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Kline J.A.,Indiana University | Jimenez D.,Ramon y Cajal Hospital IRYCIS | Courtney D.M.,University of Alcala | Ianus J.,Northwestern University | And 5 more authors.
Academic Emergency Medicine | Year: 2016

Objectives Outpatient treatment of acute venous thromboembolism (VTE) requires the selection of patients with a low risk of bleeding during the first few weeks of anticoagulation. The accuracy of four systems, originally derived for predicting bleeding in VTE treated with Vitamin K antagonists (VKAs), was assessed in VTE patients treated with rivaroxaban. Methods All patients treated with rivaroxaban in the multinational Einstein deep vein thrombosis (DVT) and pulmonary embolism (PE) trials were included. Major bleeding was defined as ≥2 g/dL drop in hemoglobin or ≥2-unit blood transfusion, bleeding in critical area, or bleeding contributing to death. The authors examined the incidence of major bleeding in patients with low-risk assignment by the systems of Ruiz-Gimenez et al. (score = 0 to 1), Beyth et al. (score = 0), Kuijer et al. (score = 0), and Landefeld and Goldman. (score = 0). For clinical relevance, the definition of low risk for all scores except Kuijer includes all patients < 65 years with no prior bleeding history and no comorbid conditions (current cancer, renal insufficiency, diabetes mellitus, anemia, prior stroke, or myocardial infarction). Results A total of 4,130 patients (1,731 with DVT only, 2,399 with PE with or without DVT) were treated with rivaroxaban for a mean (±SD) duration of 207.6 (±95.9) days. Major bleeding occurred in 1.0% (40 of 4,130; 95% confidence interval [CI] = 0.7% to 1.3%) overall. Rates of major bleeding for low-risk patients during the entire treatment period were similar: Ruiz-Gimenez et al., 12 of 2,622 (0.5%; 95% CI = 0.2% to 0.8%); Beyth et al., nine of 2,249 (0.4%; 95% CI = 0.2% to 0.8%); Kuijer et al., four of 1,186 (0.3%; 95% CI = 0.1% to 0.9%); and Landefeld and Goldman, 11 of 2,407 (0.5%; 95% CI = 0.2% to 0.8%). At 30 days, major bleed rates for low-risk patients were as follows: Ruiz-Gimenez et al., five of 2,622 (0.2%; 95% CI = 0.1% to 0.4%); Beyth et al., five of 2,249 (0.2%; 95% CI = 0.1% to 0.5%); Kuijer et al., three of 1,186 (0.3%; 95% CI = 0.1% to 0.7%); and Landefeld and Goldman, seven of 2,407 (0.3%; 95% CI = 0.1% to 0.6%). No low-risk patient had a fatal bleed. Conclusions Four scoring systems that use criteria obtained in routine clinical practice, derived to predict low bleeding risk with VKA treatment for VTE, identified patients with less than a 1% risk of major bleeding during full-course treatment with rivaroxaban. © 2016 by the Society for Academic Emergency Medicine.

Pizarro-Delgado J.,Complutense University of Madrid | Deeney J.T.,Boston University | Martin-Del-Rio R.,Ramon y Cajal Hospital IRYCIS | Corkey B.E.,Boston University | Tamarit-Rodriguez J.,Complutense University of Madrid
PLoS ONE | Year: 2015

