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Fetal growth restriction (FGR) is a common outcome in human suboptimal gestation and is related to prenatal origins of cardiovascular dysfunction in offspring. Despite this, therapy of human translational potential has not been identified. Using human umbilical and placental vessels and the chicken embryo model, we combined cellular, molecular, and functional studies to determine whether N-acetylcysteine (NAC) and hydrogen sulphide (H2S) protect cardiovascular function in growth-restricted unborn offspring. In human umbilical and placental arteries from control or FGR pregnancy and in vessels from near-term chicken embryos incubated under normoxic or hypoxic conditions, we determined the expression of the H2S gene CTH (i.e. cystathionine γ-lyase) (via quantitative PCR), the production of H2S (enzymatic activity), the DNA methylation profile (pyrosequencing) and vasodilator reactivity (wire myography) in the presence and absence of NAC treatment. The data show that FGR and hypoxia increased CTH expression in the embryonic/fetal vasculature in both species. NAC treatment increased aortic CTH expression and H2S production and enhanced third-order femoral artery dilator responses to the H2S donor sodium hydrosulphide in chicken embryos. NAC treatment also restored impaired endothelial relaxation in human third-to-fourth order chorionic arteries from FGR pregnancies and in third-order femoral arteries from hypoxic chicken embryos. This NAC-induced protection against endothelial dysfunction in hypoxic chicken embryos was mediated via nitric oxide independent mechanisms. Both developmental hypoxia and NAC promoted vascular changes in CTH DNA and NOS3 methylation patterns in chicken embryos. Combined, therefore, the data support that the effects of NAC and H2S offer a powerful mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy. KEY POINTS: Gestation complicated by chronic fetal hypoxia and fetal growth restriction (FGR) increases a prenatal origin of cardiovascular disease in offspring, increasing interest in antenatal therapy to prevent against a fetal origin of cardiovascular dysfunction. We investigated the effects between N-acetylcysteine (NAC) and hydrogen sulphide (H2S) in the vasculature in FGR human pregnancy and in chronically hypoxic chicken embryos. Combining cellular, molecular, epigenetic and functional studies, we show that the vascular expression and synthesis of H2S is enhanced in hypoxic and FGR unborn offspring in both species and this acts to protect their vasculature. Therefore, the NAC/H2S pathway offers a powerful therapeutic mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy.
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Acetilcisteína , Epigénesis Genética , Retardo del Crecimiento Fetal , Sulfuro de Hidrógeno , Hipoxia , Animales , Sulfuro de Hidrógeno/metabolismo , Acetilcisteína/farmacología , Embrión de Pollo , Humanos , Femenino , Embarazo , Retardo del Crecimiento Fetal/metabolismo , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/fisiopatología , Hipoxia/metabolismo , Hipoxia/fisiopatología , Metilación de ADN , Cistationina gamma-Liasa/genética , Cistationina gamma-Liasa/metabolismo , Vasodilatación/efectos de los fármacos , Placenta/metabolismo , Placenta/irrigación sanguínea , Arterias Umbilicales/metabolismoRESUMEN
Advances in understanding gene expression regulation through epigenetic mechanisms have contributed to elucidating the regulatory mechanisms of noncoding RNAs as pharmacological targets in several diseases. MicroRNAs (miRs) are a class of evolutionarily conserved, short, noncoding RNAs regulating in a concerted manner gene expression at the post-transcriptional level by targeting specific sequences of the 3'-untranslated region of mRNA. Conversely, mechanisms of cardiovascular disease (CVD) remain largely elusive due to their life-course origins, multifactorial pathophysiology, and co-morbidities. In this regard, CVD treatment with conventional medications results in therapeutic failure due to progressive resistance to monotherapy, which overlooks the multiple factors involved, and reduced adherence to poly-pharmacology approaches. Consequently, considering its role in regulating complete gene pathways, miR-based drugs have appreciably progressed into preclinical and clinical testing. This review summarizes the current knowledge about the mechanisms of miRs in cardiovascular disease, focusing specifically on describing how clinical chemistry and physics have improved the stability of the miR molecule. In addition, a comprehensive review of the main miRs involved in cardiovascular disease and the clinical trials in which these molecules are used as active pharmacological molecules is provided.
