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Political project and town planning: the Strasbourg of Pierre Pflimlin (1959-1983).— this article is a reflection on politics, time, and town through the analysis of the projects and realizations carried out from 1959 to 1983 by Pierre Pflimin, the mayor of Strasbourg. About 25 years of evolution in Strasbourg can be reconstructed by a thorough historical analysis, using original sources: the proceedings of the town council. Their main teachings have been confronted to observations made on the ground nowadays. This new historical knowledge is used in particular as a tool to dissect in detail the relations between political projects, urban projects, and the realizations that follow from them. The main town-related ambitions of the «Pflimlin era» are presented and analysed so that the underlying motives of these realizations can be drawn. The resources that were implemented for this policy are detailed. And finally the ensued are assed according to the initial intentions., Cet article est une réflexion sur le politique, le temps et la ville, à travers l'analyse des projets et des réalisations urbaines du maire Pierre Pflimlin à Strasbourg de 1959 à 1983. Une analyse historique précise permet de restituer un quart de siècle d'évolution de la ville de Strasbourg, grâce à la mobilisation de sources originales, les actes du Conseil municipal, dont les principaux enseignements ont été croisés aux observations de terrain effectuées de nos jours. Ces nouvelles connaissances historiques permettent notamment de décortiquer les relations existant entre les projets politiques municipaux, les projets urbains et les réalisations qui en découlent. Les principales ambitions municipales de «l'ère Pflimlin» sont présentées et analysées afin d'en dégager les intentions profondes. Les moyens mis en œuvre pour faire aboutir cette politique sont détaillés. Enfin, les réalisations qui en découlent sont évaluées à l'aune des desseins initiaux., Badariotti DominiqueBadariotti Dominique. Projet politique et urbanisme : le Strasbourg de Pierre Pflimlin (1959-1983). In: L'Espace géographique, tome 25, n°1, 1996. pp. 53-64.

[Image: see text] Anorexigenic peptides offer promise as potential therapies targeting the escalating global obesity epidemic. Prolactin-releasing peptide (PrRP), a novel member of the RFamide family secreted by the hypothalamus, shows therapeutic potential by decreasing food intake and body weight in rodent models via GPR10 activation. Here we describe the design of a long-acting PrRP using our recently developed novel multiple ethylene glycol-fatty acid (MEG-FA) stapling platform. By incorporating serum albumin binding fatty acids onto a covalent side chain staple, we have generated a series of MEG-FA stapled PrRP analogs with enhanced serum stability and in vivo half-life. Our lead compound 18-S4 exhibits good in vitro potency and selectivity against GPR10, improved serum stability, and extended in vivo half-life (7.8 h) in mouse. Furthermore, 18-S4 demonstrates a potent body weight reduction effect in a diet-induced obesity (DIO) mouse model, representing a promising long-acting PrRP analog for further evaluation in the chronic obesity setting.

Éleveur laitier et chercheur indépendant, en avance sur son temps, André Voisin a pratiqué une approche interdisciplinaire éclairant, par des lectures scientifiques tous azimuts, les observations faites dans son exploitation et dans des exploitations voisines. Sa vision écosystémique de la prairie pâturée – donnant toute sa place au temps dans les interactions herbe-animal – a produit des principes de pâturage rationnel, largement appliqués aujourd'hui dans de nombreux pays, et qui constituent des règles d'action pédagogiques très sécurisantes pour le praticien, dans un domaine où il faut s'adapter au jour le jour à la pousse de l'herbe et à la météorologie. En France, la critique qu’il fit de la politique de retournement systématique des prairies permanentes alors menée, puis son audacieuse approche holistique des liens entre nutrition minérale des plantes et santé du bétail et des hommes, l'ont fait mettre à l'index, alors même que ses ouvrages étaient traduits et réédités dans de nombreuses langues, et qu'il est célébré à Cuba, un pays qui applique son souhait de voir travailler ensemble agronomes, vétérinaires et médecins pour une médecine préventive par l'alimentation. Voisin est lu maintenant comme un précurseur de l'agroécologie

