Dual-Acting Small Molecules: Subtype-Selective Cannabinoid Receptor 2 Agonist/Butyrylcholinesterase Inhibitor Hybrids Show Neuroprotection in an Alzheimer's Disease Mouse Model.

We present the synthesis and characterization of merged human butyrylcholinesterase (hBChE) inhibitor/cannabinoid receptor 2 (hCB2R) ligands for the treatment of neurodegeneration. In total, 15 benzimidazole carbamates were synthesized and tested for their inhibition of human cholinesterases, also with regard to their pseudoirreversible binding mode and affinity toward both cannabinoid receptors in radioligand binding studies. After evaluation in a calcium mobilization assay as well as a β-arrestin 2 (βarr2) recruitment assay, two compounds with balanced activities on both targets were tested for their immunomodulatory effect on microglia activation and regarding their pharmacokinetic properties and blood-brain barrier penetration. Compound 15d, containing a dimethyl carbamate motif, was further evaluated in vivo, showing prevention of Aβ25-35-induced learning impairments in a pharmacological mouse model of Alzheimer's disease for both short- and long-term memory responses. Additional combination studies proved a synergic effect of BChE inhibition and CB2R activation in vivo

Mesure du débit cardiaque en chirurgie cardio-vasculaire (comparaison entre une méthode non invasive (NICO) et le cathétérisme artériel pulmonaire à débit continu)

BREST-BU Médecine-Odontologie (290192102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Incidence et facteurs de risque de survenue d'une fibrillation auriculaire chez les patients traumatisés dans un service de réanimation chirurgicale

RENNES1-BU Santé (352382103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

GASS Trial study protocol a multicentre, single-blind, randomised clinical trial comparing general anaesthesia and sedation during intra-arterial treatment for stroke

International audienceIntroduction - Treatment of acute stroke has drastically changed in the last 10 years. Endovascular therapy is now the standard of care for patients with a stroke caused by a large vessel occlusion in the anterior circulation. The impact of the type of anaesthesia (general anaesthesia or conscious sedation) during endovascular therapy on the outcome of the patients is still a matter of debate. Previous studies are mostly retrospective and/or focused on the early postprocedure outcome and/or without blood pressure goals and/or single-centre small size studies. We therefore designed a multicentre study hypothesising that conscious sedation is associated with a better functional outcome 3 months after endovascular therapy for the treatment of stroke compared with general anaesthesia.Methods/analysis - The General Anesthesia vs Sedation for Stroke (GASS) Trial is a randomised, parallel, single-blind, multicentre study of 350 patients undergoing endovascular therapy for the treatment of stroke. Patients will be randomly allocated to receive either a general anaesthesia or a conscious sedation. The primary outcome measure is the modified Rankin score assessed 3 months after the treatment. Data will be analysed on the intention-to-treat principle.Ethics/dissemination - The GASS Trial has been approved by an independent ethics committee for all study centres. Participant recruitment begins in September 2016. Results will be published in international peer-reviewed medical journals. Trial registration number - NCT02822144

Convolamine, a tropane alkaloid extracted from Convolvulus plauricalis , is a potent sigma‐1 receptor‐positive modulator with cognitive and neuroprotective properties

International audienceAbstract Background and Aim By using an in vivo phenotypic screening assay in zebrafish, we identified Convolamine, a tropane alkaloid from Convulvus plauricalis , as a positive modulator of the sigma‐1 receptor (S1R). The wfs1ab KO zebrafish larva, a model of Wolfram syndrome, exhibits an increased visual‐motor response due to a mutation in Wolframin, a protein involved in endoplasmic reticulum‐mitochondria communication. We previously reported that ligand activating S1R, restored the cellular and behavioral deficits in patient fibroblasts and zebrafish and mouse models. Experimental Procedures We screened a library of 108 repurposing and natural compounds on zebrafish motor response. Key Results One hit, the tropane alkaloid Convolamine, restored normal mobility in wfs1ab KO larvae without affecting wfs1ab WT controls. They did not bind to the S1R agonist/antagonist binding site nor dissociated S1R from BiP, an S1R activity assay in vitro, but behaved as a positive modulator by shifting the IC 50 value of the reference agonist PRE‐084 to lower values. Convolamine restored learning in Wfs1 ∆Exon8 , Dizocilpine‐treated, and Aβ 25‐35 ‐treated mice. These effects were observed at low ~1 mg/kg doses, not shared by Convolvine, the desmethyl metabolite, and blocked by an S1R antagonist. Conclusion and Implications Convolamine therefore acts as an S1R positive modulator and this pharmacological action is relevant to the traditional use of Shankhpushpi in memory and cognitive protection

Muscle diffusion of liposomal amphotericin B and posaconazole in critically ill burn patients receiving continuous hemodialysis

International audienceno abstrac

General Anesthesia versus Sedation, Both with Hemodynamic Control, during Intraarterial Treatment for Stroke: The GASS Randomized Trial