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Enfermedades Cardiovasculares , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/terapia , Animales , Fármacos Cardiovasculares/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacosRESUMEN
Introducción: la pandemia de COVID-19 indujo un cambio en nuestro sistema de salud y de educación. Los programas formativos también tuvieron que adaptarse y exigieron un cambio rápido. Objetivos: describir una experiencia educativa de enseñanza virtual/híbrida en investigación clínica, entre docentes del Servicio de Clínica de un hospital universitario y estudiantes de Medicina de una institución privada, que participaron del Programa ESIN (EStudiantes en INvestigación). Metodología: los contenidos y las estrategias educativas incluyeron las clases teóricas audiograbadas o videograbadas (asincrónicas y autoadministradas), el aprendizaje basado en proyectos, los talleres prácticos (encuentros sincrónicos virtuales y grupales), mediante la adopción de modelos de aprendizaje como el aula invertida, y la tutoría individual entre docente-estudiante. Los datos se recopilaron mediante la observación en contextos académicos, y basándonos en elementos de encuestas anónimas de satisfacción, previo consentimiento informado de los participantes. Resultados: participaron 14 estudiantes, 6 durante el año 2021 y 8 durante 2022. Todas mujeres y estudiantes de medicina (50% de cuarto año, 35% de sexto año y 15% de quinto año). Las técnicas implementadas favorecieron la participación y promovieron el aprendizaje activo, basado en proyectos. Mencionaron aspectos positivos como el enfoque académico práctico, la disponibilidad del equipo docente para atender cualquier duda, el tiempo y el entusiasmo por enseñar y fomentar la participación. Los videos teóricos resultaron útiles como herramientas de repaso, y los encuentros grupales fueron especialmente valorados, si bien los encuentros individuales fueron destacados como ayuda y apoyo previo a los congresos científicos. En general, manifestaron que fue una experiencia enriquecedora que demostró que se puede lograr lo que se creía imposible. Todas participaron activamente de al menos un congreso científico, y el 50% resultó coautora de una publicación académica. Conclusión: los estudiantes asumieron compromisos y responsabilidades, e incorporaron competencias y habilidades en la implementación y en la difusión de los proyectos. Esta experiencia educativa facilitó que el tiempo de clase pudiera optimizarse para intercambio, discusión y dudas. Los recursos producidos, las actividades desarrolladas y los contenidos abordados quedan disponibles a nivel institución. (AU)
Introduction: the COVID-19 pandemic brought about a change in our health and education system. Training programs also had to adapt and required rapid change. Objectives: to describe an educational experience of virtual/hybrid teaching in clinical research between teachers of the Clinical Service of a university hospital and medical students of a private institution who participated in the ESIN Program (Students in Research). Methodology: the contents and educational strategies included audio or videotaped lectures (asynchronous and self-administered), project-based learning, practical workshops (virtual and group synchronous meetings) by adopting learning models such as the inverted classroom, and individual tutoring between teacher and student. We gathered the data through observation in academic contexts and based on elements of anonymous satisfaction surveys, with prior informed consent of participants. Results: fourteen students participated, six in 2021 and eight in 2022. All were women and medical students (50% fourth year, 35% sixth year, and 15% fifth year). The techniques implemented favored participation and promoted active, project-based learning. They mentioned positive aspects such as the practical academic approach, the availability of the teaching team for any doubts, the time and enthusiasm for teaching, and encouraging participation. The theory videos were a valuable review tool, and team meetings received high praise even if the one-on-one meetings received much attention as help and support before the scientific congresses. In general, they stated that it was an enriching experience that showed that you can achieve what you thought impossible. All of them actively participated in at least one scientific congress, and 50% were co-authors of an academic publication. Conclusion: the students assumed commitments and responsibilities and incorporated competencies and skills in project implementation and dissemination. This educational experience helped to optimize class time for exchange, discussion, and doubts. The resources produced, the activities developed, and the contents addressed are now available at the institutional level. (AU)
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Humanos , Masculino , Femenino , Investigación/educación , Estudiantes de Medicina/psicología , Educación a Distancia/métodos , Educación Médica/métodos , Aprendizaje , Satisfacción Personal , Autoimagen , Protocolos Clínicos , Encuestas y Cuestionarios , Evaluación Educacional/métodos , Retroalimentación Formativa , COVID-19RESUMEN
Introduction: Adolescent health is currently undergoing a serious deterioration. The aim of this study was to identify the self-care practices in adolescents between 15 and 18 years of age attending secondary schools in four departments of the interior of the province of La Rioja, Argentina. Methodology: descriptive cross-sectional and analytical study; data collected between October and November 2022 by non-probabilistic convenience sampling, with analysis of absolute and relative frequencies, multivariate logistic regression analysis and Odds ratio with 95% CI statistical significance of p= Ë0.05. Exploratory factor analysis (EFA) using the Principal Components method as extraction and the Orthogonal Varimax method as rotation. Analysis software, SPSS version 26. Results: There are discordances between the self-perception of health care and the practice carried out by the adolescents. Gender disparity in self-care is identified. The factors that increase self-care are the use of digital health applications, annual or shorter medical check-ups, and maintaining positive thinking habits. The main concern in relation to self-care among adolescents was the consumption of alcoholic beverages.
