Time to treatment with bridging intravenous alteplase before endovascular treatment:subanalysis of the randomized controlled SWIFT-DIRECT trial.

BACKGROUND We hypothesized that treatment delays might be an effect modifier regarding risks and benefits of intravenous thrombolysis (IVT) before mechanical thrombectomy (MT). METHODS We used the dataset of the SWIFT-DIRECT trial, which randomized 408 patients to IVT+MT or MT alone. Potential interactions between assignment to IVT+MT and expected time from onset-to-needle (OTN) as well as expected time from door-to-needle (DTN) were included in regression models. The primary outcome was functional independence (modified Rankin Scale (mRS) 0-2) at 3 months. Secondary outcomes included mRS shift, mortality, recanalization rates, and (symptomatic) intracranial hemorrhage at 24 hours. RESULTS We included 408 patients (IVT+MT 207, MT 201, median age 72 years (IQR 64-81), 209 (51.2%) female). The expected median OTN and DTN were 142 min and 54 min in the IVT+MT group and 129 min and 51 min in the MT alone group. Overall, there was no significant interaction between OTN and bridging IVT assignment regarding either the functional (adjusted OR (aOR) 0.76, 95% CI 0.45 to 1.30) and safety outcomes or the recanalization rates. Analysis of in-hospital delays showed no significant interaction between DTN and bridging IVT assignment regarding the dichotomized functional outcome (aOR 0.48, 95% CI 0.14 to 1.62), but the shift and mortality analyses suggested a greater benefit of IVT when in-hospital delays were short. CONCLUSIONS We found no evidence that the effect of bridging IVT on functional independence is modified by overall or in-hospital treatment delays. Considering its low power, this subgroup analysis could have missed a clinically important effect, and exploratory analysis of secondary clinical outcomes indicated a potentially favorable effect of IVT with shorter in-hospital delays. Heterogeneity of the IVT effect size before MT should be further analyzed in individual patient meta-analysis of comparable trials. TRIAL REGISTRATION NUMBER URL: https://www. CLINICALTRIALS gov ; Unique identifier: NCT03192332

Etude d'un analogue pseudopeptidique à la neurotensine (le JMV 2012)

Injectée par différentes voies d'administration la NT induit de nombreux effets centraux parmi lesquels hypothermie , analgésie, modification de l'activité locomotrice, anorexie, potentialisation des effets de type neuroleptique., la NT interagie avec trois récepteurs clonés : NTR1, NTR2 et NTR3. Le JMV 2012 induit un effet analgésique dans les épreuves des crampes abdominales et lèchement des pattes aussi bien par voie centrale que par voie systémique. L'administration concomitante de JMV 2012 et de lévocabastine induit un antagonisme spécifique des NTR2. Le JMV 2012 induit une hypothermie aussi bien par voie i.c.v. que i.v.. Cette réduction de production de chaleur provoqué par ces analogues de la neurotensine pourrait être le point de départ du développement d'un traitement visant à diminuer les effets associés à l'ischémie tissulaire.ROUEN-BU Médecine-Pharmacie (765402102) / SudocSudocFranceF

Contribution à l'étude des endozépines (Recherche de l'implication des récepteurs métabotropiques dans les effets comportementaux de l'octadécaneuropeptide (ODN) liés au stress)

