Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease

BACKGROUND: Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD. METHODS: We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56. RESULTS: A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non-relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]). CONCLUSIONS: Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy

Ghrelin-Induced Orexigenic Effect in Rats Depends on the Metabolic Status and Is Counteracted by Peripheral CB1 Receptor Antagonism

Ghrelin is an endogenous regulator of energy homeostasis synthesized by the stomach to stimulate appetite and positive energy balance. Similarly, the endocannabinoid system is part of our internal machinery controlling food intake and energy expenditure. Both peripheral and central mechanisms regulate CB1-mediated control of food intake and a functional relationship between hypothalamic ghrelin and cannabinoid CB1 receptor has been proposed. First of all, we investigated brain ghrelin actions on food intake in rats with different metabolic status (negative or equilibrate energy balance). Secondly, we tested a sub-anxiogenic ultra-low dose of the CB1 antagonist SR141716A (Rimonabant) and the peripheral-acting CB1 antagonist LH-21 on ghrelin orexigenic actions. We found that: 1) central administration of ghrelin promotes food intake in free feeding animals but not in 24 h food-deprived or chronically food-restricted animals; 2) an ultra-low dose of SR141716A (a subthreshold dose 75 folds lower than the EC50 for induction of anxiety) completely counteracts the orexigenic actions of central ghrelin in free feeding animals; 3) the peripheral-restricted CB1 antagonist LH-21 blocks ghrelin-induced hyperphagia in free feeding animals. Our study highlights the importance of the animaĺs metabolic status for the effectiveness of ghrelin in promoting feeding, and suggests that the peripheral endocannabinoid system may interact with ghrelińs signal in the control of food intake under equilibrate energy balance conditions. © 2013 Alen et al.Peer Reviewe

Ghrelin-induced orexigenic effect in rats depends on the metabolic status and is counteracted by peripheral CB1 receptor antagonism.

Journal Article; Research Support, Non-U.S. Gov't;Ghrelin is an endogenous regulator of energy homeostasis synthesized by the stomach to stimulate appetite and positive energy balance. Similarly, the endocannabinoid system is part of our internal machinery controlling food intake and energy expenditure. Both peripheral and central mechanisms regulate CB1-mediated control of food intake and a functional relationship between hypothalamic ghrelin and cannabinoid CB1 receptor has been proposed. First of all, we investigated brain ghrelin actions on food intake in rats with different metabolic status (negative or equilibrate energy balance). Secondly, we tested a sub-anxiogenic ultra-low dose of the CB1 antagonist SR141716A (Rimonabant) and the peripheral-acting CB1 antagonist LH-21 on ghrelin orexigenic actions. We found that: 1) central administration of ghrelin promotes food intake in free feeding animals but not in 24 h food-deprived or chronically food-restricted animals; 2) an ultra-low dose of SR141716A (a subthreshold dose 75 folds lower than the EC50 for induction of anxiety) completely counteracts the orexigenic actions of central ghrelin in free feeding animals; 3) the peripheral-restricted CB1 antagonist LH-21 blocks ghrelin-induced hyperphagia in free feeding animals. Our study highlights the importance of the animaĺs metabolic status for the effectiveness of ghrelin in promoting feeding, and suggests that the peripheral endocannabinoid system may interact with ghrelińs signal in the control of food intake under equilibrate energy balance conditions.The present work has been supported by grants from the European Union 7th Framework Programme (Health-F2-2008-223713, REPROBESITY); the following grants from the Spanish Ministry of Science and Innovation: fundamental research project (SAF2010-20521), National Institute of Health National Institute of Health ‘CarlosIII’ (PI07/1226), Red de Trastornos Adictivos EU-ERDF (RD06/0001/0000), and CIBERobn EU-ERDF(CB06/03/1008); grant EU-ERDF PAIDI CTS-433 and grant PI45403 from the Andalusian Ministry of Economy, Science and Innovation; grant PR 28/11-18295 from Spanish Ministry of Education and grant from the Fundación Eugenio Rodríguez Pascual. MTRL is a recipient of a FPU fellowship from the Spanish Ministry of Education.Ye

Estimulación del talento matemático en Valladolid

Se desarrolla un proyecto de innovación educativa que pretende buscar contenidos y metodologías adecuadas para trabajar con el alumnado dotado de especial talento matemático. Se han impartido 22 sesiones de tres horas de duración para el profesorado participante, cada uno de ellos ha desarrollado trabajo individual en el que ha preparado sesiones de trabajo, ha investigado material y bibliografía. Cada profesor o profesora ha trabajado en pequeño grupo eligiendo los contenidos con los alumnos y alumnas y la metodología a emplear. Se han desarrollado ponencias a cargo de ponentes externos al centro, excursiones y jornadas de convivencia, y reuniones con las familias de los alumnos y alumnas participantes en el proyecto de innovación. El profesorado participante está muy satisfecho con la participación en el proyecto y valora positivamente la relación personal que ha propiciado que el trabajo haya sido más fácil y agradable de realizar. La realización del proyecto de innovación ha sido imprescindible y determinante para poner en marcha el 'Proyecto de detección y estimulación del Talento Matemático en Valladolid'.Castilla y LeónConsejería de Educación. Dirección General de Universidades e Investigación; Monasterio de Nuestra Señora de Prado, Autovía Puente Colgante s. n.; 47071 Valladolid; +34983411881; +34983411939ES

Pretreatment with an ultra-low dose of SR141716A or the peripheral CB1 antagonist LH-21 on the orexigenic effect induced by ghrelin in free feeding animals.

