Neuroprotección conferida por agonistas PPARs E IGF-1 y su impacto en vías de supervivencia en dos modelos in vitro de la enfermedad de Krabbe

La enfermedad de Krabbe (KD, del inglés Krabbe disease) es un desorden neurodegenerativo fatal, causado por mutaciones en el gen para la enzima lisosomal galactocerebrosidasa (GALC), con la consecuente acumulación de galactosilesfingosina (psicosina), esfingolípido altamente tóxico, que genera muerte severa de oligodendrocitos y otros tipos celulares. Los Receptores Activados por el Proliferador Peroxisomal (PPARs), son receptores nucleares conformados por al menos tres tipos: PPARα PPARγ y PPARβ, todos ellos expresados en el oligodendrocito donde no es completamente clara su función. Los receptores PPARs regulan la expresión génica a través del reconocimiento y unión a los denominados "Elementos reguladores de Respuesta a PPAR" (PPREs) presentes en la región promotora de los genes diana. Han sido intensamente documentados por cumplir un importante papel en la regulación de la expresión de genes implicados en el metabolismo de lípidos, aumentar la sensibilidad a la insulina, y recientemente estudiados por mitigar la inflamación en patologías neurológicas y asociados a algunos tipos de cáncer entre otros. Por otro lado, se ha demostrado que la acumulación de psicosina en las neuronas provoca severos daños en los axones, que pueden ser causados por alteraciones en los mecanismos de transporte axonal, y que se presentan incluso antes de la muerte celular y la desmielinización. Con el presente trabajo, se pretende estudiar los mecanismos moleculares involucrados en el desencadenamiento de la muerte celular mediados por la acumulación de psicosina y los efectos del factor de crecimiento IGF-1 y de los agonistas de PPARs sobre la supervivencia de una línea celular oligodendroglial, en dos modelos distintos de KD. Se estudió la regulación a la baja de la proteína GALC, y su efecto sobre la supervivencia de oligodendrocitos, las vías de supervivencia celular PI3K/AKT y ERK1/2. Adicionalmente, se estudió la distribución y movilización axonal de la psicosina para determinar su relación con la axonopatía y muerte neuronal. Aunque se ha avanzado en la comprensión de ésta enfermedad, se conoce poco acerca del mecanismo molecular que dispara la activación de las vías de apoptosis y por ende el desarrollo/progresión de la enfermedad sigue siendo poco entendido. Los resultados obtenidos en la presente investigación sugieren que la muerte celular producida por la psicosina puede ser atenuada mediante la activación de las vías de neuroprotección mediadas por IGF-1 y la regulación transcripcional de los PPARs. Conjuntamente, se propone un modelo de acumulación de la psicosina en la mielina y las neuronas.Abstrct. Krabbe disease (KD), also known as globoid cell leukodystrophy, is an autosomal recessive neurodegenerative disease caused by the genetic deficiency of galactocerebrosidase (GALC), a lysosomal enzyme responsible for the degradation of several glycosphingolipids like galactosylsphingosine (psychosine) and galactosylceramide. The resulting accumulation of psychosine generates severe cell death, neurodegeneration and demyelination. Peroxisome proliferator-activated receptor (PPAR)α, β, and γ are members of the nuclear receptor family of ligand-dependent transcription factors that regulate diverse aspects of energy homeostasis, lipid and lipoprotein metabolism, and glucose homeostasis through binding to PPAR-response elements (PPRE),which are located in the promoter region of target genes. All of them are expressed in oligodendrocytes but their function is not fully understood. PPARs have also emerged as key regulators of inflammatory and immune responses, opening a new area for the development of therapeutic drugs useful in the treatment of some types of cancer and chronic inflammatory diseases such as atherosclerosis, obesity-induced insulin resistance, and neurodegenerative diseases. In addition, it has been shown that the accumulation of psychosine in neurons causes severe damage to axons, which can be caused by alterations in axonal transport mechanisms, and this axonophathy is generated even before cell death and demyelination. This work aims to study the molecular mechanisms involved in triggering cell death mediated by the accumulation of psychosine in two in vitro models of KD. Istudied the downregulation of GALC protein and its effect on survival of oligodendrocytes and the survival pathways PI3K/AKT and ERK1/2.I also evaluated pharmacological alternatives such as PPAR agonists and IGF-1.Finally, I analyzed the distribution and axonal mobilization of psychosine to determine their relationship with axonopathy and neuronal death. Although some progress has been made in the understanding of this disease, little is known about the molecular mechanism that generates the activation of apoptotic pathways and thus the development / progression of the disease remains poorly understood. The results obtained in this investigation suggests that cell death triggered by psychosine accumulation can be attenuated by activation of neuroprotective pathways associated with IGF-1 and transcriptional regulation of PPARs. Further, a model of accumulation of psychosine in myelin and neurons is proposed.Maestrí