L'ODN (octadécaneuropeptide ou DBI33-50) est un peptide endogène de la famille des endozépines. Il induit une large variété d'activités comportementales par l'intermédiaire de trois types de récepteurs que sont les récepteurs des benzodiazépines de type central (CBR) ou périphérique (PBR) et un récepteur de type métabotropique. Des études réalisées ces dernières années ont montré une augmentation du taux des endozépines dans le liquide céphalorachidien des patients souffrant de dépression sévère, ainsi que des effets anxiogènes et anorexigènes de l'ODN. Ce dernier effet, relayé par le récepteur de type métabotropique,est fréquent au décours d'épisodes anxieux et/ou dépressifs. Le but du présent travail est de rechercher l'implication probable des récepteurs métabotropiques des endozépines dans les troubles anxio-dépressifs. L'ODN, administré par voie intracérébroventriculaire à des souris, suscite dans l'épreuve de la nage forcée, une forte diminution du comportement de résignation des animaux. La coadministration de l'ODN avec le flumazénil, un antagoniste des récepteurs centraux des benzodiazépines, aboutit à la réversion des effets anti-résignations de ce neuropeptide. En revanche, la coadministration de l'ODN avec le cyclo1-8[[D-Leu5]-octapeptide (cyclo1-8-[D-Leu5]-OP), un antagoniste des récepteurs de type métabotropique des endozépines, ne prévient pas les comportements de type anti-résignation induits par l'ODN. Il en est de même pour ses effets anxiogènes. En effet, le cyclo1-8-[D-Leu5]-OP, tout en étant dépourvu d'effets propres sur les comportements anxieux, n'affecte pas l'activité anxiogène de l'ODN, évaluée dans les épreuves du double compartiment noir/blanc et du labyrinthe en croix surélevé. Nos résultats montrent qu'en dépit de ses effets anxiogènes et anorexigènes, l'ODN exerce des propriétés de type antidépresseur, selon un mécanisme qui, comme pour les effets anxiogènes, impliquerait les CBRs et non pas les récepteurs de type métabotropique des endozépines. Ces derniers ne joueraient aucun rôle dans les modifications comportementales liées au stress induites par l'ODN. Les récepteurs de type métabotropique des endozépines semblent donc être une cible intéressante pour le développement de nouvelles thérapeutiques pour les troubles du comportement alimentaire, qui seraient dénuées d'effets indésirables à type de dépression et/ou d'anxiété.ROUEN-BU Médecine-Pharmacie (765402102) / SudocSudocFranceF

La recommandation d'une limitation à 4 semaines du traitement par un hypnotique est-elle respectée en médecine de ville?

Les somnifères ou hypnotiques, médicaments psychotropes destinés à lutter contre les troubles du sommeil occupent le 5e rang des médicaments les plus vendus en France. La règlementation actuelle stipule qu un patient ne peut bénéficier d une prescription supérieure à quatre semaines. Cette étude rapporte 866 patients traités au cours de l année 2011 ayant bénéficié d une prescription des deux hypnotiques les plus fréquemment dispensés : Zolpidem (Stilnox®) ou Zopiclone (Imovane®) et une benzodiazépine utilisée comme hypnotique : Lormetazepam (Noctamide®). Cette population de Haute-Normandie est pour partie semi-urbaine et pour l autre rurale. Nous nous efforçons de rapporter si cette règle de prescription est bien appliquée et nous concluons à un respect partiel de celle-ci. A l occasion de cet exposé, nous faisons un rappel sur la physiologie du sommeil, l insomnie, et expliquons l intérêt d une telle règlementation.ROUEN-BU Médecine-Pharmacie (765402102) / SudocSudocFranceF

Benchmarking of Homogeneous Electrocatalysts: Overpotential, Turnover Frequency, Limiting Turnover Number

In relation to contemporary energy challenges, a number of molecular catalysts for the activation of small molecules, mainly based on transition metal complexes, have been developed. The time has thus come to develop tools allowing the benchmarking of these numerous catalysts. Two main factors of merit are addressed. One involves their intrinsic catalytic performances through the comparison of “catalytic Tafel plots” relating the turnover frequency to the overpotential independently of the characteristics of the electrochemical cell. The other examines the effect of deactivation of the catalyst during the course of electrolysis. It introduces the notion of the limiting turnover number as a second key element of catalyst benchmarking. How these two factors combine with one another to control the course of electrolysis is analyzed in detail, leading to procedures that allow their separate estimation from measurements of the current, the charge passed, and the decay of the catalyst concentration. Illustrative examples from literature data are discussed