Introducción: La salud adolescente transcurre por un grave deterioro en la actualidad. El objetivo de este trabajo fue identificar las prácticas de autocuidado de salud en adolescentes escolarizados entre 15 y 18 años que asisten a escuelas secundarias de cuatro departamentos del interior de la provincia de La Rioja, Argentina. Metodología: estudio descriptivo transversal y analítico; datos relevados entre octubre y noviembre 2022 por muestreo no probabilístico por conveniencia, con análisis de frecuencias absolutas, relativas, análisis multivariado de regresión logística y Odds ratio con IC 95% significancia estadística de p= Ë0,05. Análisis factorial exploratorio (AFE) aplicando como extracción, el método de Componentes principales y como rotación el método Ortogonal Varimax. Software de análisis, SPSS versión 26. Resultados: Existen discordancias entre la auto-percepción del cuidado de salud y la práctica del cuidado. Se identifican disparidades del autocuidado según el género. Los factores que incrementan el autocuidado son el uso de aplicaciones digitales en salud, los controles médicos anuales o en menor tiempo, el mantener hábitos de pensamientos positivos. La principal preocupación de los adolescentes en relación al autocuidado de salud fue el consumo de bebidas con contenido etílico.
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Autocuidado , Humanos , Adolescente , ArgentinaRESUMEN
PIEZO1 is a mechanosensitive cation channel implicated in shear stress-mediated endothelial-dependent vasorelaxation. Since altered shear stress patterns induce a pro-inflammatory endothelial environment, we analyzed transcriptional profiles of human endothelial cells to determine the effect of altered shear stress patterns and subsequent prooxidant and inflammatory conditions on PIEZO1 and mechanosensitive-related genes (MRG). In silico analyses were validated in vitro by assessing PIEZO1 transcript levels in both the umbilical artery (HUAEC) and vein (HUVEC) endothelium. Transcriptional profiling showed that PIEZO1 and some MRG associated with the inflammatory response were upregulated in response to high (15 dyn/cm2) and extremely high shear stress (30 dyn/cm2) in HUVEC. Changes in PIEZO1 and inflammatory MRG were paralleled by p65 but not KLF or YAP1 transcription factors. Similarly, PIEZO1 transcript levels were upregulated by TNF-alpha (TNF-α) in diverse endothelial cell types, and pre-treatment with agents that prevent p65 translocation to the nucleus abolished PIEZO1 induction. ChIP-seq analysis revealed that p65 bonded to the PIEZO1 promoter region, an effect increased by the stimulation with TNF-α. Altogether this data showed that NF-kappa B activation via p65 signaling regulates PIEZO1 expression, providing a new molecular link for prooxidant and inflammatory responses and mechanosensitive pathways in the endothelium.
