Comparaison des résultats opératoires des remplacements valvulaires aortiques avec la nouvelle valve biologique intuity et la valve perimount

Introduction La sténose aortique est une affection courante, actuellement classée comme la troisième pathologie cardiaque par ordre de fréquence. Actuellement, la seule technique curative est le traitement chirurgical à l'aide de valves biologiques ou mécaniques. Parmi les valves biologiques, nous retrouvons la valve Perimount et la valve Intuity, toutes deux faites à partir de péricarde bovin et qui feront le sujet de cette étude. Le but de l'étude est de comparer deux groupes de patients homogènes ayant eu un remplacement de la valve aortique avec l'une des deux bioprothèses. Méthodologie Sur le site de l'Hôpital de Sion, entre Janvier 2013 et Mars 2015, 32 patients ont bénéficié d'un remplacement valvulaire aortique au moyen de la valve Intuity. Nous avons ensuite sélectionné 32 patients comparables aux précédents pour le type d'intervention et opérés durant cette même période avec la valve Perimount. Nous avons ensuite mené une étude rétrospective, visant à comparer les données intra-opératoires, les complications post- opératoires et les données hémodynamiques des deux types de valve. Résultats Dans l'ensemble, les patients recevant la valve Intuity étaient plus âgés (78 vs 73 ans) et plus souvent de sexe féminin (47% vs 22%) mais les deux groupes avaient le même profil quant aux facteurs de risque cardiovasculaires, à la présence d'une insuffisance rénale, d'une insuffisance respiratoire chronique ou d'une artériopathie périphérique. Les porteurs de valve Intuity souffraient cependant plus de maladie coronarienne (59% vs 25%). Le temps de clampage (40 vs 58min), de machine coeur-poumon (58 vs 76min) et le temps opératoire (145 vs 180min) étaient tous significativement réduits avec la valve Intuity. De plus, le temps d'implantation de cette valve est extrêmement court, de 9 minutes en moyenne, contre environ 25 minutes pour la valve Perimount. Pour ce qui est des complications post- opératoires, il n'y a aucune différence hormis l'apparition d'une insuffisance rénale aigue plus élevée dans le groupe Perimount (22% vs 9%). Quant aux données hémodynamiques, les deux groups étaient similaires en pré-opératoire mais en post-opératoire, la valve Intuity assure un gradient trans-valvulaire plus faible (9 vs 12 mmHg), avec un risque de fuite paravalvulaire identique entre les deux groupes. Conclusions Au terme de cette étude portant sur un petit collectif de patients, nous pouvons, à notre échelle, confirmer la validité du traitement de la sténose aortique au moyen de la valve à implantation rapide Intuity. Le fonctionnement de cette dernière est tout aussi bon que le gold standard actuel, avec des résultats opératoires encourageants et un risque de complications similaire

Innovative Approaches to the Imidazo[4,5-b]pyridine Ring System. Development of an Efficient Process for Industrial-Scale Production of a Key Intermediate for Potent Angiotensin II Receptor Antagonists

Two syntheses of 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine, an important intermediate for the synthesis of several potent angiotensin II antagonists, have been investigated. The first route involves conversion of 1,1-bis(methylthio)-2-nitroethene (17) to 2-amino-4,6-dimethyl-3-nitropyridine (6); catalytic hydrogenation of 2-amino-4,6-dimethyl-3-nitropyridine in propionic acid gave 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine 3 in high yield. In the second synthesis, propionitrile is converted to imidate hydrochloride 15, which is neutralised and reacted with aminoacetonitrile in the presence of acetylacetone to give 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine 3 in 55% overall yield. The propionitrile route was scaled up to produce 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine 3 in the pilot plant

Molecular Biomarkers of Neovascular Age-Related Macular Degeneration With Incomplete Response to Anti-Vascular Endothelial Growth Factor Treatment.

The standard treatment for neovascular age-related macular degeneration (nAMD) consists of intravitreal anti-vascular endothelial growth factors (VEGF). However, for some patients, even maximal anti-VEGF treatment does not entirely suppress exudative activity. The goal of this study was to identify molecular biomarkers in nAMD with incomplete response to anti-VEGF treatment. Aqueous humor (AH) samples were collected from three groups of patients: 17 patients with nAMD responding incompletely to anti-VEGF (18 eyes), 17 patients affected by nAMD with normal treatment response (21 eyes), and 16 control patients without any retinopathy (16 eyes). Proteomic and multiplex analyses were performed on these samples. Proteomic analyses showed that nAMD patients with incomplete anti-VEGF response displayed an increased inflammatory response, complement activation, cytolysis, protein-lipid complex, and vasculature development pathways. Multiplex analyses revealed a significant increase of soluble vascular cell adhesion molecule-1 (sVCAM-1) [ p = 0.001], interleukin-6 (IL-6) [ p = 0.009], bioactive interleukin-12 (IL-12p40) [ p = 0.03], plasminogen activator inhibitor type 1 (PAI-1) [ p = 0.004], and hepatocyte growth factor (HGF) [ p = 0.004] levels in incomplete responders in comparison to normal responders. Interestingly, the same biomarkers showed a high intercorrelation with r2 values between 0.58 and 0.94. In addition, we confirmed by AlphaLISA the increase of sVCAM-1 [ p < 0.0001] and IL-6 [ p = 0.043] in the incomplete responder group. Incomplete responders in nAMD are associated with activated angiogenic and inflammatory pathways. The residual exudative activity of nAMD despite maximal anti-VEGF treatment may be related to both angiogenic and inflammatory responses requiring specific adjuvant therapy. Data are available via ProteomeXchange with identifier PXD02247