<p>Administration of ghrelin (0.5 µg, i.c.v.) increased food intake in free feeding animals. A) The subeffective dose of SR141716A (0.03 mg/kg, i.p) counteracted ghrelin-induced orexigenic effect. As expected, the ultra-low dose of SR141716A showed no effect on food intake in vehicle-treated animals. B) Pretreatment with LH-21 (3 mg/kg, i.p.) counteracted the increase in food intake induced by ghrelin and had no effect in vehicle-treated rats. Data are means ± SEM of 6–10 determinations per group. Different from vehicle-injected rats: *<i>P</i><0.05. ***<i>P</i><0.001; different from ghrelin treatment: ^#<i>P</i><0.05, ^##<i>P</i><0.01, ^###<i>P</i><0.001.</p

Effects of ghrelin (0.25 µg, 0.5 µg and 1.0 µg, i.c.v.) on accumulated food intake in free feeding, 24 h food-deprived (fasted) or chronically food-restricted animals 60 min and 120 min after administration.

<p>Free-feeding animals (n = 9 in each group) had free access to standard pellets of food; fasted rats (n = 9 in each group) were totally deprived for food during 24 h before the experiment; and chronic food-restricted rats (n = 9 in each group) were limited daily for food intake until body weights reached 80% of free-feeding values (20–25 days). The amount of ingested food in vehicle-injected animals was higher in the food-restricted group, following by the fasted group and free feeding rats, respectively. Ghrelin administration induced hyperphagia at any dose tested exclusively in animals fed ad libitum. No effect of ghrelin administration was observed in fasted or food-restricted animals. Data are means ± SEM of accumulated food intake. Different from free feeding vehicle-injected rats: ^###P<0.001. Different from fasted vehicle-injected rats: ^£££P<0.001. Different from vehicle-injected rats in the same condition (free feeding): *P<0.05. **P<0.01. ***P<0.001.</p

EC₅₀ of a dose-response curve of SR141716A on food intake and anxiety.

<p>A) effect of SR141716A (0, 0.1, 1.0 and 3.0 mg/kg, i.p.) on responses for food; B) effect of SR141716A (0, 0.1, 1.0 and 3.0 mg/kg, i.p.) on anxiety, expressed as latency to emerge a defensive withdrawal behaviour. The figures represent a re-analysis of the data previously published <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060918#pone.0060918-Navarro2" target="_blank">[30]</a>. The half maximal effective concentration (EC₅₀) is 2.2 mg/kg and 2.3 mg/kg for food inhibition and induction of anxiety behavior, respectively.</p

Con voz propia : los cambios sociales y profesionales desde la experiencia de los docentes

Establecer un estado de la cuestión sobre investigaciones actuales vinculadas a procesos de reestructuración profesional de los docentes, en especial aquellos que se han basado en el estudio de historias de vida; analizar los procesos legislativos implementados en España desde la reforma de 1970 hasta la iniciada reforma de 2002; analizar los desarrollos legislativos vinculados a la reestructuración docente en seis comunidades autónomas; evaluar el alcance de la reestructuración profesional de doce profesores en las comunidades estudiadas; presentar datos comparativos y cualitativos, relacionados con el significado subjetivo del ejercicio profesional docente en las diferentes autonomías; producir resultados que puedan servir para la toma de decisiones de las políticas educativas en relación con la profesión docente desde una perspectiva autonómica, española y europea. Se presentan las historias de vida de doce profesores, en los que se reflejan mediante la narración de sus trayectorias profesionales, los procesos de cambio producidos en la docencia. Se han elegido doce docentes de seis comunidades autónomas, seis hombres, seis mujeres, seis de enseñanza primaria y seis de secundaria, y que tienen una práctica docente de entre 20 y 30 años. La narración de las distintas historias, recogidas mediante entrevistas a los docentes, se han tratado de forma individual, presentando doce historias, que se relacionan con el contexto social y legislativo sucedido en España entre 1970 y 2002. Las diferentes historias se ponen en común estableciendo relaciones con temas concretos sobre el profesorado. Las reflexiones que se derivan del estudio son: la importancia de subjetivar al profesorado; la necesidad de tener en cuenta la opinión de los docentes en los cambios de las políticas educativas; el potencial de las historias de vida como ejercicio de reflexión para el profesorado; la formación de los docentes debería ajustarse sus necesidades de todo tipo, no sólo de saber; los procesos de cambio tendrían que tener a los docentes como parte activa en estos procesos y no como simples ejecutores de las políticas.CataluñaBiblioteca de Educación del Ministerio de Educación, Cultura y Deporte; Calle San Agustín, 5 - 3 Planta; 28014 Madrid; Tel. +34917748000; Fax +34917748026; [email protected]