Background Obstructive sleep apnea (OSA) is characterized by repetitive episodes of complete or partial obstruction of the upper airways during sleep. Conscious sedation for flexible bronchoscopy (FB) places patients in a sleep-like condition. We hypothesize that oxygen desaturation during flexible bronchoscopy may help to detect undiagnosed sleep apnea. Methods Single-centre, investigator-initiated and driven study including consecutive patients undergoing FB for clinical indication. Patients completed the Epworth Sleepiness Scale (ESS), Lausanne NoSAS score, STOP-BANG questionnaire and the Berlin questionnaire and underwent polygraphy within 7 days of FB. FB was performed under conscious sedation with propofol. Oxygen desaturation during bronchoscopy was measured with continuous monitoring of peripheral oxygen saturation with ixTrend (ixellence GmbH, Germany). Results 145 patients were included in the study, 62% were male, and the average age was 65.8 ± 1.1 years. The vast majority of patients (n = 131, 90%) proved to fulfill OSA criteria based on polygraphy results: 52/131 patients (40%) had mild sleep apnea, 49/131 patients (37%) moderate sleep apnea and 30/131 patients (23%) severe sleep apnea. Patients with no oxygen desaturation had a significantly lower apnea–hypopnea index than patients with oxygen desaturation during bronchoscopy (AHI 11.94/h vs 21.02/h, p = 0.011). This association remained significant when adjusting for the duration of bronchoscopy and propofol dose (p = 0.023; 95% CI 1.382; 18.243) but did not hold when also adjusting for age and BMI. Conclusion The severity of sleep apnea was associated to oxygen desaturation during flexible bronchoscopy under conscious sedation. Patients with oxygen desaturation during bronchoscopy might be considered for sleep apnea screening. Trial registration: The Study was approved by the Ethics Committee northwest/central Switzerland, EKNZ (EK 16/13) and was carried out according to the Declaration of Helsinki and Good Clinical Practice guidelines. Due to its observational character, the study did not require registration at a clinical trial registry.

Purpose/introduction A Fracture Liaison Service (FLS) was set up at Lille University Hospital in 2016. The purpose of this study was to assess persistence with osteoporosis treatment in patients from the FLS over a period of 1 year, and to determine predictors of discontinuation. Methods The study population comprised adults of both genders, aged 50 or over, admitted to Lille University Hospital between January 2016 and January 2019 for a low-trauma fracture and managed in our FLS. Outcomes included (1) persistence rate at 1 year after treatment initiation, (2) persistence rate at 2 years after treatment initiation, (3) persistence rate at 1 and 2 years after treatment initiation according to type of treatment, (4) predictors of non-persistence, and (5) reasons for discontinuing treatment over 1 year after initiation. Persistence was determined using the Kaplan–Meier method. Results In all, 1224 patients (≥50 years old) with a recent history of low-trauma fracture (≤12 months) were identified. Of these, 380 patients – 79.2% female; mean (SD) age 76 (11) years – were seen at the FLS. In those 380 patients, 410 fractures were found and 360 of them (87.8%) were major fractures, breaking down as follows: vertebra (44%), hip (19%), proximal humerus (10%), and pelvis (8%). Osteoporosis treatment was prescribed for 367 (96.6%) patients and 275 of them began the prescribed treatment. The following anti-osteoporosis drugs were prescribed: zoledronic acid (n=150, 54.5%), teriparatide (n=63, 22.9%), and denosumab (n=39, 14.2%). Oral bisphosphonates were prescribed for a few patients (n=23, 8.4%). Persistence with osteoporosis medication (any class) was estimated at 84.1% (95% CI: 79.1% to 88.1%) at 12-month follow-up, and dropped to 70.3% (95% CI: 63.7% to 75.9%) at 24 months. When drug-specific analyses were performed using the Kaplan–Meier method, persistence rates at 12 and 24 months were found to be higher with denosumab than with any other treatment. Independent predictors of non-persistence at 12 months were ‘follow-up performed by a general practitioner (GP)’ – Odds Ratio (OR) for GP vs. FLS = 3.68; 95% CI, 1.52 to 8.90, p=0.004 – and ‘treatment with zoledronic acid’ – OR for zoledronic acid vs. denosumab = 3.39; 95% CI, 1.21 to 9.50, p=0.019; OR for zoledronic acid vs. teriparatide = 8.86; 95% CI, 1.15 to 68.10, p=0.035. Conclusions This study provides evidence of the success of our FLS in terms of long-term persistence with osteoporosis treatments. However, osteoporosis treatment initiation still needs to be improved.

