The Ergogenic Effect of Recombinant Human Erythropoietin on V̇O2max Depends on the Severity of Arterial Hypoxemia

Treatment with recombinant human erythropoietin (rhEpo) induces a rise in blood oxygen-carrying capacity (CaO2) that unequivocally enhances maximal oxygen uptake (V̇O2max) during exercise in normoxia, but not when exercise is carried out in severe acute hypoxia. This implies that there should be a threshold altitude at which V̇O2max is less dependent on CaO2. To ascertain which are the mechanisms explaining the interactions between hypoxia, CaO2 and V̇O2max we measured systemic and leg O2 transport and utilization during incremental exercise to exhaustion in normoxia and with different degrees of acute hypoxia in eight rhEpo-treated subjects. Following prolonged rhEpo treatment, the gain in systemic V̇O2max observed in normoxia (6–7%) persisted during mild hypoxia (8% at inspired O2 fraction (FIO2) of 0.173) and was even larger during moderate hypoxia (14–17% at FIO2 = 0.153–0.134). When hypoxia was further augmented to FIO2 = 0.115, there was no rhEpo-induced enhancement of systemic V̇O2max or peak leg V̇O2. The mechanism highlighted by our data is that besides its strong influence on CaO2, rhEpo was found to enhance leg V̇O2max in normoxia through a preferential redistribution of cardiac output toward the exercising legs, whereas this advantageous effect disappeared during severe hypoxia, leaving augmented CaO2 alone insufficient for improving peak leg O2 delivery and V̇O2. Finally, that V̇O2max was largely dependent on CaO2 during moderate hypoxia but became abruptly CaO2-independent by slightly increasing the severity of hypoxia could be an indirect evidence of the appearance of central fatigue

A new 3MW ECRH system at 105 GHz for WEST

The aim of the WEST experiments is to master long plasma pulses (1000s) and expose ITER-like tungsten wall to deposited heat fluxes up to 10 MW/m$^2$. To increase the margin to reach the H-Mode and to control W-impurities in the plasma, the installation of an upgraded ECRH heating system, with a gyrotron performance of 1MW/1000s per unit, is planned in 2023. With the modifications of Tore Supra to WEST, simulations at a magnetic field B$_0$∼3.7T and a central density n$_{e0}$∼6 × 10$^{19}$ m$^{−3}$ show that the optimal frequency for central absorption is 105 GHz. For this purpose, a 105 GHz/1MW gyrotron (TH1511) has been designed at KIT in 2021, based on the technological design of the 140 GHz/1.5 MW (TH1507U) gyrotron for W7-X. Currently, three units are under fabrication at THALES. In the first phase of the project, some of the previous Tore Supra Electron Cyclotron (EC) system components will be re-installed and re-used whenever possible. This paper describes the studies performed to adapt the new ECRH system to 105 GHz and the status of the modifications necessary to re-start the system with a challenging schedule

Solution structures of the Bacillus cereus metallo-β-lactamase BcII and its complex with the broad spectrum inhibitor R-thiomandelic acid

Metallo-β-lactamases, enzymes which inactivate β-lactam antibiotics, are of increasing biological and clinical significance as a source of antibiotic resistance in pathogenic bacteria. In the present study we describe the high-resolution solution NMR structures of the Bacillus cereus metallo-β-lactamase BcII and of its complex with R-thiomandelic acid, a broad-spectrum inhibitor of metallo-β-lactamases. This is the first reported solution structure of any metallo-β-lactamase. There are differences between the solution structure of the free enzyme and previously reported crystal structures in the loops flanking the active site, which are important for substrate and inhibitor binding and catalysis. The binding of R-thiomandelic acid and the roles of active-site residues are defined in detail. Changes in the enzyme structure upon inhibitor binding clarify the role of the mobile β3–β4 loop. Comparisons with other metallo-β-lactamases highlight the roles of individual amino-acid residues in the active site and the β3–β4 loop in inhibitor binding and provide information on the basis of structure–activity relationships among metallo-β-lactamase inhibitors

Operating a full tungsten actively cooled tokamak: overview of WEST first phase of operation

WEST is an MA class superconducting, actively cooled, full tungsten (W) tokamak, designed to operate in long pulses up to 1000 s. In support of ITER operation and DEMO conceptual activities, key missions of WEST are: (i) qualification of high heat flux plasma-facing components in integrating both technological and physics aspects in relevant heat and particle exhaust conditions, particularly for the tungsten monoblocks foreseen in ITER divertor; (ii) integrated steady-state operation at high confinement, with a focus on power exhaust issues. During the phase 1 of operation (2017–2020), a set of actively cooled ITER-grade plasma facing unit prototypes was integrated into the inertially cooled W coated startup lower divertor. Up to 8.8 MW of RF power has been coupled to the plasma and divertor heat flux of up to 6 MW m−2 were reached. Long pulse operation was started, using the upper actively cooled divertor, with a discharge of about 1 min achieved. This paper gives an overview of the results achieved in phase 1. Perspectives for phase 2, operating with the full capability of the device with the complete ITER-grade actively cooled lower divertor, are also described

Analyse du processus d'internationalisation du complexe agro-industriel français (1955-1980)

Byé Pascal, Mollard Amédée. Analyse du processus d'internationalisation du complexe agro-industriel français (1955-1980). In: Tiers-Monde, tome 22, n°88, 1981. Transformations agraires. pp. 775-787

L'unité d'hospitalisation de courte durée de l'hôpital de Chambéry (rapport d'activité et étude de la population sur l'année 2000)