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BACKGROUND: Biometrical and blood flow examinations are fundamental for assessing fetoplacental development during pregnancy. Guinea pigs have been proposed as a good model to study fetal development and related gestational complications; however, longitudinal growth and blood flow changes in utero have not been properly described. This study aimed to describe fetal and placental growth and blood flow of the main intrauterine vascular beds across normal guinea pig pregnancy and to discuss the relevance of this data for human pregnancy. METHODS: Pregnant guinea pigs were studied from day 25 of pregnancy until term (day ~70) by ultrasound and Doppler assessment. The results were compared to human data from the literature. RESULTS: Measurements of biparietal diameter (BPD), cranial circumference (CC), abdominal circumference, and placental biometry, as well as pulsatility index determination of umbilical artery, middle cerebral artery (MCA), and cerebroplacental ratio (CPR), were feasible to determine across pregnancy, and they could be adjusted to linear or nonlinear functions. In addition, several of these parameters showed a high correlation coefficient and could be used to assess gestational age in guinea pigs. We further compared these data to ultrasound variables from human pregnancy with high similarities. CONCLUSIONS: BPD and CC are the most reliable measurements to assess fetal growth in guinea pigs. Furthermore, this is the first report in which the MCA pulsatility index and CPR are described across guinea pig gestation. The guinea pig is a valuable model to assess fetal growth and blood flow distribution, variables that are comparable with human pregnancy.
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Umbilical and placental vessels and endothelial cells (EC) are common models to study placental function and vascular programming. Arterio-venous differences are present in the umbilical endothelium; however, the heterogeneity of small placental vessels and the expression of potential micro- vs. macro-vascular (MMV) markers are poorly described. Here, we performed a meta-analysis of transcriptomic and DNA methylation data from placental and umbilical EC. Expression and methylation profiles were compared using hierarchical clustering, dimensionality reduction (i.e., tSNE, MDS, and PHATE), and enrichment analysis to determine the occurrence of arterio-venous (AVH) and micro-macro heterogeneity (MMH). CpG sites correlated with gene expression of transcriptional markers of MMH and AVH were selected by Lasso regression and used for EC discrimination. General transcriptional profile resulted in clear segregation of EC by their specific origin. MM and AVH grouping were also observed when microvascular markers were applied. Altogether, this meta-analysis provides cogent evidence regarding the transcriptional and epigenomic profiles that differentiate among EC, proposing novel markers to define phenotypes based on MM levels.
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Células Endoteliales , Placenta , Biomarcadores/metabolismo , Metilación de ADN , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Epigenómica , Femenino , Humanos , Placenta/metabolismo , EmbarazoRESUMEN
The objective of this study was to reveal how the COVID-19 pandemic process affected the number of visits to an emergency department of a highly complex hospital located in the Ciudad Autónoma de Buenos Aires, to explore the characteristics and reasons for consultation. The monthly number of visits between January 2019 and December 2020 was analyzed. The data showed a strong decrease in the number of visits (176 370 in 2019 and 95 421 in 2020), with an abrupt drop after the lockdown disposal (In aprilshowed the maximum reduction: 77.1%), and the different stages are reflected in the evolution (a consequence of quarantine), yielding a global annual reduction of 45.9%. The number of patients admitted by ambulances increased (5.1% in 2019 to 10.4% in 2020; p < 0.05), and consequently, the number of patients in the more complex sector (area B 2019: 5.3%, 2020: 11.5%; p < 0.01), as well as unscheduled hospitalizations from 6.8% (95% CI 6.7-6.9) to 12.1% in 2020 (95%CI11.8-12.3), p < 0.01. The five most frequent reasons for consultation in 2020 were: fever (5.1%), odynophagia (4.7%), abdominal pain (2.6%), cough (1.8%) and headache (1.8%), probably all related to COVID-19. In conclusion, the number of emergency department visits decreased by half compared to the previous year.
