Hypoxia-induced fatty acid transporter translocation increases fatty acid transport and contributes to lipid accumulation in the heart

AbstractProtein-mediated LCFA transport across plasma membranes is highly regulated by the fatty acid transporters FAT/CD36 and FABPpm. Physiologic stimuli (insulin stimulation, AMP kinase activation) induce the translocation of one or both transporters to the plasma membrane and increase the rate of LCFA transport. In the hypoxic/ischemic heart, intramyocardial lipid accumulation has been attributed to a reduced rate of fatty acid oxidation. However, since acute hypoxia (15min) activates AMPK, we examined whether an increased accumulation of intramyocardial lipid during hypoxia was also attributable to an increased rate of LCFA uptake as a result AMPK-induced translocation of FAT/CD36 and FABPpm. In cardiac myocytes, hypoxia (15min) induced the redistribution of FAT/CD36 from an intracellular pool (LDM) (−25%, P<0.05) to the plasma membranes (PM) (+54%, P<0.05). Hypoxia also induced an increase in FABPpm at the PM (+56%, P<0.05) and a concomitant FABPpm reduction in the LDM (−24%, P<0.05). Similarly, in intact, Langendorff perfused hearts, hypoxia induced the translocation of a both FAT/CD36 and FABPpm to the PM (+66% and +61%, respectively, P<0.05), with a concomitant decline in FAT/CD36 and FABPpm in the LDM (−24% and −23%, respectively, P<0.05). Importantly, the increased plasmalemmal content of these transporters was associated with increases in the initial rates of palmitate uptake into cardiac myocytes (+40%, P<0.05). Acute hypoxia also redirected palmitate into intracellular lipid pools, mainly to PL and TG (+48% and +28%, respectively, P<0.05), while fatty acid oxidation was reduced (−35%, P<0.05). Thus, our data indicate that the increased intracellular lipid accumulation in hypoxic hearts is attributable to both: (a) a reduced rate of fatty acid oxidation and (b) an increased rate of fatty acid transport into the heart, the latter being attributable to a hypoxia-induced translocation of fatty acid transporters

Bosutinib plus capecitabine for selected advanced solid tumours: results of a phase 1 dose-escalation study

Background: This phase 1 study evaluated the maximum tolerated dose (MTD), safety, and efficacy of bosutinib (competitive Src/Abl tyrosine kinase inhibitor) plus capecitabine. Methods: Patients with locally advanced/metastatic breast, pancreatic, or colorectal cancers; cholangiocarcinoma; or glioblastoma received bosutinib plus capecitabine at eight of nine possible dose combinations using an ‘up-down' design to determine the toxicity contour of the combination. Results: Among 32 enrolled patients, none of the 9 patients receiving MTD (bosutinib 300 mg once daily plus capecitabine 1000 mg m−2 twice daily) experienced dose-limiting toxicities (DLTs). Overall, 2 out of 31 (6%) evaluable patients experienced DLTs (grade 3 neurologic pain (n=1); grade 3 pruritus/rash and increased alanine aminotransferase (n=1)). Most common treatment-related adverse events (AEs) were diarrhoea, nausea, vomiting, palmar-plantar erythrodysesthesia (PPE), fatigue; most frequent grade 3/4 AEs: PPE, fatigue, and increased alanine/aspartate aminotransferase. Although diarrhoea was common, 91% of affected patients experienced maximum grade 1/2 events that resolved. Best overall confirmed partial response or stable disease >24 weeks (all tumour types) was observed in 6 and 13% of patients. Conclusions: In this population of patients with advanced solid tumours, bosutinib plus capecitabine demonstrated a safety profile similar to that previously reported for bosutinib or capecitabine monotherapy; limited efficacy was observed

Use of Silver Nanoparticles as Tougheners of Alumina Ceramics

In this work, alumina/silver composites were produced through powder techniques, which involve the combination of high energy mechanical milling combined with sintering in the presence of a liquid phase and with the idea of having ceramics with good toughness values. From mechanical characterizations, it was found that increases of the silver content in the alumina origins decrease the elastic’s modulus and flexural strength of the final composite. The fracture toughness of alumina increases from 4.2 MPam−0.5 for monolithic alumina to 10 MPam−0.5 for alumina with 2 wt% silver additions. It was determined that the reinforcement mechanism of these materials is due to the deflection of cracks owing to metallic bridges formed by the silver used as toughener material

Density functional electronic spectrum of the CuO−6−10Cu O_{-6}^{-10} cluster and possible local Jahn-Teller distorsions in the La-Ba-Cu-O superconductor

