A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury.

The p75 neurotrophin receptor is important in multiple physiological actions including neuronal survival and neurite outgrowth during development, and after central nervous system injury. We have discovered a novel piperazine-derived compound, EVT901, which interferes with p75 neurotrophin receptor oligomerization through direct interaction with the first cysteine-rich domain of the extracellular region. Using ligand binding assays with cysteine-rich domains-fused p75 neurotrophin receptor, we confirmed that EVT901 interferes with oligomerization of full-length p75 neurotrophin receptor in a dose-dependent manner. Here we report that EVT901 reduces binding of pro-nerve growth factor to p75 neurotrophin receptor, blocks pro-nerve growth factor induced apoptosis in cells expressing p75 neurotrophin receptor, and enhances neurite outgrowth in vitro Furthermore, we demonstrate that EVT901 abrogates p75 neurotrophin receptor signalling by other ligands, such as prion peptide and amyloid-β. To test the efficacy of EVT901 in vivo, we evaluated the outcome in two models of traumatic brain injury. We generated controlled cortical impacts in adult rats. Using unbiased stereological analysis, we found that EVT901 delivered intravenously daily for 1 week after injury, reduced lesion size, protected cortical neurons and oligodendrocytes, and had a positive effect on neurological function. After lateral fluid percussion injury in adult rats, oral treatment with EVT901 reduced neuronal death in the hippocampus and thalamus, reduced long-term cognitive deficits, and reduced the occurrence of post-traumatic seizure activity. Together, these studies provide a new reagent for altering p75 neurotrophin receptor actions after injury and suggest that EVT901 may be useful in treatment of central nervous system trauma and other neurological disorders where p75 neurotrophin receptor signalling is affected

Evaluation of the CloudSat surface snowfall product over Antarctica using ground-based precipitation radars

In situ observations of snowfall over the Antarctic Ice Sheet are scarce. Currently, continent-wide assessments of snowfall are limited to information from the Cloud Profiling Radar on board the CloudSat satellite, which has not been evaluated up to now. In this study, snowfall derived from CloudSat is evaluated using three ground-based vertically profiling 24&thinsp;GHz precipitation radars (Micro Rain Radars: MRRs). Firstly, using the MRR long-term measurement records, an assessment of the uncertainty caused by the low temporal sampling rate of CloudSat (one revisit per 2.1 to 4.5 days) is performed. The 10–90th-percentile temporal sampling uncertainty in the snowfall climatology varies between 30&thinsp;% and 40&thinsp;% depending on the latitudinal location and revisit time of CloudSat. Secondly, an evaluation of the snowfall climatology indicates that the CloudSat product, derived at a resolution of 1∘ latitude by 2∘ longitude, is able to accurately represent the snowfall climatology at the three MRR sites (biases&thinsp;&lt;&thinsp;15&thinsp;%), outperforming ERA-Interim. For coarser and finer resolutions, the performance drops as a result of higher omission errors by CloudSat. Moreover, the CloudSat product does not perform well in simulating individual snowfall events. Since the difference between the MRRs and the CloudSat climatology are limited and the temporal uncertainty is lower than current Climate Model Intercomparison Project Phase 5 (CMIP5) snowfall variability, our results imply that the CloudSat product is valuable for climate model evaluation purposes.</p

Performance of Pyridylthiourea-Polyethylenimine Polyplex for siRNA-Mediated Liver Cancer Therapy in Cell Monolayer, Spheroid, and Tumor Xenograft Models

Medical application of siRNAs relies on methods for delivering nucleic acids into the cytosol. Synthetic carriers, which assemble with nucleic acids into delivery systems, show promises for cancer therapy but efficiency remains to be improved. In here, the effectiveness of pyridylthiourea‐polyethylenimine (πPEI), a siRNA carrier that favors both polyplex disassembly and endosome rupture upon sensing the acidic endosomal environment, in 3 experimental models of hepatocellular cancer is tested. The πPEI‐assisted delivery of a siRNA targeting the polo‐like kinase 1 into Huh‐7 monolayer produces a 90% cell death via a demonstrated RNA interference mechanism. Incubation of polyplex with Huh‐7 spheroids leads to siRNA delivery into the superficial first cell layer and a 60% reduction in spheroid growth compared to untreated controls. Administration of polyplexes into mice bearing subcutaneous implanted Huh‐7Luc tumors results in a reduced tumor progression, similar to the one observed in the spheroid model. Altogether, these results support the in vivo use of synthetic and dedicated polymers for increasing siRNA‐mediated gene knockdown, and their clinical promise in cancer therapeutics