Rhenium Carbonyl Molecular Catalysts for CO 2 Electroreduction: Effects on Catalysis of Bipyridine Substituents Mimicking Anchorage Functions to Modify Electrodes

International audienceHeterogenization of molecular catalysts on (photo)electrode surfaces is required to design devices performing processes enabling to store renewable energy in chemical bonds. Among the various strategies to immobilize molecular catalysts, direct chemical bonding to conductive surfaces presents some advantages because of the robustness of the linkage. When the catalyst is, as it is often the case, a transition metal complex, the anchoring group has to be connected to the complex through the ligands, and an important question is thus raised on the influence of this function on the redox and on the catalytic properties of the complex. Herein, we analyze the effect of conjugated and non conjugated substituents, structurally close to anchoring functions previously used to immobilize a rhenium carbonyl bipyridyl molecular catalyst for supported CO2 electroreduction. We show that carboxylic ester groups, mimicking anchoring the catalyst via carboxylate binding to the surface, have a drastic effect on the catalytic activity of the complex toward CO2 electroreduction. The reasons for such an effect are revealed via a combined spectro-electrochemical analysis showing that the reducing equivalents are mainly accumulated on the electron-withdrawing ester on the bipyridine ligand preventing the formation of the rhenium(0) center and its interaction with CO2. Alternatively, alkyl-phosphonic ester substituents, not conjugated with the bpy ligand, mimicking anchoring the catalyst via phosphonate binding to the surface, allow preserving the catalytic activity of the complex

Rational design of central selective acetylcholinesterase inhibitors by means of a "bio-oxidisable prodrug" strategy.

International audienceThis work deals with the design of a bio-oxidisable prodrug strategy for the development of new central selective acetylcholinesterase inhibitors. This prodrug approach is expected to reduce peripheral anticholinesterase activity responsible for various side effects observed with presently marketed AChE inhibitors. The design of these new AChE inhibitors in quinoline series is roughly based on cyclic analogues of rivastigmine. The key activation step of the prodrug involves an oxidation of an N-alkyl-1,4-dihydroquinoline 1 to the corresponding quinolinium salt 2 unmasking the positive charge required for binding to the catalytic anionic site of the enzyme. The synthesis of a set of 1,4-dihydroquinolines 1 and their corresponding quinolinium salts 2 is presented. An in vitro biological evaluation revealed that while all reduced forms 1 were unable to exhibit any anticholinesterase activity (IC50 > 10(6) nM), most of the quinolinium salts 2 displayed high AChE inhibitory activity (IC50 ranging from 6 microM to 7 nM). These preliminary in vitro assays validate the use of these cyclic analogues of rivastigmine in quinoline series as appealing chemical tools for further in vivo development of this bio-oxidisable prodrug approach

Proton-Coupled Electron Transfer Cleavage of Heavy-Atom Bonds in Electrocatalytic Processes. Cleavage of a C–O Bond in the Catalyzed Electrochemical Reduction of CO₂

Most of the electrocatalytic processes of interest in the resolution of modern energy challenges are associated with proton transfer. In the cases where heavy atom bond cleavage occurs concomitantly, the question arises of the exact nature of its coupling with proton–electron transfer within the catalytic cycle. The cleavage of a C–O bond in the catalyzed electrochemical conversion of CO₂ to CO offers the opportunity to address this question. Electrochemically generated iron(0) porphyrins are efficient, specific, and durable catalysts provided they are coupled with Lewis or Brönsted acids. The cocatalyst properties of four Brönsted acids of increasing strength, water, trifluoroethanol, phenol, and acetic acid, have been systematically investigated. Preparative-scale electrolyses showed that carbon monoxide is the only product of the catalytic reaction. Methodic application of a nondestructive technique, cyclic voltammetry, with catalyst and CO₂ concentrations, as well as H/D isotope effect, as diagnostic parameters allowed the dissection of the reaction mechanism. It appears that the key step of the reaction sequence consists of an electron transfer from the catalyst concerted with the cleavage of a C–O bond and the transfer of one proton. This is the second example, and an intermolecular version of such a concerted proton–electron bond-breaking reaction after a similar electrochemical process involving the cleavage of O–O bonds has been identified. It is the first time that a proton–electron transfer concerted with bond breaking has been uncovered as the crucial step in a catalytic multistep reaction

