient characteristics. Disease severity groups were defined based on free thyroxine (FT4) measurements at diagnosis.ResultsData from 44 children with GD (75% female, median age 11 years, 62% receiving monotherapy) were analyzed. FT4 measurements were collected in 13, 15, and 16 pediatric patients with mild, moderate, or severe GD, with a median FT4 at diagnosis of 59.9 pmol/l (IQR 48.4, 76.8), and a total of 494 FT4 measurements during a median follow-up of 1.89 years (IQR 1.69, 1.97). We observed no notable difference between severity groups in terms of patient characteristics, daily carbimazole starting doses, and patient years. The final pharmacometrics computer model was developed based on FT4 measurements and on carbimazole or on carbimazole and levothyroxine doses involving two clinically relevant covariate effects: age at diagnosis and disease severity.DiscussionWe present a tailored pharmacometrics computer model that is able to describe individual FT4 dynamics under both, carbimazole monotherapy and carbimazole/levothyroxine block-and-replace therapy accounting for inter-individual disease progression and treatment response in children and adolescents with GD. Such clinically practical and predictive computer model has the potential to facilitate and enhance personalized pharmacotherapy in pediatric GD, reducing over- and underdosing and avoiding negative short- and long-term consequences. Prospective randomized validation trials are warranted to further validate and fine-tune computer-supported personalized dosing in pediatric GD and other rare pediatric diseases

Analytical Performance Evaluation of New DESI Enhancements for Targeted Drug Quantification in Tissue Sections

Desorption/ionization (DI)-mass spectrometric (MS) methods offer considerable advantages of rapidity and low-sample input for the analysis of solid biological matrices such as tissue sections. The concept of desorption electrospray ionization (DESI) offers the possibility to ionize compounds from solid surfaces at atmospheric pressure, without the addition of organic compounds to initiate desorption. However, severe drawbacks from former DESI hardware stability made the development of assays for drug quantification difficult. In the present study, the potential of new prototype source setups (High Performance DESI Sprayer and Heated Transfer Line) for the development of drug quantification assays in tissue sections was evaluated. It was demonstrated that following dedicated optimization, new DESI XS enhancements present promising options regarding targeted quantitative analyses. As a model compound for these developments, ulixertinib, an inhibitor of extracellular signal-regulated kinase (ERK) 1 and 2 was used

A comparison of national approaches to setting ecological status boundaries in phytobenthos assessment for the European Water Framework Directive: results of an intercalibration exercise

The European Union (EU)'s Water Framework Directive (WFD) requires that all Member States participate in intercalibration exercises in order to ensure that ecological status concepts and assessment levels are consistent across the EU. This paper describes one such exercise, performed by the countries in the Central/Baltic Geographical Intercalibration Group stretching from Ireland in the west to Estonia in the east and from the southern parts of Scandinavia to the northern regions of Spain and Italy (but excluding alpine regions, which were intercalibrated separately). In this exercise, methods used to measure ecological status of rivers using benthic diatoms were compared. Ecological status is estimated as the ratio between the observed value of a biological element and the value expected in the absence of significant human impact. Approaches to defining the 'reference sites', from which these 'expected' values were derived, varied from country to country. Minimum criteria were established as part of the exercise but there was still considerable variation between national reference values, reflecting typological differences that could not be resolved during the exercise. A simple multimetric index was developed to compare boundary values using two widely used diatom metrics. Boundary values for high/good status and good/moderate status set by each participant were converted to their equivalent values of this intercalibration metric using linear regression. Variation of ±0.05 EQR units around the median value was considered to be acceptable and the exercise provided a means for those Member States who fell significantly above or below this line to review their approaches and, if necessary, adjust their boundaries

Large-scale genome sequencing of mycorrhizal fungi provides insights into the early evolution of symbiotic traits

