Reduction in Central H2O2 Levels Prevents Voluntary Ethanol Intake in Mice: A Role for the Brain Catalase- H2O2 System in Alcohol Binge Drinking

Background: Hydrogen peroxide (H2O2) is the cosubstrate used by the enzyme catalase to form Compound I (the catalase-H2O2 system), which is the major pathway for the conversion of ethanol (EtOH) into acetaldehyde in the brain. This centrally formed acetaldehyde has been shown to be involved in some of the psychopharmacological eðects induced by EtOH in rodents, including volun- tary alcohol intake. It has been observed that diðerent levels of this enzyme in the central nervous sys- tem (CNS) result in variations in the amount of EtOH consumed. This has been interpreted to mean that the brain catalase-H2O2 system, by determining EtOH metabolism, mediates alcohol self-adminis- tration. To date, however, the role of H2O2 in voluntary EtOH drinking has not been investigated. Methods: In the present study, we explored the consequence of a reduction in cerebral H2O2 levels in volitional EtOH ingestion. With this end in mind, we injected mice of the C57BL/6J strain intraperito- neally with the H2O2 scavengers alpha-lipoic acid (LA; 0 to 50 mg/kg) or ebselen (Ebs; 0 to 25 mg/kg) 15 or 60 minutes, respectively, prior to oðering them an EtOH (10%) solution following a drinking- in-the-dark procedure. The same procedure was followed to assess the selectivity of these compounds in altering EtOH intake by presenting mice with a (0.1%) solution of saccharin. In addition, we indirectly tested the ability of LA and Ebs to reduce brain H2O2 availability. Results: The results showed that both LA and Ebs dose-dependently reduced voluntary EtOH intake, without altering saccharin consumption. Moreover, we demonstrated that these treatments decreased the central H2O2 levels available to catalase. Conclusions: Therefore, we propose that the amount of H2O2 present in the CNS, by determining brain acetaldehyde formation by the catalase-H2O2 system, could be a factor that determines an ani- mal’s propensity to consume EtOH

Role of CA2+/calmodulin on ethanol neurobehavioral effects

Rationale. The cAMP-dependent protein kinase A (PKA) signaling transduction pathway has been shown to play an important role in the modulation of several ethanol-induced behaviors. Different studies have demonstrated intracellular calcium (Ca2+)-dependent activation of the PKA cascade after ethanol administration. Thus, the cAMP cascade mediator Ca2+-dependent calmodulin (CaM) has been strongly implicated in the central effects of ethanol. Objectives. In this study, we assessed the role of the CaM inhibitor W7 on ethanol-induced stimulation, ethanol intake, and ethanol-induced activation of PKA. Methods. Swiss mice were pretreated with W7 (0–10 mg/kg) 30 min before ethanol (0–3.75 g/kg) administration. Immediately, animals were placed during 20 min in an open-field chamber. Ethanol (10 %, v/v) intake in 2 h was assessed using a limited access paradigm. Experiments with caffeine (0–15 mg/kg), cocaine (0–4 mg/kg), and saccharine (0.1 %, w/v) were designed to compare their results to those obtained with ethanol. Western blot was assayed 45 min after ethanol administration. Results. Results showed that pretreatment with W7, reduced selectively in a dose-dependent fashion ethanol-induced locomotor stimulation and ethanol intake. The ethanol-induced activation of PKA was also prevented by W7 administration. Conclusions. These results demonstrate that CaM inhibition resulted in a selective reduction of ethanol-stimulating effects and ethanol intake. The PKA activation induced by ethanol was blocked after the CaM blockade with W7. These results provide further evidence of the key role of cellular Ca2+-dependent pathways on the central effects of ethanol

