Impact of R-carvedilol on ß2-adrenergic receptor-mediated spontaneous calcium release in human atrial myocytes

A hallmark of atrial fibrillation is an excess of spontaneous calcium release events, which can be mimicked by ß1- or ß2-adrenergic stimulation. Because ß1-adrenergic receptor blockers (ß1-blockers) are primarily used in clinical practice, we here examined the impact of ß2-adrenergic stimulation on spontaneous calcium release and assessed whether the R- and S-enantiomers of the non-selective ß- blocker carvedilol could reverse these effects. For this purpose, human atrial myocytes were isolated from patients undergoing cardiovascular surgery and subjected to confocal calcium imaging or immunofluorescent labeling of the ryanodine receptor (RyR2). Interestingly, the ß2-adrenergic agonist fenoterol increased the incidence of calcium sparks and waves to levels observed with the non-specific ß-adrenergic agonist isoproterenol. Moreover, fenoterol increased both the amplitude and duration of the sparks, facilitating their fusion into calcium waves. Subsequent application of the non ß-blocking R-Carvedilol enantiomer reversed these effects of fenoterol in a dose-dependent manner. R-Carvedilol also reversed the fenoterol-induced phosphorylation of the RyR2 at Ser-2808 dose-dependently, and 1 µM of either R- or S-Carvedilol fully reversed the effect of fenoterol. Together, these findings demonstrate that ß2-adrenergic stimulation alone stimulates RyR2 phosphorylation at Ser-2808 and spontaneous calcium release maximally, and points to carvedilol as a tool to attenuate the pathological activation of ß2-receptors.Peer ReviewedPostprint (published version

Papel de la empatía en los agresores y las víctimas del acoso escolar: un estudio transversal

El acoso escolar es un fenómeno que está presente en las aulas. Las competencias emocionales que desarrollan los niños en su crecimiento pueden tener relación con la participación en este proceso. La empatía es una competencia que se ve afectada en agresores y víctimas. Este trabajo analizó si existen diferencias en el nivel de empatía en función de los participantes del acoso escolar (víctimas y acosadores). Además, se estudia si hay diferencias en empatía en función del sexo de la persona hacia quien va dirigida la acción empática y de quién la ejerce. La muestra estuvo compuesta por 180 niños siendo el 50% chicas y 50% chicos de entre 10 y 12 años, encontrando la media en 11,23 años y la desviación típica de .914. reclutados en cinco colegios de la provincia de Alicante (Petrel, Ibi y Alicante), en España. Los niños respondieron al Cuestionario de Índice de Empatía para Niños y Adolescentes (Index of Empaty for Children and Adolescents, IECA) para evaluar la empatía y al Test Bull-S para evaluar los posibles perfiles de agresor y víctima en las aulas. Los agresores y las víctimas obtuvieron un menor índice de empatía con respecto a la media global de la muestra; aunque no hubo diferencia en empatía entre agresores y víctimas. Las chicas puntuaron más alto en empatía que los chicos. Las chicas mostraron ser más empáticas con las chicas, que con los chicos. Se concluye que las competencias emocionales pueden verse afectadas en personas involucradas en situaciones de acoso. Por tanto, se debe dar prioridad a programas de prevención basados en mejorar las competencias emocionales y así evitar el problema del acoso escolar antes de que ocurra.Role of empathy in aggressors and victims of bullying: A cross-sectional study. Bullying is a phenomenon that is present in the classroom. The emotional competences that children develop as they grow up may be related to their participation in this process. Empathy is a competence that is affected in aggressors and victims. This paper analysed whether there are differences in the level of empathy depending on the participants in bullying (victims and bullies). In addition, we studied whether there are differences in empathy according to the gender of the person towards whom the empathic action is directed and who is exercising it. The sample consisted of 180 children, 50% girls and 50% boys between 10 and 12 years of age, with a mean of 11.23 years and a standard deviation of .914, recruited from five schools in the province of Alicante (Petrel, Ibi and Alicante), Spain. The children responded to the Index of Empathy for Children and Adolescents (IECA) questionnaire to assess empathy and to the Bull-S test to assess possible aggressor and victim profiles in the classroom. Bullies and victims scored lower on empathy than the overall sample mean, although there was no difference in empathy between bullies and victims. Girls scored higher on empathy than boys. Girls were more empathetic towards girls than boys. It is concluded that emotional competences may be affected in people involved in bullying situations. Therefore, priority should be given to prevention programmes based on improving emotional competences in order to prevent the problem of bullying before it occurs