El objetivo de este estudio fue revelar cómo el COVID-19 afectó el número de visitas a un servicio de urgencias de un hospital de alta complejidad ubicado en la Ciudad Autónoma de Buenos Aires, explorar las características y los motivos de consulta. Se analizó el número mensual entre enero 2019 y diciembre 2020. Los datos mostraron una fuerte disminución en el número de visitas (176 370 en 2019 y 95 421 en 2020), con una caída abrupta luego de disposición aislamiento social, preventivo y obligatorio (el mes de abril arrojó el máximo valor de reducción: 77.1%), y se reflejan las diferentes etapas evolutivas (consecuencia de la cuarentena), arrojando una reducción global anual del 45.9%. Sin embargo, aumentó el número de pacientes que ingresaron en ambulancias (5.1% en 2019 a 10.4% en 2020; p < 0.05), y, en consecuencia, los pacientes del sector de mayor complejidad (área B 2019: 5.3%, 2020: 11.5%; p < 0.01), y las hospitalizaciones no programadas de 6.8% (IC95% 6.7-6.9) a 12.1% en 2020 (IC95% 11.8-12.3), p < 0.01. Los cinco motivos de consulta más frecuentes durante 2020 resultaron: fiebre (5.1%), odinofagia (4.7%), dolor abdominal (2.6%), tos (1.8%) y cefalea (1.8%), probablemente todos relacionados a COVID-19. En conclusión, se redujo a la mitad el número de visitas a urgencias en comparación con el año previo.
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COVID-19 , Pandemias , Argentina/epidemiología , Control de Enfermedades Transmisibles , Servicio de Urgencia en Hospital , Humanos , SARS-CoV-2RESUMEN
Resumen El objetivo de este estudio fue revelar cómo el COVID-19 afectó el número de visitas a un servicio de urgencias de un hospital de alta complejidad ubicado en la Ciudad Autónoma de Buenos Aires, explorar las características y los motivos de consulta. Se analizó el número mensual entre enero 2019 y diciem bre 2020. Los datos mostraron una fuerte disminución en el número de visitas (176 370 en 2019 y 95 421 en 2020), con una caída abrupta luego de disposición aislamiento social, preventivo y obligatorio (el mes de abril arrojó el máximo valor de reducción: 77.1%), y se reflejan las diferentes etapas evolutivas (consecuencia de la cuarentena), arrojando una reducción global anual del 45.9%. Sin embargo, aumentó el número de pacientes que ingresaron en ambulancias (5.1% en 2019 a 10.4% en 2020; p < 0.05), y, en consecuencia, los pacientes del sector de mayor complejidad (área B 2019: 5.3%, 2020: 11.5%; p < 0.01), y las hospitalizaciones no progra madas de 6.8% (IC95% 6.7-6.9) a 12.1% en 2020 (IC95% 11.8-12.3), p < 0.01. Los cinco motivos de consulta más frecuentes durante 2020 resultaron: fiebre (5.1%), odinofagia (4.7%), dolor abdominal (2.6%), tos (1.8%) y cefalea (1.8%), probablemente todos relacionados a COVID-19. En conclusión, se redujo a la mitad el número de visitas a urgencias en comparación con el año previo.
Abstract The objective of this study was to reveal how the COVID-19 pandemic process affected the number of visits to an emergency department of a highly complex hospital located in the Ciudad Autónoma de Buenos Aires, to explore the char acteristics and reasons for consultation. The monthly number of visits between January 2019 and December 2020 was analyzed. The data showed a strong decrease in the number of visits (176 370 in 2019 and 95 421 in 2020), with an abrupt drop after the lockdown disposal (In aprilshowed the maximum reduction: 77.1%), and the different stages are reflected in the evolution (a consequence of quarantine), yielding a global annual reduc tion of 45.9%. The number of patients admitted by ambulances increased (5.1% in 2019 to 10.4% in 2020; p < 0.05), and consequently, the number of patients in the more complex sector (area B 2019: 5.3%, 2020: 11.5%; p < 0.01), as well as unscheduled hospitalizations from 6.8% (95% CI 6.7-6.9) to 12.1% in 2020 (95%CI11.8- 12.3), p < 0.01. The five most frequent reasons for consultation in 2020 were: fever (5.1%), odynophagia (4.7%), abdominal pain (2.6%), cough (1.8%) and headache (1.8%), probably all related to COVID-19. In conclusion, the number of emergency department visits decreased by half compared to the previous year.
