The Treatment With the SGLT2 Inhibitor Empagliflozin Modifies the Hepatic Metabolome of Male Zucker Diabetic Fatty Rats Towards a Protective Profile

[Abstract] The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial evidenced the potential of sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of patients with diabetes and cardiovascular disease. Recent evidences have shown the benefits of the SGLT2 inhibitor empagliflozin on improving liver steatosis and fibrosis in patients with T2DM. Metabolomic studies have been shown to be very useful to improve the understanding of liver pathophysiology during the development and progression of metabolic hepatic diseases, and because the effects of empagliflozin and of other SGLT2 inhibitors on the complete metabolic profile of the liver has never been analysed before, we decided to study the impact on the liver of male Zucker diabetic fatty (ZDF) rats of a treatment for 6 weeks with empagliflozin using an untargeted metabolomics approach, with the purpose to help to clarify the benefits of the use of empagliflozin at hepatic level. We found that empagliflozin is able to change the hepatic lipidome towards a protective profile, through an increase of monounsaturated and polyunsaturated glycerides, phosphatidylcholines, phosphatidylethanolamines, lysophosphatidylinositols and lysophosphatidylcholines. Empagliflozin also induces a decrease in the levels of the markers of inflammation IL-6, chemerin and chemerin receptor in the liver. Our results provide new evidences regarding the molecular pathways through which empagliflozin could exert hepatoprotector beneficial effects in T2DM.This work was supported by Boehringer Ingelheim Pharma GmbH and Co., by the National Institute of Health “Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III” Madrid, Spain (PI15/00681, PI17/00409, PI18/00821, PI20/00902, RETICS Programme RD16/0012/0014 and CIBER de Enfermedades Cardiovasculares (CIBERCV)); European Regional Development Fund (FEDER) and European Union framework MSCA-RISE-H2020 Programme (Project number 734899). AH-A was funded by predoctoral research grants from Xunta de Galicia and FPU Program of the Spanish Ministry of Science, Innovation and Universities (Spain); MF-S was funded by the predoctoral research grants “Programa Científico do Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS) (Spain) and Xunta de Galicia; and AV-L was funded by the predoctoral research grant from the PFIS Program of the Spanish Ministry of Science and Instituto de Salud Carlos III (Spain

8‐Aminomethyl‐7‐hydroxy‐4‐methylcoumarins as Multitarget Leads for Alzheimer's Disease

This is the peer reviewed version of the following article: Domínguez, J., Fernández-Nieto, F., Brea, J., Catto, M., Paleo, M., & Porto, S. et al. (2016). 8-Aminomethyl-7-hydroxy-4-methylcoumarins as Multitarget Leads for Alzheimer's Disease. Chemistryselect, 1(11), 2742-2749, which has been published in final form at https://doi.org/10.1002/slct.201600735. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsThis work is part of our ongoing research in the discovery of multitarget therapeutic agents for Alzheimer's disease (AD). A literature screening, based on our recently proposed pharmacophore, led to the identification of 8‐aminomethyl‐7‐hydroxy‐4‐methyl coumarins as potential multitarget leads for AD. The results of a computer‐assisted protocol developed by us to validate multitarget hits for AD indicated that our coumarin candidates were viable leads only for AChE inhibition as later validated by biological assays. The results of BChE binding and propidium displacement assays indicate that our first generation compounds bind to the PAS site in AChE. We designed new generations of coumarin derivatives with a longer substituent at position 8 aimed at leads with more efficient interaction at the catalytic anionic site (CAS). Inhibition data and docking simulations indicated that an anilino‐capping group reached the CAS region of AChE and determined also a higher inhibitory potency towards BChE. The best compound obtained, with a N‐benzylpiperidine fragment, displayed sub‐micromolar affinity for AChE, affinity for BChE, and precluded Aβ‐amyloid aggregation with a potency similar to that of 9,10‐anthraquinone, making it a multitarget lead viable for further improvementFinancial support from the Ministerio de Economia y Competitividad of Spain (Project CTQ2014‐55208‐P) and the Xunta de Galicia (10CSA209063PR and GRC2014/029) is gratefully acknowledged. The Italian authors thank the University of Bari for partial financial support (Fondi di Ateneo 2014–2015)S