Diagnostic yield of early repeat colonoscopy after suboptimal bowel preparation in a fecal immunochemical test-based screening program

Background Current guidelines regarding surveillance after screening colonoscopy assume adequate bowel preparation. However, follow-up intervals after suboptimal cleansing are highly heterogeneous. We aimed to determine the diagnostic yield of early repeat colonoscopy in patients with suboptimal bowel preparation in fecal immunochemical test (FIT)-based screening colonoscopy. Methods An observational study including patients who underwent colonoscopy with suboptimal bowel preparation after positive FIT screening and then repeat colonoscopy within 1 year. Suboptimal preparation was defined as a Boston Bowel Preparation Scale (BBPS) score of 1 in any segment. Patients with a BBPS score of 0 in any segment or incomplete examination were excluded. The adenoma detection rate (ADR), advanced ADR (AADR), and colorectal cancer rate were calculated for the index and repeat colonoscopies. Results Of the 2474 patients with FIT-positive colonoscopy at our center during this period, 314 (12.7%) had suboptimal preparation. Of the 259 (82.5%) patients who underwent repeat colonoscopy, suboptimal cleansing persisted in 22 (9 %). On repeat colonoscopy, the ADR was 38.7% (95% CI 32.6% to 44.8%) and the AADR was 14.9% (95%CI 10.5% to 19.4%). The per-adenoma miss rate was 27.7% (95 %CI 24.0% to 31.6%), and the per-advanced adenoma miss rate was 17.6% (95%CI 13.3% to 22.7%). After repeat colonoscopy, the post-polypectomy surveillance recommendation changed from 10 to 3 years in 14.7% of the patients with previous 10-year surveillance recommendation. Conclusions Patients with suboptimal bowel preparation on FIT-positive colonoscopy present a high rate of advanced adenomas in repeat colonoscopy, with major changes in post-polypectomy surveillance recommendations

Elucidating dynamic behavior of synthetic supramolecular polymers in water by hydrogen/deuterium exchange mass spectrometry

A comprehensive understanding of the structure, self-assembly mechanism, and dynamics of one-dimensional supramolecular polymers in water is essential for their application as biomaterials. Although a plethora of techniques are available to study the first two properties, there is a paucity in possibilities to study dynamic exchange of monomers between supramolecular polymers in solution. We recently introduced hydrogen/deuterium exchange mass spectrometry (HDX-MS) to characterize the dynamic nature of synthetic supramolecular polymers with only a minimal perturbation of the chemical structure. To further expand the application of this powerful technique some essential experimental aspects have been reaffirmed and the technique has been applied to a diverse library of assemblies. HDX-MS is widely applicable if there are exchangeable hydrogen atoms protected from direct contact with the solvent and if the monomer concentration is sufficiently high to ensure the presence of supramolecular polymers during dilution. In addition, we demonstrate that the kinetic behavior as probed by HDX-MS is influenced by the internal order within the supramolecular polymers and by the self-assembly mechanism.MINECO, Spain, Grant/Award Number: IJCI-2015-252389; Marie Curie FP7 SASSYPOL ITN program, Grant/Award Number: 607602; European Research Council, Grant/Award Number: 788618; Dutch Ministry of Education, Culture and Science, Grant/Award Number: 024.001.03

Beta-blocker treatment of patients with atrial fibrillation attenuates spontaneous calcium release-induced electrical activity

Aims Atrial fibrillation (AF) has been associated with excessive spontaneous calcium release, linked to cyclic AMP (cAMP)-dependent phosphorylation of calcium regulatory proteins. Because ß-blockers are expected to attenuate cAMP-dependent signaling, we aimed to examine whether the treatment of patients with ß-blockers affected the incidence of spontaneous calcium release events or transient inward currents (ITI). Methods The impact of treatment with commonly used ß-blockers was analyzed in human atrial myocytes from 371 patients using patch-clamp technique, confocal calcium imaging or immunofluorescent labeling. Data were analyzed using multivariate regression analysis taking into account potentially confounding effects of relevant clinical factors Results The L-type calcium current (ICa) density was diminished significantly in patients with chronic but not paroxysmal AF and the treatment of patients with ß-blockers did not affect ICa density in any group. By contrast, the ITI frequency was elevated in patients with either paroxysmal or chronic AF that did not receive treatment, and ß-blocker treatment reduced the frequency to levels observed in patients without AF. Confocal calcium imaging showed that ß-blocker treatment also reduced the calcium spark frequency in patients with AF to levels observed in those without AF. Furthermore, phosphorylation of the ryanodine receptor (RyR2) at Ser-2808 and phospholamban at Ser-16 was significantly lower in patients with AF that received ß-blockers. Conclusion Together, our findings demonstrate that ß-blocker treatment may be of therapeutic utility to prevent spontaneous calcium release-induced atrial electrical activity; especially in patients with a history of paroxysmal AF displaying preserved ICa density.Peer ReviewedPostprint (published version

