Alteraciones histológicas y mecanismos de fibrosis en las lesiones varicosas de la vena safena interna: Estudio inmunohistoquímico, molecular y de microscopía confocal

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Anatomía Patológica. Fecha de lectura: 23-11-201

Effect of Peruvian maca (Lepidium meyenii) and melatonin on testicular development of mice exposed to continuous hypobaric hypoxia

El estudio de la hipoxia hipobárica (HH) determina un problema de salud pública y laboral en poblaciones que habitan en zonas de altura. La disminución del oxígeno afecta a diferentes órganos, incluyendo el testículo. El organismo responde frente a la hipoxia estimulando la angiogénesis, el flujo sanguíneo testicular e incrementa la temperatura intraescrotal, lo cual produce un daño de la espermatogénesis. Nuestro estudio valoró el efecto que produce la HH sobre el testículo del ratón. Se utilizó una cámara hipobárica regulada a 4.200 metros sobre el nivel del mar (msnm), en periodos de hipoxia durante 8,3; 16,6 y 24,9 días, en comparación a un grupo control en normoxia (500 msnm). En estos tres grupos, a unos ratones se administró melatonina, a otros maca (Lepidium meyenii) y a otros la combinación de melatonina y maca. Los objetivos fueron evaluar si la ingesta de maca protege al testículo, reduciendo el daño generado por la hipoxia, y determinar un posible efecto sinérgico de la melatonina y de la maca. La exposición a HH continua produjo una disminución del diámetro de los túbulos seminíferos y del lumen tubular; además, el seminograma demostró una reducción del recuento espermático, un aumento de la teratozoospermia y una reducción de la calidad del ADN espermático. La administración de maca aislada o la combinación de maca y melatonina en animales sometidos a HH produjo una notable mejoría de los parámetros relacionados con la función de los espermatozoides, siendo significativos la disminución del número de espermatozoides con morfología anormal y de la compactación del DNA, alcanzando en algunos casos valores próximos a los de los animales normóxicos. Los datos del presente modelo de HH corroboran los excelentes beneficios que la ingesta de maca tiene sobre la capacidad reproductiva de poblaciones que viven en áreas geográficas de grandes alturasHypobaric hypoxia (HH) is a decisive factor in human health in populations that reside at high altitude levels. Low oxygen rate affects most tissues and organs, including the testis. In humans, hypoxia stimulates angiogenesis, testicular blood flow and increases intrascrotal temperature which determines negative effects on sperm production. Our study researched the effects of HH in mice testicle. Mice were housed in a hypobaric chamber with a setting at 4,200 m above sea level during three different periods of hypoxia (8.3, 16.6 and 24.9 days). Control groups were housed at normoxic conditions (500 m above sea level). Hypoxic mice were treated with melatonin, maca plant (Lepidium meyenii) and melatonin and maca combination. The aim of present study was to determine if maca consumption protects testis against harmful effects of hypoxia and to determine a possible synergistic effect between melatonin and maca administration. In this article we have demonstrated that hypoxia produces a considerable decrease of seminiferous tubules diameter and lumen diameter. Moreover, seminogram showed a reduced sperm count, increased teratozoospermia and a reduction of DNA quality. The HH mice treatment with maca or maca-melatonin combination showed statistically significant improvement at sperm function parameters, and in the reduction of sperm morphology abnormalities and DNA compaction, in some cases attaining rates closer to those registered in normoxic mice. Our experimental data corroborates that maca consumption improves reproductive capacity of populations that inhabit high altitude regionsEste trabajo fue financiado por la Universidad de Tarapacá (Arica, Chile) Proyecto Mayor de Investigación Científica y Tecnológica UTA, código 4711-13

Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses

TGF-β, the most potent profibrogenic factor, acts by activating SMAD (mothers against decapentaplegic) transcription factors, which bind to SMAD-binding elements in target genes. Here, we show that the thyroid hormone triiodothyronine (T3), through binding to its nuclear receptors (TRs), is able to antagonize transcriptional activation by TGF-β/SMAD. This antagonism involves reduced phosphorylation of SMADs and a direct interaction of the receptors with SMAD3 and SMAD4 that is independent of T3-mediated transcriptional activity but requires residues in the receptor DNA binding domain. T3 reduces occupancy of SMADbinding elements in response to TGF-β, reducing histone acetylation and inhibiting transcription. In agreement with this transcriptional cross-talk, T3 is able to antagonize fibrotic processes in vivo. Liver fibrosis induced by carbon tetrachloride is attenuated by thyroid hormone administration to mice, whereas aged TR knockout mice spontaneously accumulate collagen. Furthermore, skin fibrosis induced by bleomycin administration is also reduced by the thyroid hormones. These findings define an important function of the thyroid hormone receptors and suggest TR ligands could have beneficial effects to block the progression of fibrotic diseases.This work was supported by Grants BFU2011-28058 and BFU2014-53610P from Ministerio de Economía y Competitividad; S2011/BMD-2328 TIRONET from the Comunidad de Madrid; and RD12/0036/0030 from the Instituto de Salud Carlos III. The cost of this publication has been paid in part by FEDER fund

Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis

Nuclear corepressor 1 (NCoR) associates with nuclear receptors and other transcription factors leading to transcriptional repression. We show here that NCoR depletion enhances cancer cell invasion and increases tumor growth and metastatic potential in nude mice. These changes are related to repressed transcription of genes associated with increased metastasis and poor prognosis in patients. Strikingly, transient NCoR silencing leads to heterochromatinization and stable silencing of the NCoR gene, suggesting that NCoR loss can be propagated, contributing to tumor progression even in the absence of NCoR gene mutations. Down-regulation of the thyroid hormone receptor β1 (TRβ) appears to be associated with cancer onset and progression. We found that expression of TRβ increases NCoR levels and that this induction is essential in mediating inhibition of tumor growth and metastasis by this receptor. Moreover, NCoR is down-regulated in human hepatocarcinomas and in the more aggressive breast cancer tumors, and its expression correlates positively with that of TRβ. These data provide a molecular basis for the anticancer actions of this corepressor and identify NCoR as a potential molecular target for development of novel cancer therapiesThis work was supported by Grants BFU2011-28058 and BFU2014-53610-P from Ministerio de Economía y Competitividad; Grant S2011/BMD-2328 from the Comunidad de Madrid; Grant RD12/0036/0030 from the Instituto de Salud Carlos III (to A.A.); Grants PI080971 and RD12 0036/0064 from the Instituto de Salud Carlos III (to J.P.); and Grant PI12/00386 from the Instituto de Salud Carlos III (to I.I.d.C.). O.A.M.-I. is supported by an Asociación Española Contra el Cáncer contrac

Circadian rhythms regulate the environmental responses of net CO2 exchange in bean and cotton canopies