Durant l'année 2000, 1284 hospitalisations ont eu lieu dans l'unité d'hospitalisation de courte durée de l'hôpital de Chambéry soit 4 % des passages aux urgences. Les recommandations de la Société Francophone d'Urgence Médicale ont été respectées dans l'ensemble durant cette première année complète d'exploitation. L'âge moyen est de 49,23 ans avec une prédominance féminine à 53 %. La durée moyenne du séjour est de 17 heures +- 5,7 et l'UHCD a permis d'éviter 524 hospitalisations en unité conventionnelle, 71 % des hospitalisations ont eu lieu dans un service adapté. Des efforts restent à faire notamment en ce qui concerne le respect des critères d'admission, pour que cette unité puisse tenir pleinement son rôle en terme de service médical à rendre aux malades et d'économie de santé.GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Overall, specific, and metastasis-free survival of Afro-Caribbean men with pathological Gleason 6 prostate cancer

International audienceBACKGROUND:Several studies in the Caucasian population have shown that patients with Gleason 6 prostate cancer, based on surgical specimens, have low or no risk of metastasis. However, there is no data for men of African ancestry. The objective of this study was to estimate the overall, specific, and metastasis-free survival (MFS) of patients with a Gleason 6 score, based on the surgical specimen.PATIENTS AND METHODS:This was a monocentric retrospective study that included 723 consecutive patients treated by radical prostatectomy between 1 January 1 2000 and 31 March 2018, with a Gleason score of 6 based on the surgical specimen. Specific survival (SS) was defined as the time elapsed between surgery and death attributed to prostate cancer. Overall survival was defined as the time elapsed between surgery and death from all causes. The causes of death were verified in the medical records. Survival analyses without biochemical recurrence (BCR) and without salvage treatment were performed according to the Kaplan-Meier method. The Cox model was used for univariate and multivariate analyses.RESULTS:In total, 691 patients were included because 32 were excluded for missing data. Overall 5- and 10-year survival was 94.2% and 87.1%, respectively. SS and MFS were 100%, with a median follow-up of 8.5 years. The BCR rate was 16.5%, with a median time to BCR of 5.1 years. The frequency of salvage treatment was 13.0%, with a median time to surgery of 7.3 years. In univariate analysis, PSA, pathological stage, seminal vesicle invasion, positive margins, and lymph node dissection were significantly associated with an increased risk of BCR and salvage treatment, but only PSA and positive margins were significantly associated by multivariate analysis.DISCUSSION/CONCLUSION:No metastasis or disease-specific deaths were observed for men with Gleason score ≤6 prostate cancer at radical prostatectomy, in particular, men of African ancestry

Retinoic acid signaling regulates murine bronchial tubule formation

International audienceTreatment of pseudoglandular stage fetal lungs in vitro with the pan-retinoic acid receptor (pan-RAR) antagonist, BMS493, reduces retinoic acid receptor beta (Rarb) gene expression within the proximal bronchial tubules and increases explant bud formation. Treatment with retinoic acid (RA) increases Rarb expression and reduces explant bud formation through a signaling mechanism involving RARbeta. Together these data suggest that RA through RARbeta provides morphogenetic stabilizing activity to the proximal tubules during lung branching morphogenesis. Here we further investigate RA-mediated morphogenetic stabilization of the proximal respiratory tubules during fetal lung development. We demonstrate that Rarb isoform transcripts are the only known Rar transcripts to specifically localize to the proximal tubules and that RAREhsp68lacZ reporter transgene activity reveals endogenous RA signaling activity within these same proximal tubules. Furthermore, the expression patterns of the RA-producing enzyme retinaldehyde dehydrogenase 1 (Raldh1), as well as of transforming growth factor-3beta (Tgfb3), Foxa2, and the cystic fibrosis transmembrane conductance regulator (Cftr) within the proximal tubules are all altered by the application of either RA or BMS493 in vitro. We therefore discuss an interbud/proximal tubule signaling niche involving feedback between Rarb expression and Raldh1-mediated synthesis of RA. We suggest that this feedback favors interbud morphogenetic stability by increasing expression of morphoregulatory molecules such as TGFbeta3 and Foxa2, thus promoting bronchial tubule formation rather than continual budding and branching. The relationship between this RAR signaling center and the previously described distal bud signaling center is also addressed

Multiple cytosolic calcium signals and membrane electrical events evoked in single arginine vasopressin-stimulated corticotrophs

The action of arginine vasopressin (AVP) on cytosolic free Ca2+ concentration ([Ca2+]i) was investigated in single rat pituitary corticotrophs using indo-1 microfluorimetry, in part in combination with the monitoring of membrane electrical events with the perforated patch-clamp technique. In corticotrophs showing the series of short-lived [Ca2+]i rises (transient pattern) in response to corticotropin-releasing factor, 100 nM AVP evoked either the transient pattern or a [Ca2+]i spike followed by a sustained plateau (spike/plateau pattern). Not all corticotrophs responded to changes in AVP concentration in the same manner. Some cells exhibited a concentration-dependent increase in [Ca2+]i transient activity, whereas others showing the spike/plateau at high AVP concentrations responded to low agonist concentrations by two [Ca2+]i responses: a slow rising step or two to three sinusoidal-like oscillations. Combined [Ca2+]i and patch-clamp recordings as well as manipulation of extracellular Ca2+ showed that both transient pattern and the plateau of spike/plateau response depended on Ca2+ entry mainly through voltage-gated, dihydropyridine-sensitive Ca2+ channels. By contrast, step, oscillations, and spike were due to Ca2+ release from internal stores. These Ca(2+)-mobilizing responses caused the activation of Ca(2+)-activated, apamin-sensitive K+ channels, which led to a membrane hyperpolarization. These results reveal cell-specific [Ca2+]i signals and associated electrical events in individual AVP-stimulated corticotrophs