Comment on Yeste et al.: Polyphenols and IUGR Pregnancies: Intrauterine Growth Restriction and Hydroxytyrosol Affect the Development and Neurotransmitter Profile of the Hippocampus in a Pig Model

Intrauterine growth restriction (IUGR) affects 5-10% of newborns and increases the risks of intrauterine demise, neonatal morbidity, and death. In their recent publication, Yeste et al. found the benefits of hydroxytyrosol supplementation on brain remodeling from an IUGR pig model. Additionally, we found a significant decrease in phenolic alcohol (tyrosol and hydroxytyrosol) intake in IUGR pregnant women. Altogether, these findings support the notion that dietetic interventions, through supplementation but mostly via a balanced diet, can ameliorate IUGR complications. Furthermore, diet intervention combined with early biomarkers may allow clinicians to eventually anticipate IUGR diagnosis and help avoid one of the most frequent causes of newborn mortality and morbidity

FGF21 gene therapy as treatment for obesity and insulin resistance

Prevalence of type 2 diabetes (T2D) and obesity is increasing worldwide. Currently available therapies are not suited for all patients in the heterogeneous obese/T2D population, hence the need for novel treatments. Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent for T2D/obesity. Native FGF21 has, however, poor pharmacokinetic properties, making gene therapy an attractive strategy to achieve sustained circulating levels of this protein. Here, adeno-associated viral vectors (AAV) were used to genetically engineer liver, adipose tissue, or skeletal muscle to secrete FGF21. Treatment of animals under long-term high-fat diet feeding or of ob/ob mice resulted in marked reductions in body weight, adipose tissue hypertrophy and inflammation, hepatic steatosis, inflammation and fibrosis, and insulin resistance for > 1 year. This therapeutic effect was achieved in the absence of side effects despite continuously elevated serum FGF21. Furthermore, FGF21 overproduction in healthy animals fed a standard diet prevented the increase in weight and insulin resistance associated with aging. Our study underscores the potential of FGF21 gene therapy to treat obesity, insulin resistance, and T2D.This work was supported by grants from Ministerio de Economía y Competi- tividad (MINECO) and FEDER, Plan Nacional I+D+I (SAF2014-54866R), andGeneralitat de Catalunya (2014SGR1669and ICREA Academia Award to F.B.), Spain, from the European Commission (MYOCURE, PHC-14-2015 667751) and the European Foundation for the Study of Diabetes (EFSD/MSD European Research Programme on Novel Therapies for Type 2 Diabetes,2013). V.J. was recipient of a post-doctoral research fellowship from EFSD/ Lilly. E.C., V.S., and C.M. received a predoctoral fellowship from Ministerio de Educación, Cultura y Deporte, and J.R. from Ministerio de Economía y Competitividad, Spain. The authors thank Marta Moya and Maria Molas for technical assistance.S

Identificación de regiones de homocigosidad y heterocigosidad en 22 razas ovinas españolas

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Famílies botàniques de plantes medicinals

Facultat de Farmàcia, Universitat de Barcelona. Ensenyament: Grau de Farmàcia, Assignatura: Botànica Farmacèutica, Curs: 2013-2014, Coordinadors: Joan Simon, Cèsar Blanché i Maria Bosch.Els materials que aquí es presenten són els recull de 175 treballs d’una família botànica d’interès medicinal realitzats de manera individual. Els treballs han estat realitzat per la totalitat dels estudiants dels grups M-2 i M-3 de l’assignatura Botànica Farmacèutica durant els mesos d’abril i maig del curs 2013-14. Tots els treballs s’han dut a terme a través de la plataforma de GoogleDocs i han estat tutoritzats pel professor de l’assignatura i revisats i finalment co-avaluats entre els propis estudiants. L’objectiu principal de l’activitat ha estat fomentar l’aprenentatge autònom i col·laboratiu en Botànica farmacèutica