Impact of obstructive sleep apnea on the levels of placental growth factor (PlGF) and their value for predicting short-term adverse outcomes in patients with acute coronary syndrome

Background Placental growth factor (PlGF) induces angiogenesis and promotes tissue repair, and plasma PlGF levels change markedly during acute myocardial infarction (AMI). Currently, the impact of obstructive sleep apnea (OSA) in patients with AMI is a subject of debate. Our objective was to evaluate the relationships between PlGF levels and both the severity of acute coronary syndrome (ACS) and short-term outcomes after ACS in patients with and without OSA. Methods A total of 538 consecutive patients (312 OSA patients and 226 controls) admitted for ACS were included in this study. All patients underwent polygraphy in the first 72 hours after hospital admission. The severity of disease and short-term prognoses were evaluated during the hospitalization period. Plasma PlGF levels were measured using an electrochemiluminescence immunoassay. Results Patients with OSA were significantly older and more frequently hypertensive and had higher BMIs than those without OSA. After adjusting for age, smoking status, BMI and hypertension, PlGF levels were significantly elevated in patients with OSA compared with patients without OSA (19.9 pg/mL, interquartile range: 16.6–24.5 pg/mL; 18.5 pg/mL, interquartile range: 14.7–22.7 pg/mL; p<0.001), and a higher apnea-hypopnea index (AHI) was associated with higher PlGF concentrations (p<0.003). Patients with higher levels of PlGF had also an increased odds ratio for the presence of 3 or more diseased vessels and for a Killip score>1, even after adjustment. Conclusions The results of this study show that in patients with ACS, elevated plasma levels of PlGF are associated with the presence of OSA and with adverse outcomes during short-term followup. Trial Registration ClinicalTrials.gov NCT0133508

Soluble RAGE in COPD, with or without coexisting obstructive sleep apnoea

Background: Hypoxia can reduce the levels of soluble receptor for advanced glycation end-products (sRAGE), a new anti-infammatory biomarker of COPD. We assessed sRAGE in patients with hypoxia-related diseases such as COPD, OSA and OSA-COPD overlap. Methods: Plasma levels of sRAGE were measured in 317 subjects at baseline (57 heathy nonsmokers [HNS], 84 healthy smokers [HS], 79 OSA, 62 COPD and 35 OSA-COPD overlap patients) and in 294 subjects after one year of follow-up (50 HNS, 74 HS, 77 OSA, 60 COPD and 33 overlap). Results: After adjusting for age, sex, smoking status and body mass index, sRAGE levels showed a reduction in OSA (− 12.5%, p=0.005), COPD (− 14.8%, p<0.001) and OSA-COPD overlap (− 12.3%, p=0.02) compared with HNS. There were no diferences when comparing sRAGE plasma levels between overlap patients and those with OSA or COPD alone. At follow-up, sRAGE levels did not change signifcantly in healthy subjects, COPD and OSA or OSA-COPD overlap nontreated with continuous positive airway pressure (CPAP). Moreover, in patients with OSA and OSA-COPD overlap who were treated with CPAP, sRAGE increased signifcantly. Conclusions: The levels of sRAGE are reduced in COPD and OSA. Treatment with CPAP appears to improve sRAGE levels in patients with OSA who also had COPD.The EPIOSA study (NCT02131610) was supported by Grants Number PI12/02175, PI15/01940 and PI18/01524 from the Instituto Salud Carlos III, Spanish Ministry of Health, Madrid, Spain and the European Regional Development Fund (FEDER) and by a Grant Number 01/2010 from the SADAR-Pneumo Aragón, Zaragoza, Spain

