Kv1.3 channels can modulate cell proliferation during phenotypic switch by an ion-flux independent mechanism

Producción CientíficaObjective: Phenotypic modulation of vascular smooth muscle cells has been associated with a decreased expression of all voltage-dependent potassium channel (Kv)1 channel encoding genes but Kcna3 (which encodes Kv1.3 channels). In fact, upregulation of Kv1.3 currents seems to be important to modulate proliferation of mice femoral vascular smooth muscle cells in culture. This study was designed to explore if these changes in Kv1 expression pattern constituted a landmark of phenotypic modulation across vascular beds and to investigate the mechanisms involved in the proproliferative function of Kv1.3 channels. Methods and Results: Changes in Kv1.3 and Kv1.5 channel expression were reproduced in mesenteric and aortic vascular smooth muscle cells, and their correlate with protein expression was electrophysiologicaly confirmed using selective blockers. Heterologous expression of Kv1.3 and Kv1.5 channels in HEK cells has opposite effects on the proliferation rate. The proproliferative effect of Kv1.3 channels was reproduced by “poreless” mutants but disappeared when voltagedependence of gating was suppressed. Conclusion: These findings suggest that the signaling cascade linking Kv1.3 functional expression to cell proliferation is activated by the voltage-dependent conformational change of the channels without needing ion conduction. Additionally, the conserved upregulation of Kv1.3 on phenotypic modulation in several vascular beds makes this channel a good target to control unwanted vascular remodeling.Instituto de Salud Carlos III (grant R006/009)Ministerio de Ciencia, Innovación y Universidades (grant BFU2010-15898)Junta de Castilla y León (grant VA094A11-2

Changes in Day/Night Activity in the 6-OHDA-Induced Experimental Model of Parkinson's Disease: Exploring Prodromal Biomarkers.

The search for experimental models mimicking an early stage of Parkinson's disease (PD) before motor manifestations is fundamental in order to explore early signs and get a better prognosis. Interestingly, our previous studies have indicated that 6-hydroxydopamine (6-OHDA) is a suitable model to induce an early degeneration of the nigrostriatal system without any gross motor impairment. Considering our previous findings, we aim to implement a novel system to monitor rats after intrastriatal injection of 6-OHDA to detect and analyze physiological changes underlying prodromal PD. Twenty male Sprague-Dawley rats were unilaterally injected with 6-OHDA (n = 10) or saline solution (n = 10) into the right striatum and placed in enriched environment cages where the activity was monitored. After 2 weeks, the amphetamine test was performed before the sacrifice. Immunohistochemistry was developed for the morphological evaluation and western blot analysis to assess molecular changes. Home-cage monitoring revealed behavioral changes in response to 6-OHDA administration including significant hyperactivity and hypoactivity during the light and dark phase, respectively, turning out in a change of the circadian timing. A preclinical stage of PD was functionally confirmed with the amphetamine test. Moreover, the loss of tyrosine hydroxylase expression was significantly correlated with the motor results, and 6-OHDA induced early proapoptotic events. Our findings provide evidence for a novel prodromal 6-OHDA model following a customized monitoring system that could give insights to detect non-motor deficits and molecular targets to test neuroprotective/neurorestorative agents

Relationship between Retinal Microvasculature, Cardiovascular Risk and Silent Brain Infarction in Hypertensive Patients

Objective: The aims of this study are to analyze the role of artery-vein ratio AVR assessment using VesselMap 2 software (Imedos Systems) and cardiovascular risk evaluation by means of REGICOR in the prediction of silent brain infarction (SBI) in middle-age hypertensive patients from the ISSYS study. Material and Methods: A cross-sectional study with 695 patients with hypertension aged 50 to 70 years who participated in the project Investigating Silent Strokes in HYpertensives: a Magnetic Resonance Imaging Study (ISSYS), was conducted in two Primary Care Centres of Barcelona. Participants agreed to a retinography and an MRI to detect silent brain infarction (SBI). The IMEDOS software was used for the semiautomatic caliber measurement of retinal arteries and veins, and the AVR was considered abnormal when <0.66. The REGICOR score was calculated for all patients. Results: Multivariate logistic regression analysis was used to evaluate the impact of AVR and REGICOR scores on SBI. The OR (odds ratio) for a high REGICOR score and an abnormal AVR were 3.16 and 4.45, respectively. When analysing the interaction of both factors, the OR of an abnormal AVR and moderate REGICOR score was 3.27, whereas with a high REGICOR score it reached 13.07. Conclusions: The measurement of AVR in patients with hypertension and with a high REGICOR score can contribute to the detection of silent brain infarction

Novel deep targeted sequencing method for minimal residual disease monitoring in acute myeloid leukemia