Our previous work has demonstrated that islet depolarization with KCl opens connexin36 hemichannels in β-cells of mouse pancreatic islets allowing the exchange of small metabolites with the extracellular medium. In this study, the opening of these hemichannels has been further characterized in rat islets and INS-1 cells. Taking advantage of hemicannels'opening, the uptake of extracellular ATP and its effect on insulin release were investigated. 70 mM KCl stimulated light emission by luciferin in dispersed rat islets cells transduced with the fire-fly luciferase gene: it was suppressed by 20 mM glucose and 50 μM mefloquine, a specific connexin36 inhibitor. Extracellular ATP was taken up or released by islets depolarized with 70 mM KCl at 5 mM glucose, depending on the external ATP concentration. 1 mM ATP restored the loss of ATP induced by the depolarization itself. ATP concentrations above 5 mM increased islet ATP content and the ATP/ADP ratio. No ATP uptake occurred in non-depolarized or KCl-depolarized islets simultaneously incubated with 50 μM mefloquine or 20 mM glucose. Extracellular ATP potentiated the secretory response induced by 70 mM KCl at 5 mM glucose in perifused rat islets: 5 mM ATP triggered a second phase of insulin release after the initial peak triggered by KCl-depolarization itself; at 10 mM, it increased both the initial, KCl-dependent, peak and stimulated a greater second phase of secretion than at 5 mM. These stimulatory effects of extracellular ATP were almost completely suppressed by 50 μM mefloquine. The magnitude of the second phase of insulin release due to 5 mM extracellular ATP was decreased by addition of 5 mM ADP (extracellular ATP/ADP ratio = 1). ATP acts independently of KATP channels closure and its intracellular concentration and its ATP/ADP ratio seems to regulate the magnitude of both the first (triggering) and second (amplifying) phases of glucose-induced insulin secretion. Copyright: © 2015 Pizarro-Delgado et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Campos-Martorell M.,Institute Of Recerca | Salvador N.,Ramon y Cajal Hospital IRYCIS | Monge M.,Autonomous University of Barcelona | Canals F.,Autonomous University of Barcelona | And 7 more authors.
Journal of Neurochemistry | Year: 2014

Finding an efficient neuroprotectant is of urgent need in the field of stroke research. The goal of this study was to test the effect of acute simvastatin administration after stroke in a rat embolic model and to explore its mechanism of action through brain proteomics. To that end, male Wistar rats were subjected to a Middle Cerebral Arteria Occlusion and simvastatin (20 mg/kg s.c) (n = 11) or vehicle (n = 9) were administered 15 min after. To evaluate the neuroprotective mechanisms of simvastatin, brain homogenates after 48 h were analyzed by two-dimensional fluorescence Difference in Gel Electrophoresis (DIGE) technology. We confirmed that simvastatin reduced the infarct volume and improved neurological impairment at 48 h after the stroke in this model. Considering our proteomics analysis, 66 spots, which revealed significant differences between groups, were analyzed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry allowing the identification of 27 proteins. From these results, we suggest that simvastatin protective effect can be partly explained by the attenuation of the oxidative and stress response at blood-brain barrier level after cerebral ischemia. Interestingly, analyzing one of the proteins (HSP75) in plasma from stroke patients who had received simvastatin during the acute phase, we confirmed the results found in the pre-clinical model. © 2014 International Society for Neurochemistry.

Pizarro-Delgado J.,Complutense University of Madrid | Fasciani I.,Ramon y Cajal Hospital IRYCIS | Temperan A.,Ramon y Cajal Hospital IRYCIS | Romero M.,Ramon y Cajal Hospital IRYCIS | And 16 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2014

The existence of functional connexin36 (Cx36) hemichannels in β-cells was investigated in pancreatic islets of rat and wild-type (Cx36+/+), monoallelic (Cx36+/-), and biallelic (Cx36-/-) knockout mice. Hemichannel opening by KCl depolarization was studied by measuring ATP release and changes of intracellular ATP (ADP). Cx36+/+ islets lost ATP after depolarization with 70 mM KCl at 5 mM glucose; ATP loss was prevented by 8 and 20 mM glucose or 50 μM mefloquine (connexin inhibitor). ATP content was higher in Cx36-/- than Cx36+/+ islets and was not decreased by KCl depolarization; Cx36+/- islets showed values between that of control and homozygous isletFive minimolar extracellular ATP increased ATP content and ATP/ADP ratio and induced a biphasic insulin secretion in depolarized Cx36+/+ and Cx36+/- but not Cx36-/- islets. Cx36 hemichannels expressed in oocytes opened upon depolarization of membrane potential, and their activation was inhibited by mefloquine and glucose (IC50 ~8 mM). It is postulated that glucose-induced inhibition of Cx36 hemichannels in islet β-cells might avoid depolarization-induced ATP loss, allowing an optimum increase of the ATP/ADP ratio by sugar metabolism and a biphasic stimulation of insulin secretion. Gradual suppression of glucose-induced insulin release in Cx36+/- and Cx36-/- islets confirms that Cx36 gap junction channels are necessary for a full secretory stimulation and might account for the glucose intolerance observed in mice with defective Cx36 expression. Mefloquine targeting of Cx36 on both gap junctions and hemichannels also suppresses glucose-stimulated secretion. By contrast, glucose stimulation of insulin secretion requires Cx36 hemichannels' closure but keeping gap junction channels opened. © 2014 the American Physiological Society.

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