The UKC3 regional coupled environmental prediction system

This paper describes an updated configuration of the regional coupled research system, termed UKC3, developed and evaluated under the UK Environmental Prediction collaboration. This represents a further step towards a vision of simulating the numerous interactions and feedbacks between different physical and biogeochemical components of the environment across sky, sea and land using more integrated regional coupled prediction systems at kilometre-scale resolution. The UKC3 coupled system incorporates models of the atmosphere (Met Office Unified Model), land surface with river routing (JULES), shelf-sea ocean (NEMO) and ocean surface waves (WAVEWATCH III®), coupled together using OASIS3-MCT libraries. The major update introduced since the UKC2 configuration is an explicit representation of wave–ocean feedbacks through introduction of wave-to-ocean coupling. Ocean model results demonstrate that wave coupling, in particular representing the wave-modified surface drag, has a small but positive improvement on the agreement between simulated sea surface temperatures and in situ observations, relative to simulations without wave feedbacks. Other incremental developments to the coupled modelling capability introduced since the UKC2 configuration are also detailed. Coupled regional prediction systems are of interest for applications across a range of timescales, from hours to decades ahead. The first results from four simulation experiments, each of the order of 1 month in duration, are analysed and discussed in the context of characterizing the potential benefits of coupled prediction on forecast skill. Results across atmosphere, ocean and wave components are shown to be stable over time periods of weeks. The coupled approach shows notable improvements in surface temperature, wave state (in near-coastal regions) and wind speed over the sea, whereas the prediction quality of other quantities shows no significant improvement or degradation relative to the equivalent uncoupled control simulations

Heterogeneity of Melanoma Cell Responses to Sleep Apnea-Derived Plasma Exosomes and to Intermittent Hypoxia

Obstructive sleep apnea (OSA) is associated with increased cutaneous melanoma incidence and adverse outcomes. Exosomes are secreted by most cells, and play a role in OSA-associated tumor progression and metastasis. We aimed to study the effects of plasma exosomes from OSA patients before and after adherent treatment with continuous positive airway pressure (CPAP) on melanoma cells lines, and also to identify exosomal miRNAs from melanoma cells exposed to intermittent hypoxia (IH) or normoxia. Plasma-derived exosomes were isolated from moderate-tosevere OSA patients before (V1) and after (V2) adherent CPAP treatment for one year. Exosomes were co-incubated with three3 different melanoma cell lines (CRL 1424; CRL 1619; CRL 1675) that are characterized by genotypes involving different mutations in BRAF, STK11, CDKN2A, and PTEN genes to assess the effect of exosomes on cell proliferation and migration, as well as on pAMK activity in the presence or absence of a chemical activator. Subsequently, CRL-1424 and CRL-1675 cells were exposed to intermittent hypoxia (IH) and normoxia, and exosomal miRNAs were identified followed by GO and KEG pathways and gene networks. The exosomes from these IH-exposed melanoma cells were also administered to THP1 macrophages to examine changes in M1 and M2 polarity markers. Plasma exosomes from V1 increased CRL-1424 melanoma cell proliferation and migration compared to V2, but not the other two cell lines. Exposure to CRL-1424 exosomes reduced pAMPK/tAMPK in V1 compared to V2, and treatment with AMPK activator reversed the effects. Unique exosomal miRNAs profiles were identified for CRL-1424 and CRL-1675 in IH compared to normoxia, with six miRNAs being regulated and several KEGG pathways were identified. Two M1 markers (CXCL10 and IL6) were significantly increased in monocytes when treated with exosomes from IH-exposed CRL-1424 and CRL-1625 cells. Our findings suggest that exosomes from untreated OSA patients increase CRL-1424 melanoma malignant properties, an effect that is not observed in two other melanoma cell lines. Exosomal cargo from CRL-1424 cells showed a unique miRNA signature compared to CRL-1675 cells after IH exposures, suggesting that melanoma cells are differentially susceptible to IH, even if they retain similar effects on immune cell polarity. It is postulated that mutations in STK-11 gene encoding for the serine/threonine kinase family that acts as a tumor suppressor may underlie susceptibility to IH-induced metabolic dysfunction, as illustrated by CRL1424 cells

The diverse meteorology of Jezero crater over the first 250 sols of Perseverance on Mars