International audienceBackground: It is speculated that the anesthetic strategy during endovascular therapy for stroke may have an impact on the outcome of the patients. The authors hypothesized that conscious sedation is associated with a better functional outcome 3 months after endovascular therapy for the treatment of stroke compared with general anesthesia. Methods: In this single-blind, randomized trial, patients received either a standardized general anesthesia or a standardized conscious sedation. Blood pressure control was also standardized in both groups. The primary outcome measure was a modified Rankin score less than or equal to 2 (0 = no symptoms; 5 = severe disability) assessed 3 months after treatment. The main secondary outcomes were complications, mortality, reperfusion results, and National Institutes of Health Stroke Scores at days 1 and 7. Results: Of 351 randomized patients, 345 were included in the analysis. The primary outcome occurred in 129 of 341 (38%) of the patients: 63 (36%) in the conscious sedation group and 66 (40%) in the general anesthesia group (relative risk, 0.91 [95% CI, 0.69 to 1.19]; P = 0.474). Patients in the general anesthesia group experienced more intraoperative hypo- or hypertensive episodes, while the cumulative duration was not different (mean +/- SD, 36 +/- 31 vs. 39 +/- 25 min; P = 0.079). The time from onset and from arrival to puncture were longer in the general anesthesia group (mean difference, 19 min [i.e., -00:19] [95% CI, -0:38 to 0] and mean difference, 9 min [95% CI, -0:18 to -0:01], respectively), while the time from onset to recanalization was similar in both groups. Recanalization was more often successful in the general anesthesia group (144 of 169 [85%] vs. 131 of 174 [75%]; P = 0.021). The incidence of symptomatic intracranial hemorrhage was similar in both groups. Conclusions: The functional outcomes 3 months after endovascular treatment for stroke were similar with general anesthesia and sedation. Our results, therefore, suggest that clinicians can use either approach

Low cardiac index and stroke volume on admission are associated with poor outcome in critically ill burn patients: a retrospective cohort study.

BackgroundImpact of early systemic hemodynamic alterations and fluid resuscitation on outcome in the modern burn care remains controversial. We investigate the association between acute-phase systemic hemodynamics, timing of fluid resuscitation and outcome in critically ill burn patients.MethodsRetrospective, single-center cohort study was conducted in a university hospital. Forty critically ill burn patients with total body surface area (TBSA) burn-injured >20 % with invasive blood pressure and cardiac output monitoring (transpulmonary thermodilution technique) within 8 h from trauma were included. We retrospectively examined hemodynamic variables during the first 24 h following admission, and their association with 90-day mortality.ResultsThe median (interquartile range 25th-75th percentile) TBSA, Simplified Acute Physiology Score II (SAPS II) and Abbreviated Burn Severity Index of the study population were 41 (29-56), 31 (23-50) and 9 (7-11) %, respectively. 90-Day mortality was 42 %. There was no statistical difference between the median pre-hospital and 24-h administered fluid volume in survivors and non-survivors. On admission, stroke volume (SV), cardiac index (CI), oxygen delivery index and mean arterial pressure (MAP) were significantly lower in patients who died despite similar fluid resuscitation volume. ROC curves comparing the ability of initial SV, CI, MAP and lactate to discriminate 90-day mortality gave areas under curves of, respectively, 0.89 (CI 0.77-1), 0.77 (CI 0.58-0.95), 0.73 (CI 0.53-0.93) and 0.78 (CI 0.63-0.92); (p value <0.05 for all). In multivariate analysis, SAPS II and initial SV were independently associated with 90-day mortality (best cutoff value for SV was 27 mL, sensitivity 92 %, specificity 69 %). During 24 h, no interaction was found between time and outcome regarding macrocirculatory parameters changes. Hemodynamic parameters improved during the first 24-h resuscitation in all patients but patients who died had lower SV and CI on admission, which remained through the first 24 h.ConclusionLow initial SV and CI were associated with poor outcome in critically ill burn patients. Very early hemodynamic monitoring may in help detecting under-resuscitated patients. Future prospective interventional studies should explore the impact of early goal-directed therapy in these specific patients

MOESM3 of Low cardiac index and stroke volume on admission are associated with poor outcome in critically ill burn patients: a retrospective cohort study

Additional file 3: Table S1. Characteristics of the main clinical studies assessing the association between hemodynamics on admission and outcome in critically ill burn patients

Impact of an Acinetobacter baumannii outbreak on kidney events in a burn unit: A targeted machine learning analysis

International audienceBackground: Multidrug-resistant (MDR) bacteria outbreaks represent a major threat in intensive care units. Patients may then be exposed to drug-related direct toxicity during such outbreaks. The objective of this study was to explore the impact of an outbreak of imipenem-resistant Acinetobacter baumannii (IR-AB) on renal outcomes.Methods: We performed a before-and-after observational study in a French burn intensive care unit during an IR-AB outbreak: a 13-month period before (period A, October 2013-October 2014) and a 13-month period after outbreak control (period B, December 2014-December 2015). A total of 409 patients were included, 195 during period A and 214 during period B. The main endpoint was major adverse kidney events at day 90 (MAKE 90). Secondary endpoints were acute kidney injury (AKI) and persistent renal dysfunction.Results: Incidence of MAKE 90 was 15.9% during period A versus 11.2% during period B (P = .166) and AKI 28.2% versus 18.7% (P = .023). The use of colistin was associated with renal outcomes in univariate analysis. After adjustment of potential confounding factors using a targeted Machine Learning Analysis (ie, IR-AB-related infection, septic shock, severity scores, other nephrotoxics, chronic kidney disease, serum creatinine at admission, Staphylococcus aureus), colistin remained associated with the risk of MAKE and AKI (relative risk = 2.909, 95% confidence interval [CI] [1.364, 6.204], P = .006 for MAKE 90, and relative risk = 2.14, 95% CI [1.52, 3.02], P<.0001 for AKI).Conclusions: The episode of IR-AB outbreak was associated with an increased risk of kidney events, which appears to be driven by the use of colistin