We present a density functional theory (DFT) calculation in the generalized gradient approximation to study the possibility for the existence of Jahn-Teller (JT) or pseudo Jahn-Teller (PJT) type local distortions in the La-Ba-Cu-O superconducting system. We performed the calculation and correspondingly group theory classification of the electronic ground state of the CuO${_{6}}^{-10}$ elongated octahedra cluster, immersed in a background simulating the superconductor. Part of the motivation to do this study is that the origin of the apical deformation of the CuO${_{6}}^{-10}$ cluster is not due to a pure JT effect, having therefore a non {\it a priori} condition to remove the degeneracy of the electronic ground state of the parent regular octahedron. We present a comparative analysis of the symmetry classified electron spectrum with previously reported results using unrestricted Hartree-Fock calculations (UHF). Both the DFT and UHF calculations produced a non degenerate electronic ground state, not having therefore the necessary condition for a pure JT effect. However, the appearance of a degenerate E$_{g}$ state near to the highest occupied molecular orbital in the DFT calculation, suggests the possibility for a PJT effect responsible for a local distortion of the oxidized CuO$_{6}^{-9}$ cluster.Comment: 12 pages, 3 figures, submitted to International Journal of Modern Physics B (IJMPB

Plan de Erradicación de la Poliomielitis. Vigilancia de Parálisis Flácida Aguda. España, 2013

Pese a los enormes avances conseguidos hacia la erradicación mundial de la poliomielitis, aún quedan tres países con circulación endémica de poliovirus salvaje y brotes de polio paralítica en áreas previamente libres de polio, como Siria y varios países de África. Debido a esto la Organización Mundial de la salud (OMS) ha declarado que la extensión internacional de la transmisión del poliovirus salvaje, es un Evento de Salud Pública de Importancia Internacional (ESPII) y que para su control se necesita una repuesta internacional coordinada. En las zonas del mundo ya declaradas libres de polio (Europa 2002) hay que asegurar altos niveles de inmunidad en la población, mantener sistemas de vigilancia eficaces y planes nacionales de respuesta capaces de interrumpir la transmisión tras una eventual importación del virus de la polio. Además, en una situación de dispersión internacional, la vacunación y el control de viajeros procedentes de zonas del mundo con casos de polio cobra especial importancia. En este contexto y debido al flujo de personas entre España y zonas el mundo donde hay circulación de poliovirus, no se puede descartar la reintroducción del virus en nuestro país. Aunque las altas coberturas de vacunación reducen el riesgo de transmisión, hay que mantener activos los sistemas de vigilancia de poliovirus, particularmente la vigilancia de PFA, para poder identificar importaciones y establecer a tiempo medidas de control

Biases in study design, implementation, and data analysis that distort the appraisal of clinical benefit and ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) scoring

BACKGROUND: The European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a validated, widely used tool developed to score the clinical benefit from cancer medicines reported in clinical trials. ESMO-MCBS scores assume valid research methodologies and quality trial implementation. Studies incorporating flawed design, implementation, or data analysis may generate outcomes that exaggerate true benefit and are not generalisable. Failure to either indicate or penalise studies with bias undermines the intention and diminishes the integrity of ESMO-MCBS scores. This review aimed to evaluate the adequacy of the ESMO-MCBS to address bias generated by flawed design, implementation, or data analysis and identify shortcomings in need of amendment. METHODS: As part of a refinement of the ESMO-MCBS, we reviewed trial design, implementation, and data analysis issues that could bias the results. For each issue of concern, we reviewed the ESMO-MCBS v1.1 approach against standards derived from Helsinki guidelines for ethical human research and guidelines from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, the Food and Drugs Administration, the European Medicines Agency, and European Network for Health Technology Assessment. RESULTS: Six design, two implementation, and two data analysis and interpretation issues were evaluated and in three, the ESMO-MCBS provided adequate protections. Seven shortcomings in the ability of the ESMO-MCBS to identify and address bias were identified. These related to (i) evaluation of the control arm, (ii) crossover issues, (iii) criteria for non-inferiority, (iv) substandard post-progression treatment, (v) post hoc subgroup findings based on biomarkers, (vi) informative censoring, and (vii) publication bias against quality-of-life data. CONCLUSION: Interpretation of the ESMO-MCBS scores requires critical appraisal of trials to understand caveats in trial design, implementation, and data analysis that may have biased results and conclusions. These will be addressed in future iterations of the ESMO-MCBS.SCOPUS: re.jinfo:eu-repo/semantics/publishe

The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study

Objectives To investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin (haemoglobin A1C) achieved during therapy