Mycorrhizal fungi are mutualists that play crucial roles in nutrient acquisition in terrestrial ecosystems. Mycorrhizal symbioses arose repeatedly across multiple lineages of Mucoromycotina, Ascomycota, and Basidiomycota. Considerable variation exists in the capacity of mycorrhizal fungi to acquire carbon from soil organic matter. Here, we present a combined analysis of 135 fungal genomes from 73 saprotrophic, endophytic and pathogenic species, and 62 mycorrhizal species, including 29 new mycorrhizal genomes. This study samples ecologically dominant fungal guilds for which there were previously no symbiotic genomes available, including ectomycorrhizal Russulales, Thelephorales and Cantharellales. Our analyses show that transitions from saprotrophy to symbiosis involve (1) widespread losses of degrading enzymes acting on lignin and cellulose, (2) co-option of genes present in saprotrophic ancestors to fulfill new symbiotic functions, (3) diversification of novel, lineage-specific symbiosis-induced genes, (4) proliferation of transposable elements and (5) divergent genetic innovations underlying the convergent origins of the ectomycorrhizal guild. Mycorrhizal symbioses have evolved repeatedly in diverse fungal lineages. A large phylogenomic analysis sheds light on genomic changes associated with transitions from saprotrophy to symbiosis, including divergent genetic innovations underlying the convergent origins of the ectomycorrhizal guild.Peer reviewe

Historical Biogeography and Diversification of Truffles in the Tuberaceae and Their Newly Identified Southern Hemisphere Sister Lineage

Truffles have evolved from epigeous (aboveground) ancestors in nearly every major lineage of fleshy fungi. Because accelerated rates of morphological evolution accompany the transition to the truffle form, closely related epigeous ancestors remain unknown for most truffle lineages. This is the case for the quintessential truffle genus Tuber, which includes species with socio-economic importance and esteemed culinary attributes. Ecologically, Tuber spp. form obligate mycorrhizal symbioses with diverse species of plant hosts including pines, oaks, poplars, orchids, and commercially important trees such as hazelnut and pecan. Unfortunately, limited geographic sampling and inconclusive phylogenetic relationships have obscured our understanding of their origin, biogeography, and diversification. To address this problem, we present a global sampling of Tuberaceae based on DNA sequence data from four loci for phylogenetic inference and molecular dating. Our well-resolved Tuberaceae phylogeny shows high levels of regional and continental endemism. We also identify a previously unknown epigeous member of the Tuberaceae - the South American cup-fungus Nothojafnea thaxteri (E.K. Cash) Gamundi. Phylogenetic resolution was further improved through the inclusion of a previously unrecognized Southern hemisphere sister group of the Tuberaceae. This morphologically diverse assemblage of species includes truffle (e.g. Gymnohydnotrya spp.) and non-truffle forms that are endemic to Australia and South America. Southern hemisphere taxa appear to have diverged more recently than the Northern hemisphere lineages. Our analysis of the Tuberaceae suggests that Tuber evolved from an epigeous ancestor. Molecular dating estimates Tuberaceae divergence in the late Jurassic (~156 million years ago), with subsequent radiations in the Cretaceous and Paleogene. Intra-continental diversification, limited long-distance dispersal, and ecological adaptations help to explain patterns of truffle evolution and biodiversity

Role des phénomènes de canalisation dans la pénétration des ions dans les cristaux

After having outlined the main features of the classical theory of ion penetration into matter and the dominant energy loss mechanisms, the author studies more precisely the effects of the correlation between successive collisions due to the presence of a crystal lattice. The different aspects of the channelling process at different energies are related to the variations in the dominant energy loss mechanism.Après un rappel des théories classiques de la pénétration des ions rapides dans la matière et des principaux modes de freinage de ces ions, on étudie plus particulièrement les effets dus à la présence d'un réseau cristallin qui introduit une corrélation entre les chocs successifs. Les différences d'aspect du phénomène de canalisation en fonction de l'énergie sont expliquées par la variation du mode de freinage dominant