Thermochemical stability: A comparison between experimental and predicted data

The first step to be performed during the development of a new industrial process should be the assessment of all hazards associated to the involved compounds. Particularly, the knowledge of all substances thermochemical parameters is a primary feature for such a hazard evaluation. CHETAH (CHEmical Thermodynamic And Hazard evaluation) is a prediction software suitable for calculating potential hazards of chemicals, mixtures or a single reaction that, using only the structure of the involved molecules and Benson's group contribution method, is able to calculate heats of formation, entropies, Gibbs free energies and reaction enthalpies. Because of its ability to predict the potential hazards of a material or mixture, CHETAH is part of the so-called \u201cdesktop methods\u201d for early stage chemical safety analysis. In this work, CHETAH software has been used to compile a complete risk database reporting heats of decomposition and Energy Release Potential (ERP) for 342 common use chemicals. These compounds have been gathered into classes depending on their functional groups and similarities in their thermal behavior. Calculated decomposition enthalpies for each of the compounds have also been compared with experimental data obtained with either thermoanalytic or calorimetric techniques (Differential Scanning Calorimeter \u2013 DSC \u2013 and Accelerating Rate Calorimeter \u2013 ARC)

Loss of Extracellular Signal-Regulated Kinase 1/2 in the Retinal Pigment Epithelium Leads to RPE65 Decrease and Retinal Degeneration.

Recent work suggested that the activity of extracellular signal-regulated kinase 1/2 (ERK1/2) is increased in the retinal pigment epithelium (RPE) of age-related macular degeneration (ARMD) patients and therefore could be an attractive therapeutic target. Notably, ERK1/2 pathway inhibitors are used in cancer therapy, with severe and noncharacterized ocular side effects. To decipher the role of ERK1/2 in RPE cells, we conditionally disrupted the Erk1 and Erk2 genes in mouse RPE. The loss of ERK1/2 activity resulted in a significant decrease in the level of RPE65 expression, a decrease in ocular retinoid levels concomitant with low visual function, and a rapid disorganization of RPE cells, ultimately leading to retinal degeneration. Our results identify the ERK1/2 pathway as a direct regulator of the visual cycle and a critical component of the viability of RPE and photoreceptor cells. Moreover, our results caution about the need for a very fine adjustment of kinase inhibition in cancer or ARMD treatment in order to avoid ocular side effects

Nanoscale stiffness topography reveals structure and mechanics of the transport barrier in intact nuclear pore complexes

The nuclear pore complex (NPC) is the gate for transport between the cell nucleus and the cytoplasm. Small molecules cross the NPC by passive diffusion, but molecules larger than ∼5 nm must bind to nuclear transport receptors to overcome a selective barrier within the NPC1. Although the structure and shape of the cytoplasmic ring of the NPC are relatively well characterized2, 3, 4, 5, the selective barrier is situated deep within the central channel of the NPC and depends critically on unstructured nuclear pore proteins5, 6, and is therefore not well understood. Here, we show that stiffness topography7 with sharp atomic force microscopy tips can generate nanoscale cross-sections of the NPC. The cross-sections reveal two distinct structures, a cytoplasmic ring and a central plug structure, which are consistent with the three-dimensional NPC structure derived from electron microscopy2, 3, 4, 5. The central plug persists after reactivation of the transport cycle and resultant cargo release, indicating that the plug is an intrinsic part of the NPC barrier. Added nuclear transport receptors accumulate on the intact transport barrier and lead to a homogenization of the barrier stiffness. The observed nanomechanical properties in the NPC indicate the presence of a cohesive barrier to transport and are quantitatively consistent with the presence of a central condensate of nuclear pore proteins in the NPC channel

Acute Hypoglycemia Induces Retinal Cell Death in Mouse

BACKGROUND: Glucose is the most important metabolic substrate of the retina and maintenance of normoglycemia is an essential challenge for diabetic patients. Glycemic excursions could lead to cardiovascular disease, nephropathy, neuropathy and retinopathy. A vast body of literature exists on hyperglycemia namely in the field of diabetic retinopathy, but very little is known about the deleterious effect of hypoglycemia. Therefore, we decided to study the role of acute hypoglycemia in mouse retina. METHODOLOGY/PRINCIPAL FINDINGS: To test effects of hypoglycemia, we performed a 5-hour hyperinsulinemic/hypoglycemic clamp; to exclude an effect of insulin, we made a hyperinsulinemic/euglycemic clamp as control. We then isolated retinas from each group at different time-points after the clamp to analyze cells apoptosis and genes regulation. In parallel, we used 661W photoreceptor cells to confirm in vivo results. We showed herein that hypoglycemia induced retinal cell death in mouse via caspase 3 activation. We then tested the mRNA expression of glutathione transferase omega 1 (Gsto1) and glutathione peroxidase 3 (Gpx3), two genes involved in glutathione (GSH) homeostasis. The expression of both genes was up-regulated by low glucose, leading to a decrease of reduced glutathione (GSH). In vitro experiments confirmed the low-glucose induction of 661W cell death via superoxide production and activation of caspase 3, which was concomitant with a decrease of GSH content. Moreover, decrease of GSH content by inhibition with buthionine sulphoximine (BSO) at high glucose induced apoptosis, while complementation with extracellular glutathione ethyl ester (GSHee) at low glucose restored GSH level and reduced apoptosis. CONCLUSIONS/SIGNIFICANCE: We showed, for the first time, that acute insulin-induced hypoglycemia leads to caspase 3-dependant retinal cell death with a predominant role of GSH content