Solo se diagnostica lo que se conoce: síndrome de ACNE

We report a case of a patient followed-up in Internal Medicine Department for a chronic abdominal pain with poor pain control. Normal analytical and imaging studies. Exploratory gynecological laparoscopy negative. After reviewing the literature abdominal wall pathology is suspected. We proceed to a lidocaine 5% ecoguide infiltration with pain resolution. Diagnosis. Abdominal cutaneous nerve entrapment syndrome. This syndrome is the most common cause of pain originated in the abdominal wall. A good medical history and a physical examination including Carnett’s test is enough to guide the diagnosis.Se presenta un caso de una paciente en seguimiento en consultas de Medicina Interna por un dolor abdominal crónico con mal control analgésico. Estudios analíticos y de imagen sin alteraciones. Laparoscopia exploratoria ginecológica negativa. Tras revisar la bibliografía, se sospecha patología de la pared abdominal. Se procede a la infiltración ecoguiada con lidocaína 5% con resolución del cuadro. Diagnóstico. Síndrome de atrapamiento del nervio cutáneo abdominal. Este síndrome es la causa más frecuente de dolor originado en la pared abdominal. Una buena historia clínica y una exploración física que incluya el test de Carnett es suficiente para orientar el diagnóstico

Effective practice for proceduralization of L2 knowledge in EFL classrroms

Tesis (Profesor de Inglés para la Enseñanza Básica y Media y al grado académico de Licenciado en Educación)This quasi-experimental study investigated the differential effects of types of practice (decontextualized practice, contextualized practice and practice elicited by prompts) on the development of grammatical knowledge in a foreign language classroom context. Four 10th grade classes (82 students) from a Spanish-speaking school served as participants for this study. Three classes were randomly assigned to one of the three experimental conditions and were exposed to six intervention sessions, and one served as a control group by development of L2 knowledge, we mean the proceduralization of declarative knowledge through practice, the basic tenet of the theoretical framework of this study, Skill Acquisition Theory Proceduralization is explained as a shift from declarative knowledge, which refers to the consciously accessible knowledge that learners have about an L2, to procedural knowledge, which refers to the unconsciously accessible knowledge that learners have about an L2 Throughout this project, declarative knowledge is represented as both regular and irregular past tense (mental grammar and mental lexicon, respectively). This differentiation helped us to explore the process of proceduralization on rule-based and item-based knowledge, separately Interpretations of the results from pretest and posttest measures of implicit and exphc1t knowledge of the target structures evidenced differential effects of each type of practice on the development of each type of knowledge, and suggest that a combination of contextualized and decontextualized practice would have the most positive impact on L2 development. Finally, future directions regarding research, in addition to actual pedagogical implications, are suggested.El presente estudio cuasi-experimental investigó los efectos diferenciales de los tipos de práctica (práctica descontextualizada, práctica contextualizada y práctica contextualizada con provisión de indicaciones correctivas) en el desarrollo de conocimiento gramatical en un contexto de aula de lengua extranjera Cuatro clases de Segundo Medio (82 estudtantes) de un colegio hispano-hablante participaron en este estudto. Tres grupos fueron asignados al azar a cada una de las tres condiciones experimentales y fueron expuestos a seis sesiones de intervenciones, con la excepción de uno de los grupos, el cual sirvió como grupo de control. Al hablar de desarrollo de conocimiento de una segunda lengua, nos referimos a la procedimentahzación de conocimiento declarativo a traves de la práctica, el principio basico del marco teórico de este estudio, 'teoría de la adquisición de habilidades' . El proceso de procedimentalización es explicado como el cambio de conocimiento declarativo, que se refiere al conocimiento de acceso consciente que los alumnos tienen sobre una segunda lengua, al conocimiento procedimental, el cual representa el conocimiento de acceso inconsciente que los alumnos tienen sobre una segunda lengua. A lo largo de este proyecto, el conocimiento declarativo es representado por el pasado simple de verbos regulares e irregulares (conocimiento de propiedades gramaticales y léxicas). Esta diferenciacion nos ayudó a explorar el proceso de procedimentalización de conocimiento basado en reglas y conocimiento basado en ítems por separado. Las interpretaciones de los resultados de las evaluaciones de pretest y posttest de conocimiento implícito y explícito acerca de las estructuras propuestas como objetivo evidenciaron efectos diferenciales de cada tipo de práctica en el desarrollo de cada tipo de conocimiento, y sugieren que una combinación entre práctica con textual izada y descontextualizada tendría el impacto más positivo en el desarrollo de una segunda lengua. Como conclusión, direcciones futuras en materia de investigación. además de implicaciones pedagógicas actuales, son sugeridas

Preclinical evaluation of an innovative bone graft of marine origin for the treatment of critical-sized bone defects in an animal model