A high proportion of patients with acute myeloid leukemia who achieve minimal residual disease (MRD) negative status ultimately relapse because a fraction of pathological clones remains undetected by standard methods. We designed and validated a high-throughput sequencing method for MRD assessment of cell clonotypes with mutations of NPM1, IDH1/2 and/or FLT3-SNVs. For clinical validation, 106 follow-up samples from 63 patients in complete remission were studied by NGS, evaluating the level of mutations detected at diagnosis. The predictive value of MRD status by NGS, multiparameter flow cytometry, or quantitative PCR was determined by survival analysis. The method achieved a sensitivity of 10-4 for SNV mutations and 10-5 for insertions/deletions and could be used in acute myeloid leukemia patients who carry any mutation (86% in our diagnosis data set). NGS-determined MRD positive status was associated with lower disease-free survival (hazard ratio [HR] 3.4, p=0.005) and lower overall survival (HR 4.2, p<0.001). Multivariate analysis showed that MRD positive status by NGS was an independent factor associated with risk of death (HR 4.54, p =0.005) and the only independent factor conferring risk of relapse (HR 3.76, p =0.012). This NGS based method simplifies and standardizes MRD evaluation, with high applicability in acute myeloid leukemia. It also improves upon flow cytometry and quantitative PCR to predict acute myeloid leukemia outcome and could be incorporated in clinical settings and clinical trials.This study was supported by the Subdirección General de Investigación Sanitaria (Instituto de Salud Carlos III, Spain) grants PI13/02387 and PI16/01530, and the CRIS against Cancer foundation grant 2014/0120. M.L. holds a postdoctoral fellowship of the Spanish Ministry of Economy and Competitiveness (FPDI-2013-16409). P.R.P. holds a postdoctoral fellowship of the Spanish of Instituto de Salud Carlos III: Contrato Predoctoral de Formación en Investigación en Salud i-PFIS (IFI 14/00008).S

Changes in Day/Night Activity in the 6-OHDA-Induced Experimental Model of Parkinson’s Disease: Exploring Prodromal Biomarkers

The search for experimental models mimicking an early stage of Parkinson's disease (PD) before motor manifestations is fundamental in order to explore early signs and get a better prognosis. Interestingly, our previous studies have indicated that 6-hydroxydopamine (6-OHDA) is a suitable model to induce an early degeneration of the nigrostriatal system without any gross motor impairment. Considering our previous findings, we aim to implement a novel system to monitor rats after intrastriatal injection of 6-OHDA to detect and analyze physiological changes underlying prodromal PD. Twenty male Sprague-Dawley rats were unilaterally injected with 6-OHDA (n = 10) or saline solution (n = 10) into the right striatum and placed in enriched environment cages where the activity was monitored. After 2 weeks, the amphetamine test was performed before the sacrifice. Immunohistochemistry was developed for the morphological evaluation and western blot analysis to assess molecular changes. Home-cage monitoring revealed behavioral changes in response to 6-OHDA administration including significant hyperactivity and hypoactivity during the light and dark phase, respectively, turning out in a change of the circadian timing. A preclinical stage of PD was functionally confirmed with the amphetamine test. Moreover, the loss of tyrosine hydroxylase expression was significantly correlated with the motor results, and 6-OHDA induced early proapoptotic events. Our findings provide evidence for a novel prodromal 6-OHDA model following a customized monitoring system that could give insights to detect non-motor deficits and molecular targets to test neuroprotective/neurorestorative agents.This study has been financially supported by the University of the Basque Country (UPV/EHU) PPG 17/51 and GIU 092/19, the Basque Government (Saiotek SA-2010/00028, ELEKIN, Engineering and Society and Bioengineering, and ELKARTEK 18/99), "Ministerio de Ciencia e Innovacion" (SAF2016 77758 R), FEDER funds, the European Union COST Action (CA15225, CA18106), DomusVi Foundation (FP18/76), and Government of Gipuzkoa (HELENA: Multisensory stimulation tools for Alzheimer Disease). CR appreciates the previous economic support received from UPV/EHU and the current postdoctoral fellowship received from Alfonso Martin Escudero Foundation