INNOVA Research Journal

El presente trabajo tiene por objetivo determinar la importancia del Órgano de Solución de Diferencias de la OMC dentro de las negociaciones sobre el acceso a los mercados internacionales. El área que se está investigando es el funcionamiento de la OMC especialmente, cómo esta resuelve las diferencias entre países, especialmente teniendo en cuenta el análisis de costo-beneficio que se incurre. La investigación se lleva a cabo a través de la revisión de fuentes primarias y secundarias con un enfoque cualitativo y comparativo así como perspectiva analítica y descriptiva. El resultado que se obtuvo después de estudiar dos casos específicamente en Ecuador, nos muestra cómo el organismo proporciona buenas oportunidades de desarrollo comercial a nivel mundial con ahorro de recursos. Se recomienda que los países hagan conciencia y permitan que estos organismos les asesoren al momento de tomar decisiones y resolver conflictos en búsqueda de un comercio más eficaz y eficiente

4to. Congreso Internacional de Ciencia, Tecnología e Innovación para la Sociedad. Memoria académica

Este volumen acoge la memoria académica de la Cuarta edición del Congreso Internacional de Ciencia, Tecnología e Innovación para la Sociedad, CITIS 2017, desarrollado entre el 29 de noviembre y el 1 de diciembre de 2017 y organizado por la Universidad Politécnica Salesiana (UPS) en su sede de Guayaquil. El Congreso ofreció un espacio para la presentación, difusión e intercambio de importantes investigaciones nacionales e internacionales ante la comunidad universitaria que se dio cita en el encuentro. El uso de herramientas tecnológicas para la gestión de los trabajos de investigación como la plataforma Open Conference Systems y la web de presentación del Congreso http://citis.blog.ups.edu.ec/, hicieron de CITIS 2017 un verdadero referente entre los congresos que se desarrollaron en el país. La preocupación de nuestra Universidad, de presentar espacios que ayuden a generar nuevos y mejores cambios en la dimensión humana y social de nuestro entorno, hace que se persiga en cada edición del evento la presentación de trabajos con calidad creciente en cuanto a su producción científica. Quienes estuvimos al frente de la organización, dejamos plasmado en estas memorias académicas el intenso y prolífico trabajo de los días de realización del Congreso Internacional de Ciencia, Tecnología e Innovación para la Sociedad al alcance de todos y todas

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Antimicrobial Lessons From a Large Observational Cohort on Intra-abdominal Infections in Intensive Care Units