Autogenous cancellous bone graft is the current gold standard of treatment for the management of bone defects since it possesses the properties of osteoinduction, osteoconduction, and osteogenesis. Xenografts and synthetic grafts have been widely reported as available and low-cost alternatives, which retain good osteoconductive and mechanical properties. Given the rich biodiversity of ocean organisms, marine sources are of particular interest in the search for alternative bone grafts with enhanced functionalities. The purpose of this paper is to assess the biocompatibility of a marine-derived bone graft obtained from shark tooth, which is an environmentally sustainable and abundant raw material from fishing. This research presents the findings of a preclinical trial—following UNE-EN ISO 10993—that induced a critical-sized bone defect in a rabbit model and compared the results with a commercial bovine-derived bone graft. Evaluation by micro-computed tomography and histomorphometric analysis 12 weeks after implantation revealed good osseointegration, with no signs of inflammatory foreign body reactions, fibrosis, or necrosis in any of the cases. The shark tooth-derived bone graft yielded significantly higher new bone mineral density values (54 ± 6%) than the control (27 ± 8%). Moreover, the percentage of intersection values were much higher (86 ± 8%) than the bovine-derived bone graft (30 ± 1%) used as control. The area of occupancy by bone tissue in the test material (38 ± 5%) also gave higher values than the control (30 ± 6%). The role of physicochemical properties, biphasic structure, and composition on the stimulation of bone regeneration is also discussed.Xunta de Galicia | Ref. IN855A 2016/06Xunta de Galicia | Ref. ED431C 2017/51Xunta de Galicia | Ref. ED431D 2017/13European Commission | Ref. 0245_IBEROS_1_E, POCTEP 2015European Commission | Ref. 0302_CVMAR_I_1_P, POCTEP 2015European Commission | Ref. EAPA_151 / 2016, Espacio Atlántico 201

Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models

Sodium-glucose co-transporter 2 inhibitors, also known as gliflozins, were developed as a novel class of anti-diabetic agents that promote glycosuria through the prevention of glucose reabsorption in the proximal tubule by sodium-glucose co-transporter 2. Beyond the regulation of glucose homeostasis, they resulted as being effective in different clinical trials in patients with heart failure, showing a strong cardio-renal protective effect in diabetic, but also in non-diabetic patients, which highlights the possible existence of other mechanisms through which gliflozins could be exerting their action. So far, different gliflozins have been approved for their therapeutic use in T2DM, heart failure, and diabetic kidney disease in different countries, all of them being diseases that have in common a deregulation of the inflammatory process associated with the pathology, which perpetuates and worsens the disease. This inflammatory deregulation has been observed in many other diseases, which led the scientific community to have a growing interest in the understanding of the biological processes that lead to or control inflammation deregulation in order to be able to identify potential therapeutic targets that could revert this situation and contribute to the amelioration of the disease. In this line, recent studies showed that gliflozins also act as an anti-inflammatory drug, and have been proposed as a useful strategy to treat other diseases linked to inflammation in addition to cardio-renal diseases, such as diabetes, obesity, atherosclerosis, or non-alcoholic fatty liver disease. In this work, we will review recent studies regarding the role of the main sodium-glucose co-transporter 2 inhibitors in the control of inflammation

Plan de emergencias de Galicia : organización de la respuesta sanitaria a las urgencias y emergencias

A publicación Plan de emerxencias de Galicia presenta ao longo de 21 capítulos os protocolos específicos de actuación para a atención a múltiples vítimas e catástrofes no contexto da Comunidade Autónoma de GaliciaLa publicación Plan de emergencias de Galicia presenta a lo largo de 21 capítulos los protocolos específicos de actuación para la atención a múltiples víctimas y catástrofes en el contexto de la Comunidad Autónoma de Galici

The lipidomic and inflammatory profiles of visceral and subcutaneous adipose tissues are distinctly regulated by the SGLT2 inhibitor empagliflozin in Zucker diabetic fatty rats

The pharmacological inhibition of sodium-glucose cotransporter 2 (SGLT2) has emerged as a treatment for patients with type 2 diabetes mellitus (T2DM), cardiovascular disease and/or other metabolic disturbances, although some of the mechanisms implicated in their beneficial effects are unknown. The SGLT2 inhibitor (SGLT2i) empagliflozin has been suggested as a regulator of adiposity, energy metabolism, and systemic inflammation in adipose tissue. The aim of our study was to evaluate the impact of a 6-week-empagliflozin treatment on the lipidome of visceral (VAT) and subcutaneous adipose tissue (SAT) from diabetic obese Zucker Diabetic Fatty (ZDF) rats using an untargeted metabolomics approach. We found that empagliflozin increases the content of diglycerides and oxidized fatty acids (FA) in VAT, while in SAT, it decreases the levels of several lysophospholipids and increases 2 phosphatidylcholines. Empagliflozin also reduces the expression of the cytokines interleukin-1 beta (IL-1β), IL-6, tumor necrosis factor-alpha (TNFα), monocyte-chemotactic protein-1 (MCP-1) and IL-10, and of Cd86 and Cd163 M1 and M2 macrophage markers in VAT, with no changes in SAT, except for a decrease in IL-1β. Empagliflozin treatment also shows an effect on lipolysis increasing the expression of hormone-sensitive lipase (HSL) in SAT and VAT and of adipose triglyceride lipase (ATGL) in VAT, together with a decrease in the adipose content of the FA transporter cluster of differentiation 36 (CD36). In conclusion, our data highlighted differences in the VAT and SAT lipidomes, inflammatory profiles and lipolytic function, which suggest a distinct metabolism of these two white adipose tissue depots after the empagliflozin treatment