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Humanos , Pandemias , COVID-19 , Argentina/epidemiología , Control de Enfermedades Transmisibles , Servicio de Urgencia en Hospital , SARS-CoV-2RESUMEN
BACKGROUND: To date, there is no specific antiviral therapy for severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) that causes Coronavirus disease 2019 (Covid-19). Since there is no specific therapy against SARS-CoV2, current efforts aim to prevent contagion through public health measures and develop a protective vaccine. While waiting for the latter, it is necessary to evaluate the drugs that at least, in initial studies, suggested some degree of utility in the management of Covid-19 or its complications. The main objective of the study was to describe the clinical manifestations and outcomes of patients with severe Covid-19 Pneumonia treated with corticosteroids and colchicine. MATERIALS AND METHODS: A cross sectional study of 301 adult patients with Covid-19 Pneumonia confirmed by Real-Time Polymerase Chain Reaction for SARS-CoV2 (RT-PCR SARS-CoV2), Berlin protocol, who required hospitalization in three hospitals in Antioquia, Colombia. Patients were treated according to the institutional protocol (from March 20, 2020 to June 30, 2020) with corticosteroid if the patient required supplemental oxygen. From July 1, 2020, the management protocol changed with the addition of colchicine to all patients admitted to the institutions. The treatment was supervised and monitored by the same specialist in Infectology of the institutions. We describe the clinical manifestations and outcomes of the patients who received these treatments. The information of the patients was analyzed according to the outcome of interest (alive/dead) with univariate, bivariate, and multivariate measures to adjust the variables that presented statistical association. RESULTS: All patients had pneumonia documented by chest computed tomography with ground glass images and presented an alveolar pressure/inspired oxygen fraction (PaFi) less than 300. Three hundred one patients were included, 240 (79.7%) received corticosteroids, within these 145 (48.2%) received colchicine also, and the remaining 61 (20.3%) patients did not receive corticosterioids or colchicine. Mortality in the group that received colchicine was lower compared to the group that did not receive it (9.6 vs 14.6%, p-value = 0.179). CONCLUSIONS: Treatment with corticosteroids and colchicine for managing patients with severe Covid-19 Pneumonia was associated with low mortality at the hospital level. Randomized, placebo-controlled studies are required to evaluate the effect of corticosteroids and colchicine on complications or death from Covid-19.
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Corticoesteroides/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Colchicina/uso terapéutico , Adulto , Anciano , COVID-19/diagnóstico , Prueba de Ácido Nucleico para COVID-19 , Colombia , Estudios Transversales , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , ARN Viral , SARS-CoV-2/efectos de los fármacos , Resultado del TratamientoRESUMEN
Diagnosing asthma in preschool children remains an unsolved challenge, at a time when early identification would allow for better education and treatment to prevent morbidity and lung function deterioration. OBJECTIVE: To evaluate if the asthma predictive index (API) can be used as surrogate for asthma diagnosis in preschoolers. METHODS: Birth cohort of 339 pregnant women enrolled at delivery and their offspring, who were followed for atopy, wheezing, and other respiratory illnesses through 30 months of age. The API was determined at 30 months of age by the researchers; and examined its association with physician-diagnosed asthma during the first 30 months, made independently by the primary care physician not involved in the study. RESULTS: Among 307 offspring with complete follow-up, 44 (14.3%) were API+. Maternal body mass index, maternal education, past oral contraceptive use, birthweight, placenta weight, age of daycare at 12 m, gastroesophageal reflux disease at 12 m, acute otitis media at 18 m, bronchiolitis, croup and pneumonia, cord blood adiponectin were all associated with API+. In the multivariable analysis, API+ was associated with almost sixfold odds of asthma diagnosis (adjusted OR = 5.7, 95% CI [2.6-12.3]), after adjusting for the relevant covariates above including respiratory infections like bronchiolitis and pneumonia. The API sensitivity was 48%, specificity 92%, 61% PPV, 88% NPV, 6.4 LR+, 0.56 LR-, 0.84 diagnosis accuracy. The adjusted odds for asthma was 11.4. CONCLUSIONS: This longitudinal birth cohort suggests, for first time, that API (a structured definition for asthma), could be used as a diagnostic tool, not only as a prognostic tool, in toddlers and preschoolers.