Guía de práctica clínica SENPE/SEGHNP/SEFH sobre nutrición parenteral pediátrica

Introduction: Parenteral nutrition (PN) in childhood is a treatment whose characteristics are highly variable depending on the age and pathology of the patient. Material and methods: The Standardization and Protocols Group of the Spanish Society for Parenteral and Enteral Nutrition (SENPE) is an interdisciplinary group formed by members of the SENPE, the Spanish Society of Gastroenterology, Hepatology and Pediatric Nutrition (SEGHNP) and the Spanish Society of Hospital Pharmacy (SEFH) that intends to update this issue. For this, a detailed review of the literature has been carried out, looking for the evidences that allow us to elaborate a Clinical Practice Guide following the criteria of the Oxford Center for Evidence-Based Medicine. Results: This manuscript summarizes the recommendations regarding indications, access routes, requirements, modifications in special situations, components of the mixtures, prescription and standardization, preparation, administration, monitoring, complications and home NP. The complete document is published as a monographic number. Conclusions: This guide is intended to support the prescription of pediatric PN. It provides the basis for rational decisions in the context of the existing evidence. No guidelines can take into account all of the often compelling individual clinical circumstances.Introducción: la nutrición parenteral (NP) en la infancia es un tratamiento cuyas características son muy variables en función de la edad y la patología que presente el paciente. Material y métodos: el grupo de Estandarización y Protocolos de la Sociedad Española de Nutrición Parenteral y Enteral (SENPE) es un grupo interdisciplinar formado por miembros de la SENPE, Sociedad Española de Gastroenterología, Hepatología y Nutrición Pediátrica (SEGHNP) y Sociedad Española de Farmacia Hospitalaria (SEFH) que pretende poner al día este tema. Para ello, se ha realizado una revisión pormenorizada de la literatura buscando las evidencias que nos permiten elaborar una Guía de Práctica Clínica siguiendo los criterios del Oxford Centre for Evidence-Based Medicine. Resultados: este manuscrito expone de forma resumida las recomendaciones en cuanto a indicaciones, vías de acceso, requerimientos, modificaciones en situaciones especiales, componentes de las mezclas, prescripción y estandarización, preparación, administración, monitorización, complicaciones y NP domiciliaria. El documento completo se publica como número monográfico. Conclusiones: esta guía pretende servir de apoyo para la prescripción de la NP pediátrica. Constituye la base para tomar decisiones en el contexto de la evidencia existente. Ninguna guía puede tener en cuenta todas las circunstancias clínicas individuale

Gender inequalities in research in public health and epidemiology in Spain (2007-2014)

Objetivo: Analizar las desigualdades de género en investigación en salud pública y epidemiología en España, en el periodo 2007-2014. Método: Estudio descriptivo según sexo de posiciones de liderazgo del Centro de Investigación Biomédica en Red (CIBER), especialmente en el área temática de epidemiología y salud pública (CIBERESP) en 2014; de sociedades científicas de salud pública (SESPAS) y epidemiología (SEE), 2009-2014; y de proyectos de investigación solicitados (13.320) y financiados (4699), e importes de convocatorias de Acción Estratégica en Salud (AES), 2007-2013. Resultados: Existe una clara infrarrepresentación de mujeres líderes y contratadas en investigación de excelencia en salud pública (CIBERESP), con predominio de los hombres en puestos de decisión. Aunque los proyectos de investigación de la Acción Estratégica en Salud (AES) liderados por mujeres han crecido ligeramente entre 2007 y 2013, entre los solicitados no alcanzan el 50%, con excepción de los de la Comisión de Salud Pública. La brecha de género es aún mayor en proyectos financiados. Los proyectos liderados por hombres tienen mayor probabilidad de obtener financiación, alcanzando el 29% en los de salud pública. Persiste una segregación horizontal de género en posiciones de reconocimiento científico en congresos de SESPAS y SEE. Conclusiones: La sobrerrepresentación de líderes masculinos en la investigación en salud pública en España debe entenderse como indicador y consecuencia del androcentrismo en las sociedades científicas y los grupos profesionales. Esta situación sexista pone en riesgo la existencia de productos y servicios innovadores desde la perspectiva de género que den respuestas a necesidades y demandas de toda la sociedad. Se necesitan más mujeres en investigación que tengan incorporada esta perspectiva.Objective: To analyse gender inequalities in research on public health and epidemiology in Spain for the period 2007-2014. Method: A descriptive study was conducted by sex of leadership positions in the Centre for Biomedical Research Network (CIBER), especially in the subject area of epidemiology and public health (CIBERESP) in 2014; scientific societies of public health (SESPAS) and epidemiology (SEE) 2009-2014; research projects requested (13,320) and financed (4,699), and monetary amounts of calls for Strategic Action in Health (AES), 2007-2013. Results: Women were clearly under-represented in positions of leadership and in research excellence in public health (CIBER), with a predominance of men in decision-making positions. Although research projects led by women in AES increased slightly between 2007 and 2013, among proposed projects this figure was less than 50%, with the exception of the public health commission. The gender gap was even greater in funded projects. Projects led by men were more likely to be funded, representing 29% in public health. There was also a persistence of horizontal gender segregation in positions of scientific recognition in the SESPAS and SEE Congresses. Conclusions: The overrepresentation of male leaders in public health research in Spain can be understood as an indicator and a consequence of androcentrism in scientific societies and professional groups. This sexist situation threatens the existence of innovative products and services from a gender perspective that respond to the needs and demands of society as a whole. More women are needed in research incorporating this perspective.Este trabajo ha recibido financiación parcial de la Acción Estratégica en Salud del Instituto de Salud Carlos III (Exp. PI12/00498) y Fondos FEDER