Studies on the dependence of the rates of ecosystem gas exchange on environmental parameters often rely on the up-scaling of leaf-level response curves ('bottom-up' approach), and/or the down-scaling of ecosystem fluxes ('top-down' approach), where one takes advantage of the natural diurnal covariation between the parameter of interest and photosynthesis rates. Partly independent from environmental variation, molecular circadian clocks drive ∼24 h oscillations in leaf-level photosynthesis, stomatal conductance and other physiological processes in plants under controlled laboratory conditions. If present and of sufficient magnitude at ecosystem scales, circadian regulation could lead to different results when using the bottom-up approach (where circadian regulation exerts a negligible influence over fluxes because the environment is modified rapidly) relative to the top-down approach (where circadian regulation could affect fluxes as it requires the passage of a few hours). Here we dissected the drivers of diurnal net CO2 exchange in canopies of an annual herb (bean) and of a perennial shrub (cotton) through a set of experimental manipulations to test for the importance of circadian regulation of net canopy CO2 exchange, relative to that of temperature and vapor pressure deficit, and to understand whether circadian regulation could affect the derivation of environmental flux dependencies. Contrary to conventional wisdom, we observed how circadian regulation exerted controls over net CO2 exchange that were of similar magnitude to the controls exerted by direct physiological responses to temperature and vapor pressure deficit. Diurnal patterns of net CO2 exchange could only be explained by considering effects of environmental responses combined with circadian effects. Consequently, we observed significantly different results when inferring the dependence of photosynthesis over temperature and vapor pressure deficit when using the top-down and the bottom up approaches.We remain indebted to E. Gerardeau, D. Dessauw, J. Jean, P. Prudent (Aïda CIRAD), J.-J. Drevon, C. Pernot (Eco&Sol INRA), B. Buatois, A. Rocheteau (CEFE CNRS), A. Pra, A. Mokhtar and the full Ecotron team, in particular C. Escape, for outstanding technical assistance during experiment set-up, plant cultivation and measurements. Earlier versions of the manuscript benefitted from comments by M. Dietze, B. Medlyn, R. Duursma and Y.-S. Lin. This study benefited from the CNRS human and technical resources allocated to the ECOTRONS Research Infrastructures as well as from the state allocation ‘Investissement d'Avenir’ ANR-11-INBS-0001, ExpeER Transnational Access program, Ramón y Cajal fellowships (RYC-2012-10970 to VRD and RYC-2008-02050 to JPF), the Erasmus Mundus Master Course Mediterranean Forestry and Natural Resources Management (MEDfOR) and internal grants from UWS-HIE to VRD and ZALF to AG. We thank the Associate Editor T. Vesala and two anonymous reviewers for their help to improve this manuscript

Historia de la RAMSA. 50º aniversario (1971-2021)

Libro conmemorativo de los 50 años de existencia de la Real Academia de Medicina de Salamanca, donde se recogen todas las actividades llevadas a cabo durante ese tiempo, los premios concedidos, los miembros elegidos, etc., así como se gestó su nacimiento en el contexto de la existencia de otras academias médicas.Universidad de Salamanc

Night and day - Circadian regulation of night-time dark respiration and light-enhanced dark respiration in plant leaves and canopies

The potential of the vegetation to sequester C is determined by the balance between assimilation and respiration. Respiration is under environmental and substrate-driven control, but the circadian clock might also contribute. To assess circadian control on night-time dark respiration (RD) and on light enhanced dark respiration (LEDR) - the latter providing information on the metabolic reorganization in the leaf during light-dark transitions - we performed experiments in macrocosms hosting canopies of bean and cotton. Under constant darkness (plus constant air temperature and air humidity), we tested whether circadian regulation of RD scaled from leaf to canopy respiration. Under constant light (plus constant air temperature and air humidity), we assessed the potential for leaf-level circadian regulation of LEDR. There was a clear circadian oscillation of leaf-level RD in both species and circadian patterns scaled to the canopy. LEDR was under circadian control in cotton, but not in bean indicating species-specific controls. The circadian rhythm of LEDR in cotton might indicate variable suppression of the normal cyclic function of the tricarboxylic-acid-cycle in the light. Since circadian regulation is assumed to act as an adaptive memory to adjust plant metabolism based on environmental conditions from previous days, circadian control of RD may help to explain temporal variability of ecosystem respiration.This study benefited from the CNRS human and technical resources allocated to the ECOTRONS Research Infrastructures as well as from the state allocation ‘Investissement d'Avenir’ AnaEE-France ANR-11-INBS-0001, ExpeER Transnational Access program, Ramón y Cajal fellowships (RYC-2012-10970 to VRD and RYC-2008-02050 to JPF), the Erasmus Mundus Master Course MEDfOR, internal grants from UWS-HIE to VRD and ZALF to AG and Juan de la Cierva-fellowships (IJCI-2014-21393 to JGA). We remain indebted to E. Gerardeau, D. Dessauw, J. Jean, P. Prudent (Aïda CIRAD), J.-J. Drevon, C. Pernot (Eco&Sol INRA), B. Buatois, A. Rocheteau (CEFE CNRS), A. Pra, A. Mokhtar and the full Ecotron team, in particular C. Escape, for outstanding technical assistance