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Asma , Hipersensibilidad Inmediata , Infecciones del Sistema Respiratorio , Asma/diagnóstico , Asma/epidemiología , Cohorte de Nacimiento , Preescolar , Femenino , Humanos , Lactante , Embarazo , Ruidos Respiratorios/diagnóstico , Ruidos Respiratorios/etiologíaRESUMEN
Whether arterial-venous differences of primary endothelial cells commonly used for vascular research are preserved in vitro remains under debate. To address this issue, a meta-analysis of Affymetrix transcriptomic data sets from human umbilical artery (HUAECs) and vein (HUVEC) endothelial cells was performed. The meta-analysis showed 2,742 transcripts differentially expressed (false discovery rate <0.05), of which 78% were downregulated in HUVECs. Comparisons with RNA-seq data sets showed high levels of agreement and correlation (p < 0.0001), identifying 84 arterial-venous identity markers. Functional analysis revealed enrichment of key vascular processes in HUAECs/HUVECs, including nitric oxide- (NO) and hypoxia-related genes, as well as differences in miRNA- and ncRNA-mRNA interaction profiles. A proof of concept of these findings in primary cells exposed to hypoxia in vitro and in vivo confirmed the arterial-venous differences in NO-related genes and miRNAs. Altogether, these data defined a cross-platform arterial-venous transcript profile for cultured HUAEC-HUVEC and support a preserved identity involving key vascular pathways post-transcriptionally regulated in vitro.
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More than 30 years have passed since endothelial nitric oxide synthesis was described using the umbilical artery and vein endothelium. That seminal report set the cornerstone for unveiling the molecular aspects of endothelial function. In parallel, the understanding of placental physiology has gained growing interest, due to its crucial role in intrauterine development, with considerable long-term health consequences. This review discusses the evidence for nitric oxide (NO) as a critical player of placental development and function, with a special focus on endothelial nitric oxide synthase (eNOS) vascular effects. Also, the regulation of eNOS-dependent vascular responses in normal pregnancy and pregnancy-related diseases and their impact on prenatal and postnatal vascular health are discussed. Recent and compelling evidence has reinforced that eNOS regulation results from a complex network of processes, with novel data concerning mechanisms such as mechano-sensing, epigenetic, posttranslational modifications, and the expression of NO- and l-arginine-related pathways. In this regard, most of these mechanisms are expressed in an arterial-venous-specific manner and reflect traits of the fetal systemic circulation. Several studies using umbilical endothelial cells are not aimed to understand placental function but general endothelial function, reinforcing the influence of the placenta on general knowledge in physiology.
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Endotelio Vascular/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Óxido Nítrico/metabolismo , Placenta/metabolismo , Femenino , Feto/metabolismo , Humanos , Embarazo , Venas Umbilicales/metabolismoRESUMEN
The new coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), detected in Wuhan, China, causes coronavirus disease 2019 (COVID-19), which was declared pandemic, and has caused more than 19 million confirmed cases and more than 700 thousand deaths worldwide. When our institution was converted to COVID's hospital since early April 2020, specific care protocols were developed, with the aim of improving the quality of care and safety of patients and the staff involved in their management. Airway management represents one of the highest risks of direct contact infection with aerosol generation (orotracheal intubation, secretion aspiration, extubation, cardiopulmonary resuscitation, high flow oxygen therapy, noninvasive ventilation, and invasive ventilation). We present the current recommendations for airway management as well as a step-by-step airway management protocol to carry out a more secure procedure based on the literature reported so far.
El nuevo coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), detectado en Wuhan (China), causante de la enfermedad por coronavirus 2019 (COVID-19), que se declaró como pandemia, ha causado más de 19 millones de casos confirmados y más de 700 mil muertes en el mundo. Nuestra institución se reconvirtió a hospital COVID desde principios de abril del 2020, con lo que se desarrollaron protocolos de atención específicos, con el objetivo de mejorar la calidad de atención y seguridad de los pacientes y el personal involucrado en su manejo. El manejo de la vía aérea representa uno de los riesgos más altos de contagio por contacto directo en la generación de aerosoles (intubación orotraqueal, aspiración de secreciones, extubación, resucitación cardiopulmonar, terapia de oxígeno de alto flujo, ventilación no invasiva y ventilación invasiva). Presentamos las recomendaciones actuales para el manejo de la vía aérea, así como un protocolo de manejo paso a paso para llevar a cabo un procedimiento con mayor seguridad basados en la literatura reportada hasta el momento.