Vigilancia de Parálisis Flácida Aguda. España, 2011

Desde que en el año 2002 Europa recibiera la certificación de Región Libre de Polio, no han cesado los esfuerzos para mejorar las coberturas de vacunación y evitar que se relaje la vigilancia de la Parálisis Flácida Aguda (PFA). El importante brote de polio que se registró en Tayikistán en el año 2010 puso de manifiesto la necesidad real de alerta ante la importación de poliovirus. Todo apunta, no obstante, a que el éxito para conseguir el objetivo de erradicación de la polio, no sólo radica en las cuestiones técnicas, sino también en el compromiso veraz de todas las partes involucradas. A nivel mundial, el número de casos de polio ha descendido en un 99%, pasando de 350.000 casos notificados en más de 150 países en 1988 a 650 casos declarados en 2011. En la actualidad sólo algunas zonas de tres países (Afganistán, Nigeria y Pakistán) se consideran endémicas de polio, lo que supone que la polio está geográficamente más confinada que nunca. En España, desde el año 1996 las coberturas de vacunación frente a polio son superiores al 90% en todas las regiones; en 2011 la cobertura nacional para la serie primaria con vacuna de polio fue 97,1% (rango 92,6% - 100%). En 2011 el sistema de vigilancia de la PFA ha mantenido los estándares de calidad en cuanto a la investigación epidemiológica y al estudio en el laboratorio de los casos notificados, sin embargo la sensibilidad en la identificación de casos está por debajo de la esperada

Vigilancia del Sarampión, Rubéola y Síndrome de Rubéola Congénita. España 2011

Entre 2010 y 2012 España, igual que otros países europeos, ha sufrido una onda epidémica de sarampión; se han registrado las mayores incidencias desde que se implantó el Plan Nacional de Eliminación de Sarampión: 0,66 casos/100.000 habitantes en 2010, 7,45/100.000 habitantes en 2011 y 2,54/100.00 habitantes en 2012. En 2011 se notificaron 3.518 casos confirmados de sarampión; los niños < 4 años y los adultos jóvenes (20-29 años) han sido los más afectados; la mayoría de los casos (96 %) estaban sin vacunar o mal vacunados. Grupos de niños mal vacunados y profesionales sanitarios sin inmunizar han tenido mucha importancia en la generación y difusión de los brotes. Los países de la Región Europea de la Organización Mundial de la Salud (OMS), están inmersos en la última fase del proceso con el objetivo de interrumpir la circulación del sarampión y de la rubéola endémicos en la región en 2015. El avance hacia la eliminación se conseguirá si se mantiene la calidad del sistema de vigilancia y se mantienen altas coberturas de vacunación (> 95 %) con dos dosis de vacuna triple vírica en todos los niveles geográficos y grupos de población; establecer recordatorios sistemáticos para las dosis del calendario de vacunación infantil y asegurar que los profesionales sanitarios se vacunen son intervenciones eficaces para evitar que un caso importado origine un brote cuando el sarampión y la rubéola están próximos a la eliminación

The relationship between maternal education and mortality among women giving birth in health care institutions: Analysis of the cross sectional WHO Global Survey on Maternal and Perinatal Health

Background: Approximately one-third of a million women die each year from pregnancy-related conditions. Three-quarters of these deaths are considered avoidable. Millennium Development Goal five calls for a reduction in maternal mortality and the establishment of universal access to high quality reproductive health care. There is evidence of a relationship between lower levels of maternal education and higher maternal mortality. This study examines the relationship between maternal education and maternal mortality among women giving birth in health care institutions and investigates the association of maternal age, marital status, parity, institutional capacity and state-level investment in health care with these relationships.Methods: Cross-sectional information was collected on 287,035 inpatients giving birth in 373 health care institutions in 24 countries in Africa, Asia and Latin America, between 2004-2005 (in Africa and Latin America) and 2007-2008 (in Asia) as part of the WHO Global Survey on Maternal and Perinatal Health. Analyses investigated associations between indicators measured at the individual, institutional and country level and maternal mortality during the intrapartum period: from admission to, until discharge from, the institution where women gave birth. There were 363 maternal deaths.Results: In the adjusted models, women with no education had 2.7 times and those with between one and six years of education had twice the risk of maternal mortality of women with more than 12 years of education. Institutional capacity was not associated with maternal mortality in the adjusted model. Those not married or cohabiting had almost twice the risk of death of those who were. There was a significantly higher risk of death among those aged over 35 (compared with those aged between 20 and 25 years), those with higher numbers of previous births and lower levels of state investment in health care. There were also additional effects relating to country of residence which were not explained in the model.Conclusions: Lower levels of maternal education were associated with higher maternal mortality even amongst women able to access facilities providing intrapartum care. More attention should be given to the wider social determinants of health when devising strategies to reduce maternal mortality and to achieve the increasingly elusive MDG for maternal mortality