Manual de soporte vital avanzado en urgencias prehospitalarias: normas de actuación

O Manual de soporte vital avanzado en urgencias prehospitalarias adapta os procedementos e técnicas de actuación ás urxencias prehospitalarias ás últimas recomendacións en resucitación cardiopulmonar aprobadas polo International Liaison Commitee on Resuscitation en outubro do ano 2010.El Manual de soporte vital avanzado en urgencias prehospitalarias adapta los procedimientos y técnicas de actuación a las urgencias prehospitalarias a las últimas recomendaciones en resucitación cardiopulmonar aprobadas por el International Liaison Commitee on Resuscitation en octubre del año 2010

Podcasts como ferramenta para aprender sobre Direito

La proliferación de nuevas formas de transmisión del conocimiento, así como de su difusión constituye una oportunidad que la enseñanza del Derecho no puede dejar pasar. La elaboración de podcast o podcasting con fines educativos o de aplicación a la docencia ha sido ya objeto de utilización en el contexto anglosajón y, en un nivel mucho menor, en el contexto español. Como ya alude Piñero-Otero, T. en su investigación “La utilización de los podcasts en la universidad española: entre la institución y la enseñanza”, la incorporación de los podcasts como herramienta docente en las universidades españolas fue tardía respecto a otras universidades, como las norteamericanas. Y, no sólo eso, sino que su aplicación en la práctica es escasa. Los podcasts muestran relevantes potencialidades para la formación universitaria y, en específico, para la formación en Derecho. El formato de fragmentos o episodios de audio que desarrollan conocimiento, online, público, gratuito y accesible en cualquier momento se evidencia pertinente para captar el interés del estudiantado. Evidencia que queda patente en los estudios que ya han aplicado esta herramienta. El presente proyecto busca fomentar la extensión de este instrumento en el entorno universitario como recurso formativo complementario y de apoyo a la clase magistral y práctica establecida en la regulación de las enseñanzas superiores. Tal y como se ha apuntado en numerosas ocasiones por docentes que ya han aplicado los podcasts en la educación, se trata de una fuente más que, en ningún caso, se propone como sustitutoria de las clases ordinarias. Ello supondría el desencadenamiento de efectos negativos como una insuficiencia de formación, falta de intercambio de pensamiento y debate y riesgo de asistencia y participación en el aula, entre otros. Respecto de este último aspecto, estudios como el de Parson, V., Reddy, P., Wood, J. y Senior, C. (2009), “Educating and iPod generation: undergraduate attitudes, experiences and understanding of vodcast and podcast use”, reflejan que los estudiantes consideran como un aspecto muy positivo el hecho de que los podcasts permitan aprender y revisar el contenido de la asignatura; aspecto que quedaría desvirtuado si la docencia tradicional quedará completamente subsumida al empleo del podcast.El objetivo del Proyecto de Innovación Docente es ofrecer una herramienta para el aprendizaje del Derecho, basada en la digitalización mediante podcast, que permita a los estudiantes disponer de contenidos jurídicos para su proceso formativo.The aim of the Teaching Innovation Project is to offer a tool for learning law, based on digitalisation through podcasts, which allows students to have access to legal content for their learning process.L'obiettivo del Progetto di Innovazione Didattica è quello di offrire uno strumento per l'apprendimento del diritto, basato sulla digitalizzazione attraverso i podcast, che permetta agli studenti di avere accesso a contenuti giuridici per il loro processo di formazione.O objetivo do Projeto de Inovação Didática é oferecer uma ferramenta de aprendizagem do direito, baseada na digitalização através de podcasts, que permita aos estudantes ter acesso a conteúdos jurídicos para o seu processo de formação.Depto. de Derecho del Trabajo y Seguridad SocialFac. de DerechoFALSEsubmitte