Centrally formed acetaldehyde mediates ethanol-induced brain PKA activation

Centrally formed acetaldehyde has proven to be responsible for several psychopharmacological effects induced by ethanol. In addition, it has been suggested that the cAMP-PKA signaling transduction pathway plays an important role in the modulation of several ethanol-induced behaviors. Therefore, we hypothesized that acetaldehyde might be ultimately responsible for the activation of this intracellular pathway. We used three pharmacological agents that modify acetaldehyde activity (α-lipoic acid, aminotriazole, and d-penicillamine) to study the role of this metabolite on EtOH-induced PKA activation in mice. Our results show that the injection of α-lipoic acid, aminotriazole and d-penicillamine prior to acute EtOH administration effectively blocks the PKA-enhanced response to EtOH in the brain. These results strongly support the hypothesis of a selective release of acetaldehyde-dependent Ca2+ as the mechanism involved in the neurobehavioral effects elicited by EtOH.This research was supported by a grant from the Spanish Ministerio de Ciencia e Innovacion (PSI2011-28934/PSIC). Pablo Baliño was supported by a fellowship from the CICYT (BES-2009-024438). Ernesto Tarragon was supported at the time by Red de Trastornos Adictivos, Ministerio de Sanidad y Politica Social (RD06/0001/0028), Spain

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Gestión del conocimiento. Perspectiva multidisciplinaria. Volumen 7

El libro “Gestión del Conocimiento. Perspectiva Multidisciplinaria”, volumen 7, de la Colección Unión Global, es resultado de investigaciones. Los capítulos del libro, son resultados de investigaciones desarrolladas por sus autores. El libro es una publicación internacional, seriada, continua, arbitrada de acceso abierto a todas las áreas del conocimiento, que cuenta con el esfuerzo de investigadores de varios países del mundo, orientada a contribuir con procesos de gestión del conocimiento científico, tecnológico y humanístico que consoliden la transformación del conocimiento en diferentes escenarios, tanto organizacionales como universitarios, para el desarrollo de habilidades cognitivas del quehacer diario. La gestión del conocimiento es un camino para consolidar una plataforma en las empresas públicas o privadas, entidades educativas, organizaciones no gubernamentales, ya sea generando políticas para todas las jerarquías o un modelo de gestión para la administración, donde es fundamental articular el conocimiento, los trabajadores, directivos, el espacio de trabajo, hacia la creación de ambientes propicios para el desarrollo integral de las instituciones

Diseño estratégico de vanguardia

La integración del diseño con la vanguardia se observa natural, esto es, el diseño es una disciplina abductiva y la vanguardia persigue fines prospectivos, es decir, en ambos casos se trata de objetivos de posibilidad futura. De tal suerte, este libro, emanado de una parte de las ponencias rigurosamente arbitradas del Coloquio Internacional de Diseño 2016, está dividido en tres secciones o capítulos, a saber, el capítulo uno relacionado con la teoría y metodología para proyectos de diseño de vanguardia, el segundo sobre la tecnología, la innovación y la sostenibilidad de vanguardia de dichos proyectos, y finalmente el último capítulo, vinculado con la gestión estratégica de proyectos de vanguardia.La historia se forja de hechos e interpretaciones, de pasados construidos y de presentes en procesos constantes, estudiados en forma estricta por las ciencias. Por su parte, el futuro ostenta la posibilidad de ser indefinidamente planeado con base en las variopintas aproximaciones teóricas y empíricas que dan fundamento a este tipo de ciencia; éstas son denominadas prospectivas y sus bases vanguardias. Resulta importante señalar, que estas posibilidades sólo permiten tener una idea hipotética de lo que será la realidad y el mundo de vida de los seres vivos y su contexto, no obstante, se trata de la única manera racional que tiene el ser humano de prever ese futuro posible. Las distintas ciencias y disciplinas nos permiten construir históricamente estas posibilidades partiendo de datos, hechos, significados y un sinfín de informaciones que le dan cuerpo y sentido a tales posibilidades. En este sentido, la vanguardia, como base del conocimiento prospectivo, observa la necesidad de ser escrita, leída y discutida en los términos más estrictos con el fin de volver las predicciones más precisas. El diseño por su parte, es definido de manera sucinta como la disciplina proyectual estratégica y sistémica de la posibilidad, dirigida a procesos de significación utilitaria y simbólica para la comprensión –o interpretación– y modificación –o proyectación– de niveles de realidad (referentes y sujetos) desde diversos aparatos teóricos y empíricos –perspectivas disciplinarias–

Çédille, revista de estudios franceses

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