Avulsion d’une dent surnuméraire incluse par découpe puis repositionnement de l’épine nasale antérieure

Les avulsions de dents incluses sont d’une pratique courante. Le plus fréquemment, le dégagement osseux n’a pas de conséquences. Dans certains cas, il peut poser problème, s’il concerne un futur site d’implantation ou des structures anatomiques spécifiques, notamment dans le prémaxillaire (Sukegawa et al. Case Rep Dent. 2015; 2015: 974169). Pour ces situations, la piézochirugie apparait comme une technique peu invasive puisque la découpe est plus fine et plus précise qu’avec les instruments rotatifs (Pavlıékovaé et al. Int J Oral Maxillofac Surg. 2011 40:451-7). De plus, le fait de découper un volet puis de le repositionner en fin d’intervention constitue un moyen de préserver le volume osseux. Le cas rapporté est celui d’une avulsion d’un mesiodens par découpe puis repositionnement de l’épine nasale antérieure. Une jeune fille de 13 ans a été adressée par son orthodontiste pour avulsion d’un mesiodens avant prise en charge ODF. Un examen cone beam a précisé la position de cet odontoïde. D’une morphologie évoquant une incisive conoïde, la dent surnuméraire se présentait en position verticale ; sa couronne faisait saillie dans les fosses nasales, sous le vomer, et sa racine était en arrière de celles des incisives centrales. Lors d’une intervention menée sous anesthésie générale, l’ENA a été découpée par piézochirugie (incision en V de part et d’autre du plan médian) et luxée vers le haut, sans décollement de la muqueuse nasale. L’odontoïde a été sectionné au collet. Sa couronne d’abord puis sa racine ont été avulsées. Enfin, l’ENA a été repositionnée et fixée par une vis d’ostosynthèse positionnée légèrement en biais. Les suites ont été bonnes. La vis d’ostéosynthèse a été déposée un an plus tard. L’avulsion de cette dent, profondément incluse, par les techniques conventionnelles utilisant des instruments rotatifs aurait entraîné un délabrement important. Compte tenu de la situation inversée de l’axe de la dent, il aurait été difficile de la retirer par un abord palatin. De plus, son axe vertical compliquait la séparation couronne-racine, qui n’aurait été possible que par un accès nasal. Le choix d’une technique conservatrice de l’os (découpe puis repositionnement) semblait judicieux dans la mesure où il autorisait une bonne exposition du site et le morcellement cervical de la dent, tout en épargnant le volume osseux. Le fait de ne pas avoir décollé la muqueuse palatine a probablement contribué à la trophicité et la cicatrisation de l’ENA repositionnée. Les opérateurs ont pris le soin de ne pas placer la vis d’ostéosynthèse dans la suture entre les deux parties droite et gauche de l’ENA, afin de ne pas risquer de séparer ces deux os. Ce cas illustre une technique minimalement invasive qui a permis l’avulsion d’une dent surnuméraire profondément incluse en position verticale inversée, sans entraîner de lésion des dents voisines ni de la muqueuse nasale, tout en préservant le volume osseux de l’ENA

Severe systemic cytomegalovirus infections in patients with steroid-refractory ulcerative colitis treated by an oral microemulsion form of cyclosporine: report of two cases.

International audienceCMV reactivation is frequently observed in acute flares of ulcerative colitis (UC), particularly those which do not respond to intravenous steroids. Several recent series have suggested that, in most cases, CMV reactivation does not lead to severe complications and resolves spontaneously with the UC flare and discontinuation of immunosuppression. In the present paper, we describe two patients with active UC who developed a severe systemic CMV infection during a treatment with an oral microemulsion form of cyclosporine. This is of concern, particularly in a context of increasing use of immunosuppressive drugs in UC. We propose a prophylactic and curative approach to decrease morbidity related to CMV infection in active UC