International audience; Oxytocin (OT) and its receptor (OT-R) are implicated in the etiology of autism spectrum disorders (ASD), and OT-R is a potential target for therapeutic intervention. Very few nonpeptide oxytocin agonists have currently been reported. Their molecular and in vivo pharmacology remain to be clarified, and none of them has been shown to be efficient in improving social interaction in animal models relevant to ASD. In an attempt to rationalize the design of centrally active nonpeptide full agonists, we studied in a systematic way the structural determinants of the affinity and efficacy of representative ligands of the V-1a and V-2 vasopressin receptor subtypes (V-1a-R and V-2-R) and of the oxytocin receptor. Our results confirm the subtlety of the structure affinity and structure efficacy relationships around vasopressin/oxytocin receptor ligands and lead however to the first nonpeptide OT receptor agonist active in a mouse model of ASD after peripheral ip administration.

Peter Grendelmeier, Michael Tamm, Kathleen Jahn, Eric Pflimlin, Daiana Stolz Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital Basel, Petersgraben, Basel, Switzerland Background: Flexible bronchoscopy is increasingly used for diagnostic and therapeutic purposes. We aimed to examine the safety of flexible bronchoscopy with moderate sedation in patients with COPD. Methods: This study is a prospective, longitudinal, case–control, single-center study including 1,400 consecutive patients. After clinical and lung function assessments, patients were dichotomized in COPD or non-COPD groups. The primary end point was the combined incidence of complications. Results: The incidence of complications was similar in patients with and without COPD and independent of forced expiratory volume in the first second % predicted. Patients with COPD more frequently required insertion of a naso- or oropharyngeal airway; however, this difference was no longer significant after adjustment for age, gender, and duration of the procedure. Hypotension was significantly more common among patients with COPD. The number of episodes of hypoxemia ≤90% did not differ between the groups. However, patients with COPD had a lower mean and nadir transcutaneous oxygen saturation. Transcutaneous carbon dioxide tension (PtcCO2) change over the time course was similar in both groups, but both peak PtcCO2 and time on PtcCO2 >45 mmHg were higher in the COPD group. There were no differences in patient-reported outcomes. Conclusion: The safety of flexible bronchoscopy is similar in patients with and without COPD. This finding confirms the suitability of the procedure for both clinical and research indications. Keywords: bronchoalveolar lavage, propofol, complication, risk, respiratory insufficiency

Additional file 1: Table 1. Variables related to sleep apnea measured during REM sleep and non-REM sleep. Table 2. Epworth sleepiness score and Lausanne NoSAS were not associated with oxygen desaturation during conscious bronchoscopy. Table 3. The sensitivity and specificity of OSAS as calculated from AHI > 15/h and a positive symptom score using the Berlin questionnaire, Epworth sleepiness scale, Lausanne NoSAS and STOP-BANG and using desaturation as a reference standard. Figure 1. Apnea-Hypopnea Index (AHI) was significantly higher in patients who had any SaO2 < 90% for ≥ 1min compared to patients who did not develop hypoxemia.