Imprime escultura en 3D

Catálogo de la exposición de mismo nombre que tuvo lugar en el Hall del Salón de Actos de la Facultad de Bellas Artes de la Universidad Complutense de Madrid del 20 de febrero al 6 de marzo de 2019. Artistas Participantes: Camacho Pérez, Rigoberto; De Domingo Murillo, Juan José; Espinel Velasco, José Carlos ; Fanelli, Yaiza; García Peco, Víctor; Garzón Arenas, Nerea; Groba, Iria ; Hernández Tadeo, Mauro; Jiménez Sánchez-Tirado, Gabriel;López Pastor, César ; Martín, David ;Pozas Pérez, Miguel; Terrón Manrique, Pedro Ánge

Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.J.P.L.’s lab is sponsored by Grant PID2020-118527RB-I00 funded by MCIN/AEI/10.13039/ 501100011039; Grant PDC2021-121735-I00 funded by MCIN/AEI/10.13039/501100011039 and by the “European Union Next Generation EU/PRTR”, the Regional Government of Castile and León (CSI144P20). J.P.L. and P.L.S. are supported by the Carlos III Health Institute (PIE14/00066). AGN laboratory and human patients’ studies are supported by an ISCIII project grant (PI18/01242). The Human Genotyping unit is a member of CeGen, PRB3, and is supported by grant PT17/0019 of the PE I + D + i 2013–2016, funded by ISCIII and ERDF. SCLl is supported by MINECO/FEDER research grants (RTI2018-094130-B-100). CH was supported by the Department of Defense (DoD) BCRP, No. BC190820; and the National Cancer Institute (NCI) at the National Institutes of Health (NIH), No. R01CA184476. Lawrence Berkeley National Laboratory (LBNL) is a multi-program national laboratory operated by the University of California for the DOE under contract DE AC02-05CH11231. The Proteomics Unit belongs to ProteoRed, PRB3-ISCIII, supported by grant PT17/0019/0023 of the PE I + D +i, 2017–2020, funded by ISCIII and FEDER. RCC is funded by fellowships from the Spanish Regional Government of Castile and León. NGS is a recipient of an FPU fellowship (MINECO/FEDER). hiPSC-CM studies were funded in part by the “la Caixa” Banking Foundation under the project code HR18-00304 and a Severo Ochoa CNIC Intramural Project (Exp. 12-2016 IGP) to J.J.S

Impact of operatoŕs experience on peri-procedural outcomes with Watchman FLX: Insights from the FLX-SPA registry

Background: The Watchman FLX is a device upgrade of the Watchman 2.5 that incorporates several design enhancements intended to simplify left atrial appendage occlusion (LAAO) and improve procedural outcomes. This study compares peri-procedural results of LAAO with Watchman FLX (Boston Scientific, Marlborough, Massachusetts) in centers with varying degrees of experience with the Watchman 2.5 and Watchman FLX. Methods: Prospective, multicenter, 'real-world' registry including consecutive patients undergoing LAAO with the Watchman FLX at 26 Spanish sites (FLX-SPA registry). Implanting centers were classified according to the center's prior experience with the Watchman 2.5. A further division of centers according to whether or not they had performed ≤ 10 or > 10Watchman FLX implants was prespecified at the beginning of the study. Procedural outcomes of institutions stratified according to their experience with the Watchman 2.5 and FLX devices were compared. Results: 359 patients [mean age 75.5 (SD8.1), CHA2DS2-VASc 4.4 (SD1.4), HAS-BLED 3.8(SD0.9)] were included. Global success rate was 98.6%, successful LAAO with the first selected device size was achieved in 95.5% patients and the device was implanted at first attempt in 78.6% cases. There were only 9(2.5%) major peri-procedural complications. No differences in efficacy or safety results according to the centeŕs previous experience with Watchman 2.5 and procedural volume with Watchman FLX existed. Conclusions: The Watchman FLX attains high procedural success rates with complete LAA sealing in unselected, real-world patients, along with a low incidence of peri-procedural complications, regardless of operatoŕs experience with its previous device iteration or the number of Watchman FLX devices implanted