evere intra-abdominal infection commonly requires intensive care. Mortality is high and is mainly determined by disease-specific characteristics, i.e. setting of infection onset, anatomical barrier disruption, and severity of disease expression. Recent observations revealed that antimicrobial resistance appears equally common in community-acquired and late-onset hospital-acquired infection. This challenges basic principles in anti-infective therapy guidelines, including the paradigm that pathogens involved in community-acquired infection are covered by standard empiric antimicrobial regimens, and second, the concept of nosocomial acquisition as the main driver for resistance involvement. In this study, we report on resistance profiles of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecalis and Enterococcus faecium in distinct European geographic regions based on an observational cohort study on intra-abdominal infections in intensive care unit (ICU) patients. Resistance against aminopenicillins, fluoroquinolones, and third-generation cephalosporins in E. coli, K. pneumoniae and P. aeruginosa is problematic, as is carbapenem-resistance in the latter pathogen. For E. coli and K. pneumoniae, resistance is mainly an issue in Central Europe, Eastern and South-East Europe, and Southern Europe, while resistance in P. aeruginosa is additionally problematic in Western Europe. Vancomycin-resistance in E. faecalis is of lesser concern but requires vigilance in E. faecium in Central and Eastern and South-East Europe. In the subcohort of patients with secondary peritonitis presenting with either sepsis or septic shock, the appropriateness of empiric antimicrobial therapy was not associated with mortality. In contrast, failure of source control was strongly associated with mortality. The relevance of these new insights for future recommendations regarding empiric antimicrobial therapy in intra-abdominal infections is discussed.Severe intra-abdominal infection commonly requires intensive care. Mortality is high and is mainly determined by diseasespecific characteristics, i.e. setting of infection onset, anatomical barrier disruption, and severity of disease expression. Recent observations revealed that antimicrobial resistance appears equally common in community-acquired and late-onset hospital-acquired infection. This challenges basic principles in anti-infective therapy guidelines, including the paradigm that pathogens involved in community-acquired infection are covered by standard empiric antimicrobial regimens, and second, the concept of nosocomial acquisition as the main driver for resistance involvement. In this study, we report on resistance profiles of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecalis and Enterococcus faecium in distinct European geographic regions based on an observational cohort study on intra-abdominal infections in intensive care unit (ICU) patients. Resistance against aminopenicillins, fluoroquinolones, and third-generation cephalosporins in E. coli, K. pneumoniae and P. aeruginosa is problematic, as is carbapenem-resistance in the latter pathogen. For E. coli and K. pneumoniae, resistance is mainly an issue in Central Europe, Eastern and South-East Europe, and Southern Europe, while resistance in P. aeruginosa is additionally problematic in Western Europe. Vancomycin-resistance in E. faecalis is of lesser concern but requires vigilance in E. faecium in Central and Eastern and South-East Europe. In the subcohort of patients with secondary peritonitis presenting with either sepsis or septic shock, the appropriateness of empiric antimicrobial therapy was not associated with mortality. In contrast, failure of source control was strongly associated with mortality. The relevance of these new insights for future recommendations regarding empiric antimicrobial therapy in intra-abdominal infections is discussed

Poor timing and failure of source control are risk factors for mortality in critically ill patients with secondary peritonitis

Purpose: To describe data on epidemiology, microbiology, clinical characteristics and outcome of adult patients admitted in the intensive care unit (ICU) with secondary peritonitis, with special emphasis on antimicrobial therapy and source control. Methods: Post hoc analysis of a multicenter observational study (Abdominal Sepsis Study, AbSeS) including 2621 adult ICU patients with intra-abdominal infection in 306 ICUs from 42 countries. Time-till-source control intervention was calculated as from time of diagnosis and classified into 'emergency' (< 2 h), 'urgent' (2-6 h), and 'delayed' (> 6 h). Relationships were assessed by logistic regression analysis and reported as odds ratios (OR) and 95% confidence interval (CI). Results: The cohort included 1077 cases of microbiologically confirmed secondary peritonitis. Mortality was 29.7%. The rate of appropriate empiric therapy showed no difference between survivors and non-survivors (66.4% vs. 61.3%, p = 0.1). A stepwise increase in mortality was observed with increasing Sequential Organ Failure Assessment (SOFA) scores (19.6% for a value ≤ 4-55.4% for a value > 12, p < 0.001). The highest odds of death were associated with septic shock (OR 3.08 [1.42-7.00]), late-onset hospital-acquired peritonitis (OR 1.71 [1.16-2.52]) and failed source control evidenced by persistent inflammation at day 7 (OR 5.71 [3.99-8.18]). Compared with 'emergency' source control intervention (< 2 h of diagnosis), 'urgent' source control was the only modifiable covariate associated with lower odds of mortality (OR 0.50 [0.34-0.73]). Conclusion: 'Urgent' and successful source control was associated with improved odds of survival. Appropriateness of empirical antimicrobial treatment did not significantly affect survival suggesting that source control is more determinative for outcome