Skeletal muscle myosin (SkM) is a muscle protein consisting of a dimer of heterotrimers, each trimer comprising a regulatory light chain (RLC), an essential light chain (ELC), and a heavy chain (HC). Recently it was discovered that SkM has potent procoagulant and prothrombotic activity (Deguchi H, et al, Blood. 2016;128:1870-1878). Mechanistic studies showed that SkM's potent prothrombotic activity involved enhancing thrombin generation due to SkM's ability to bind coagulation factors Xa and Va which accelerates prothrombin activation. However, detailed molecular mechanisms for SkM's binding of these coagulation factors have not been described. Since a well-known myosin inhibitor, trifluoperazine (TFP), inhibited SkM's procoagulant activity and since this inhibitor binds to the ELC in SkM's "neck" region which connects the HC head region to the HC tail (Figure, panel A), we hypothesized that SkM's TFP binding region on the ELC in the neck region directly contributes to SkM's procoagulant activity. To identify potential binding site(s) on SkM for factors Xa and Va, 22 peptides representing the neck region's RLC, ELC, and HC were screened for inhibition of SkM-supported prothrombin activation by purified factor Xa, factor Va, and calcium ions. These peptides contained 25-40 residues and overlapped by approximately 5-10 amino acids. Peptides ELC109-138 and ELC129-159, corresponding to amino acid residues 109-138 and 129-159 of the ELC, inhibited SkM-supported prothrombin activation at 100 μM, whereas their partially overlapping neighboring peptides, ELC99-122 and ELC149-173, did not. Three HC peptides (peptides HC781-810, HC796-835, HC815-854) and one RLC peptide (RLC133-162) inhibited SkM-supported prothrombin activation at 100 μM, and each was also inhibitory, to varying degrees, when assayed at 5 μM. Dose-dependency inhibition assays gave IC50 values (50% inhibition of activity) for the peptides HC781-810, HC796-835, HC815-854, and RLC133-162 of 64, 1.2, 2.3 and 26 μM. Peptides HC781-810 and HC815-854 also inhibited prothrombin activation in the absence of myosin but in the presence of phospholipid vesicles containing 20 % phosphatidylserine (IC50 = 7.5 and 104 μM, respectively). In contrast, the strong inhibitory effects of peptides HC796-835, RLC133-162, ELC109-138 and ELC129-159 seen in the presence of myosin were not at all apparent in the presence of phospholipid-supported prothrombin activation when myosin was absent. This suggests that peptides HC796-835, RLC133-162, ELC109-138 and ELC129-159 specifically inhibit SkM-supported prothrombin activation. The 19 synthetic peptides representing the SkM neck region were also screened at 25 µM (final) for their inhibition of recalcification-induced thrombin generation in human plasma which contains significant circulating levels of SkM. Among the 19 peptides tested, HC796-835 and HC815-854 significantly inhibited thrombin generation when screened at 25 µM in plasma. Immobilized peptide HC796-835 showed direct binding of purified factor Xa with apparent Kd of 1.4 μM. This very potent inhibitory peptide, HC796-835, exhibited 50% inhibition of SkM-enhanced prothrombin activation at 1.2 μM, indicating that this peptide's sequence provides a factor Xa binding site on SkM which contributes to its inhibitory action. More specifically, an overlapping peptide containing amino acid residues 815-835 inhibited SkM-enhanced prothrombin activation by factors Xa and Va while a peptide comprising residues 796-811 did not. These studies suggest that residues 815-835 of SkM's HC are responsible for directly binding factor Xa and implies that this binding is responsible for SkM's procoagulant activity (Figure, panel B). In summary, we identified human SkM peptides which specifically blocked SkM-enhanced thrombin generation but not phospholipid-stimulated prothrombin activation in purified reaction mixtures and which inhibited blood clotting in plasma. The most potent anticoagulant HC peptide also directly binds purified factor Xa. These findings strongly suggest that the neck region of SkM, as defined by these inhibitory peptides (Figure, panel B), provides a phospholipid-independent procoagulant surface for thrombin generation that, depending on the in vivo physiologic context, may contribute to either hemostasis or thrombosis. Figure Disclosures No relevant conflicts of interest to declare.

The original version of this article, published on 5 June 2019, an author's name was misspelled.

Le déploiement du véhicule communicant est inscrit dans celui des systèmes de transport intelligents coopératifs dont le fonctionnement est basé sur des dispositifs de communications sans fil permettant les échanges d'informations en temps réel entre véhicules ou entre véhicule et environnement routier. Le véhicule à conduite déléguée (partielle ou totale), quant à lui, pourrait fonctionner exclusivement à l'aide de capteurs pour saisir son environnement proche. Concrètement, il sera nécessairement connecté. Ces véhicules sont pourvus de programmes logiciels déterminants pour mettre en oeuvre les actions permettant d'informer, d'aider ou de remplacer le conducteur. Sources de progrès pour la mobilité et la sécurité routière, ces systèmes doivent présenter les meilleures garanties possibles d'intégrité. Des failles de sécurité peuvent toutefois permettre des intrusions illégitimes et la prise de contrôle de tout ou partie du système de conduite, posant ainsi la question des responsabilités. La délégation de conduite, même partielle, suscite elle aussi une réflexion sur ces responsabilités. Il s'agit donc ici de dresser un état des règles applicables dans le contexte juridique français en abordant d'abord l'encadrement juridique de la sécurité du véhicule avant d'exposer les principaux aspects des responsabilités.

Long-term potentiation (LTP) and neurogenesis in the dentate gyrus (DG) are correlated forms of hippocampal plasticity which share, under physiological conditions, common regulatory mechanisms. In Alzheimer's disease (AD), their alterations are potentially associated with the early cellular pathology and cognitive decline. We analyzed DG LTP and neurogenesis in B6.152H mice, an amyloid precursor protein and presenilin 2 double-transgenic mouse model of amyloidosis and observed that DG LTP was strongly enhanced before and after amyloid plaque formation. Whereas proliferation of DG neuronal progenitor cells was unchanged, survival of newborn neurons was strongly decreased already before plaque formation. As similar alteration of neurogenesis was observed in PS2APP mice without changes in DG LTP (Richards et al. 2003), this study suggests that enhanced synaptic plasticity did not rescue impaired neurogenesis, and supports decreased survival of newborn neurons as an early event associated with AD detectable even before plaque formation.