NASA’s Perseverance rover’s Mars Environmental Dynamics Analyzer is collecting data at Jezero crater, characterizing the physical processes in the lowest layer of the Martian atmosphere. Here we present measurements from the instrument’s first 250 sols of operation, revealing a spatially and temporally variable meteorology at Jezero. We find that temperature measurements at four heights capture the response of the atmospheric surface layer to multiple phenomena. We observe the transition from a stable night-time thermal inversion to a daytime, highly turbulent convective regime, with large vertical thermal gradients. Measurement of multiple daily optical depths suggests aerosol concentrations are higher in the morning than in the afternoon. Measured wind patterns are driven mainly by local topography, with a small contribution from regional winds. Daily and seasonal variability of relative humidity shows a complex hydrologic cycle. These observations suggest that changes in some local surface properties, such as surface albedo and thermal inertia, play an influential role. On a larger scale, surface pressure measurements show typical signatures of gravity waves and baroclinic eddies in a part of the seasonal cycle previously characterized as low wave activity. These observations, both combined and simultaneous, unveil the diversity of processes driving change on today’s Martian surface at Jezero crater.This work has been funded by the Spanish Ministry of Economy and Competitiveness, through the projects no. ESP2014-54256-C4- 1-R (also -2-R, -3-R and -4-R); Ministry of Science, Innovation and Universities, projects no. ESP2016-79612-C3-1-R (also -2-R and -3-R); Ministry of Science and Innovation/State Agency of Research (10.13039/501100011033), projects no. ESP2016-80320-C2-1-R, RTI2018-098728-B-C31 (also -C32 and -C33), RTI2018-099825-B-C31, PID2019-109467GB-I00 and PRE2020-092562; Instituto Nacional de Técnica Aeroespacial; Ministry of Science and Innovation’s Centre for the Development of Industrial Technology; Spanish State Research Agency (AEI) Project MDM-2017-0737 Unidad de Excelencia “María de Maeztu”—Centro de Astrobiología; Grupos Gobierno Vasco IT1366- 19; and European Research Council Consolidator Grant no 818602. The US co-authors performed their work under sponsorship from NASA’s Mars 2020 project, from the Game Changing Development programme within the Space Technology Mission Directorate and from the Human Exploration and Operations Directorate. Part of this research was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration (80NM0018D0004). G.M. acknowledges JPL funding from USRA Contract Number 1638782. A.G.F. is supported by the European Research Council, Consolidator Grant no. 818602.Peer ReviewedPostprint (published version

The UKC2 regional coupled environmental prediction system

It is hypothesized that more accurate prediction and warning of natural hazards, such as of the impacts of severe weather mediated through various components of the environment, require a more integrated Earth System approach to forecasting. This hypothesis can be explored using regional coupled prediction systems, in which the known interactions and feedbacks between different physical and biogeochemical components of the environment across sky, sea and land can be simulated. Such systems are becoming increasingly common research tools. This paper describes the development of the UKC2 regional coupled research system, which has been delivered under the UK Environmental Prediction Prototype project. This provides the first implementation of an atmosphere–land–ocean–wave modelling system focussed on the United Kingdom and surrounding seas at km-scale resolution. The UKC2 coupled system incorporates models of the atmosphere (Met Office Unified Model), land surface with river routing (JULES), shelf-sea ocean (NEMO) and ocean waves (WAVEWATCH III). These components are coupled, via OASIS3-MCT libraries, at unprecedentedly high resolution across the UK within a north-western European regional domain. A research framework has been established to explore the representation of feedback processes in coupled and uncoupled modes, providing a new research tool for UK environmental science. This paper documents the technical design and implementation of UKC2, along with the associated evaluation framework. An analysis of new results comparing the output of the coupled UKC2 system with relevant forced control simulations for six contrasting case studies of 5-day duration is presented. Results demonstrate that performance can be achieved with the UKC2 system that is at least comparable to its component control simulations. For some cases, improvements in air temperature, sea surface temperature, wind speed, significant wave height and mean wave period highlight the potential benefits of coupling between environmental model components. Results also illustrate that the coupling itself is not sufficient to address all known model issues. Priorities for future development of the UK Environmental Prediction framework and component systems are discussed