Behavior of Iron Tetraphenylsulfonato Porphyrin Intercalated into LDH and LSH as Materials for Electrocatalytic Applications

International audienceOrganic–inorganic hybrid materials were prepared by intercalation of iron 5,10,15,20 tetrakis(4-sulfonatophenyl)porphyrin complex into layered double hydroxides (ZnCr-FeTSPP LDH) and layered simple hydroxides (Zn-FeTSPP LSH) by coprecipitation. They have been characterized by ancillary techniques to compare their structural characteristics, their morphology and their ability to form films on conductive substrates in view of preparing modified electrodes for CO2 electroreduction reaction (CO2ERR). The electrochemical behavior of intercalated FeTSPP was studied by cyclic voltammetry (CV) showing the role of the nature and pH of aqueous electrolyte solutions on the FeIII/II signal. Evaluation of the CO2ERR of ZnCr-FeTSPP modified electrode was investigated by CV and preparative scale CO2 electrolysis in 0.1 M Na2SO4 aqueous solution. Whereas FeTSPP in the same electrolyte solution exhibits 18% of CO2 conversion to CO, once intercalated into ZnCr-LDH, there is no CO formation, only H2 (FY = 75%). Using the ZnCr-NO3 modified electrode, without porphyrin, the same FY of H2 was obtained. The study illustrates the problematic and the complexity of an attractive approach for the development of innovative hybrid catalysts for heterogeneous CO2ERR

Insights into OCP Identification and Quantification in the Context of Apatite Biomineralization

International audienceCalcium phosphates (CaPs) are one of the major mineral families of wide interest in biomineralization and biomaterial development. The identification and quantification of the different CaP phases (crystalline and amorphous) remains a major challenge in both in vitro and in vivo systems. This work aims to provide critical analysis of the different analytical techniques, Raman spectroscopy, solid-state NMR spectroscopy (ssNMR) and X-ray diffraction (XRD), which are used for the discrimination of octacalcium phosphate (OCP) from hydroxyapatite (HAp). Low amounts of OCP (∼10 wt%) can be detected by Raman spectroscopy in the presence of biomimetic carbonated apatite (cHAp), provided that the ν(HPO4) contribution with weak intensity from OCP at 1008 cm−1 is observable or that the spectral decomposition of the overlapped ν1(PO4) bands from OCP and cHAp is performed. However, Raman is not suitable for quantification purposes. In contrast, the quantification of OCP in proportions down to 10 wt% is easily performed with 31P solid state NMR. Opposite to solid state NMR, Raman can be implemented under in situ conditions to monitor the time dependence of the biomineralization process without any sampling perturbation. An approach combining the advantages of in situ micro-Raman spectroscopy and the sensitivity of ex situ solid state NMR was used to monitor the formation of biomimetic carbonated apatite from an acidic aqueous solution of phosphate, carbonate and calcium ions. In relation with the progressive increase of pH, we identify the transient phases, the precursors of cHAp: it is shown that an amorphous calcium phosphate phase (ACP) is first formed and subsequently transforms into OCP that then progressively turns into cHAp. Finally, powder X-ray diffraction coupled to Rietveld refinement was found to be very powerful in quantifying very small amounts of residual OCP in cHAp (down to 2 wt%). Upon the OCP transformation into cHAp, the decrease of the relative intensity of the (100) diffraction peak of the transient OCP phase was ascribed to an alteration of its hydrated layers, related to incorporation of water molecules and/or carbonate anions with reaction time. Such carbonate uptake in the course of transformation of OCP into cHAp could explain the origin of carbonate substitutions in the final biomimetic carbonated apatite