International conference on the healthy effect of virgin olive oil

Ageing represents a great concern in developed countries because the number of people involved and the pathologies related with it, like atherosclerosis, morbus Parkinson, Alzheime's disease, vascular dementia, cognitive decline, diabetes and cancer. Epidemiological studies suggest that a Mediterranean diet (which is rich in virgin olive oil) decreases the risk of cardiovascular disease. The Mediterranean diet, rich in virgin olive oil, improves the major risk factors for cardiovascular disease, such as the lipoprotein profile, blood pressure, glucose metabolism and antithrombotic profile. Endothelial function, inflammation and oxidative stress are also positively modulated. Some of these effects are attributed to minor components of virgin olive oil. Therefore, the definition of the Mediterranean diet should include virgin olive oil. Different observational studies conducted in humans have shown that the intake of monounsaturated fat may be protective against age-related cognitive decline and Alzheimer's disease. Microconstituents from virgin olive oil are bioavailable in humans and have shown antioxidant properties and capacity to improve endothelial function. Furthermore they are also able to modify the haemostasis, showing antithrombotic properties. In countries where the populations fulfilled a typical Mediterranean diet, such as Spain, Greece and Italy, where virgin olive oil is the principal source of fat, cancer incidence rates are lower than in northern European countries. The protective effect of virgin olive oil can be most important in the first decades of life, which suggests that the dietetic benefit of virgin olive oil intake should be initiated before puberty, and maintained through life. The more recent studies consistently support that the Mediterranean diet, based in virgin olive oil, is compatible with a healthier ageing and increased longevity. However, despite the significant advances of the recent years, the final proof about the specific mechanisms and contributing role of the different components of virgin olive oil to its beneficial effects requires further investigations. © 2005 Blackwell Publishing Ltd

Prospective Latin American cohort evaluating outcomes of patients with COVID-19 and abnormal liver tests on admission

Introduction & objectives: The independent effect of liver biochemistries as a prognostic factor in patients with COVID-19 has not been completely addressed. We aimed to evaluate the prognostic value of abnormal liver tests on admission of hospitalized patients with COVID-19. Materials & methods: We performed a prospective cohort study including 1611 hospitalized patients with confirmed SARS-CoV-2 infection from April 15, 2020 through July 31, 2020 in 38 different Hospitals from 11 Latin American countries. We registered clinical and laboratory parameters, including liver function tests, on admission and during hospitalization. All patients were followed until discharge or death. We fit multivariable logistic regression models, further post-estimation effect through margins and inverse probability weighting. Results: Overall, 57.8% of the patients were male with a mean age of 52.3 years, 8.5% had chronic liver disease and 3.4% had cirrhosis. Abnormal liver tests on admission were present on 45.2% (CI 42.7–47.7) of the cohort (n = 726). Overall, 15.1% (CI 13.4–16.9) of patients died (n = 244). Patients with abnormal liver tests on admission presented higher mortality 18.7% (CI 15.9–21.7), compared to those with normal liver biochemistries 12.2% (CI 10.1–14.6); P 30. Conclusions: The presence of abnormal liver tests on admission is independently associated with mortality and severe COVID-19 in hospitalized patients with COVID-19 infection and may be used as surrogate marker of inflammation.Fil: Mendizabal, Manuel. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Piñero, Federico. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Ridruejo, Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Anders, Margarita. Hospital Aleman; ArgentinaFil: Silveyra, María Dolores. Sanatorio Anchorena; ArgentinaFil: Torre, Aldo. Centro Médico ABC; MéxicoFil: Montes, Pedro. Hospital Nacional Daniel A. Carrión; PerúFil: Urzúa, Alvaro. Hospital Clínico de la Universidad de Chile; ChileFil: Pages, Josefina. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Toro, Luis G.. Hospitales de San Vicente Fundación de Medellín y Rionegro; ColombiaFil: Díaz, Javier. Hospital Nacional Edgardo Rebagliati Martins; PerúFil: Gonzalez Ballerga, Esteban. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Miranda Zazueta, Godolfino. Instituto Nacional de Ciencias Médicas y Nutrición; MéxicoFil: Peralta, Mirta. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Gutiérrez, Isabel. Centro Médico ABC; MéxicoFil: Michelato, Douglas. Hospital Especializado en Enfermedades Infecciosas Instituto Couto Maia; BrasilFil: Venturelli, Maria Grazia. Hospital Nacional Guillermo Almenara Irigoyen; PerúFil: Varón, Adriana. Fundación Cardio-Infantil; ColombiaFil: Vera Pozo, Emilia. Hospital Regional Dr. Teodoro Maldonado Carbo; EcuadorFil: Tagle, Martín. Clínica Anglo-Americana; PerúFil: García, Matías. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; ArgentinaFil: Tassara, Alfredo. Hospital Aleman; ArgentinaFil: Brutti, Julia. Sanatorio Anchorena; ArgentinaFil: Ruiz García, Sandro. Hospital de Víctor Lazarte Echegaray; PerúFil: Bustios, Carla. Clínica Delgado; PerúFil: Escajadillo, Nataly. Hospital Nacional Almanzor Aguinaga Asenjo; PerúFil: Macias, Yuridia. No especifíca;Fil: Higuera de la Tijera, Fátima. Hospital General de México “Dr. Eduardo Liceaga"; MéxicoFil: Gómez, Andrés J.. Hospital Universitario Fundación Santa Fé de Bogotá; ColombiaFil: Dominguez, Alejandra. Hospital Padre Hurtado; ChileFil: Castillo Barradas, Mauricio. Hospital de Especialidades del Centro Médico Nacional La Raza; MéxicoFil: Contreras, Fernando. No especifíca;Fil: Scarpin, Aldana. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; ArgentinaFil: Schinoni, Maria Isabel. Hospital Alianza; BrasilFil: Toledo, Claudio. Universidad Austral de Chile; ChileFil: Girala, Marcos. Universidad Nacional de Asunción; ParaguayFil: Mainardi, Victoria. Hospital Central De las Fuerzas Armadas; UruguayFil: Sanchez, Abel. Hospital Roosevelt; GuatemalaFil: Bessone, Fernando. Provincia de Santa Fe. Ministerio de Salud y Medio Ambiente - Rosario. Hospital Provincial del Centenario; ArgentinaFil: Rubinstein, Fernando Adrian. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Silva, Marcelo Oscar. Universidad Austral. Hospital Universitario Austral; Argentin

Pαx6 Expression in Postmitotic Neurons Mediates the Growth of Axons in Response to SFRP1

During development, the mechanisms that specify neuronal subclasses are coupled to those that determine their axonal response to guidance cues. Pax6 is a homedomain transcription factor required for the specification of a variety of neural precursors. After cell cycle exit, Pax6 expression is often shut down in the precursor progeny and most postmitotic neurons no longer express detectable levels of the protein. There are however exceptions and high Pax6 protein levels are found, for example, in postmitotic retinal ganglion cells (RGCs), dopaminergic neurons of the olfactory bulb and the limbic system in the telencephalon. The function of Pax6 in these differentiating neurons remains mostly elusive. Here, we demonstrate that Pax6 mediates the response of growing axons to SFRP1, a secreted molecule expressed in several Pax6-positive forebrain territories. Forced expression of Pax6 in cultured postmitotic cortical neurons, which do not normally express Pax6, was sufficient to increment axonal length. Growth was blocked by the addition of anti-SFRP1 antibodies, whereas exogenously added SFRP1 increased axonal growth of Pax6-transfected neurons but not that of control or untransfected cortical neurons. In the reverse scenario, shRNA-mediated knock-down of Pax6 in mouse retinal explants specifically abolished RGCs axonal growth induced by SFRP1, but had no effect on RGCs differentiation and it did not modify the effect of Shh or Netrin on axon growth. Taken together these results demonstrate that expression of Pax6 is necessary and sufficient to render postmitotic neurons competent to respond to SFRP1. These results reveal a novel and unexpected function of Pax6 in postmitotic neurons and situate Pax6 and SFRP1 as pair regulators of axonal connectivity