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Manejo de la Vía Aérea/métodos , COVID-19 , Cardiología , Manejo de la Vía Aérea/normas , COVID-19/terapia , Cardiología/métodos , Cardiología/normas , HumanosRESUMEN
Adverse childhood experiences (ACEs) are associated with a high risk of developing chronic diseases and decreased life expectancy, but no ACE epigenetic biomarkers have been identified until now. The latter may result from the interaction of multiple factors such as age, sex, degree of adversity, and lack of transcriptional effects of DNA methylation changes. We hypothesize that DNA methylation changes are related to childhood adversity levels and current age, and these markers evolve as aging proceeds. Two Gene Expression Omnibus datasets, regarding ACE, were selected (GSE72680 and GSE70603), considering raw- and meta-data availability, including validated ACE index (Childhood Trauma Questionnaire (CTQ) score). For DNA methylation, analyzed probes were restricted to those laying within promoters and first exons, and samples were grouped by CTQ scores terciles, to compare highly (ACE) with non-abused (control) cases. Comparison of control and ACE methylome profile did not retrieve differentially methylated CpG sites (DMCs) after correcting by false discovery rate < 0.05, and this was also observed when samples were separated by sex. In contrast, grouping by decade age ranges (i.e., the 20s, 30s, 40s, and 50s) showed a progressive increase in the number of DMCs and the intensity of changes, mainly related with hypomethylation. Comparison with transcriptome data for ACE subjects in the 40s, and 50s showed a similar age-dependent effect. This study provides evidence that epigenetic markers of ACE are age-dependent, but not defined in the long term. These differences among early, middle, and late adulthood epigenomic profiles suggest a window for interventions aimed to prevent the detrimental effects of ACE.
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Experiencias Adversas de la Infancia/clasificación , Envejecimiento/psicología , Metilación de ADN/fisiología , Factores de Tiempo , Adulto , Epigénesis Genética/fisiología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Aim: To determine changes in global DNA methylation in monocytes from neonates of women with obesity, as markers of an immune programming resulting from maternal obesity. Materials & methods: Cord blood monocytes were obtained from neonates born to women with obesity and normal weight, genome-wide differentially methylated CpGs were determined using an Infinium MethylationEPIC-BeadChip (850K). Results: No clustering of samples according to maternal BMI was observed, but sex-specific analysis revealed 71,728 differentially methylated CpGs in female neonates from women with obesity (p < 0.01). DAVID analysis showed increased methylation levels within genes involved in the innate immune response and inflammation. Conclusion: Maternal obesity induces, in a sex-specific manner, an epigenetic programming of monocytes that could contribute to disease later in life. Clinical trial registry: This study is registered in ClinicalTrials.gov NCT02903134.
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Epigénesis Genética , Monocitos/metabolismo , Obesidad Materna , Adolescente , Adulto , Células Cultivadas , Islas de CpG , Metilación de ADN , Femenino , Humanos , Inmunidad Innata/genética , Recién Nacido , Mediadores de Inflamación/sangre , Masculino , Embarazo , Caracteres Sexuales , Adulto JovenRESUMEN
Aim: To evaluate the risk of nonsyndromic orofacial clefts (NSOFCs) associated with LINE-1 methylation, as a marker of global DNA methylation, and the effect of MTHFR functional variants on this variable. Patients & methods: LINE-1 methylation was evaluated by bisulfite modification coupled to DNA pyrosequencing in 95 NSOFC cases and 95 controls. In these subjects, MTHFR genotypes for variants c.C677T (rs1801133) and c.A1298C (rs1801131) were obtained. Results: Middle levels (second tertile) of LINE-1 methylation increase the risk of NSOFCs. In addition, LINE-1 methylation depends on c.A1298C genotypes in controls but not in cases. Conclusion: A nonlinear association between global DNA methylation and NSOFCs was detected in this Chilean population, which appears to be influenced by MTHFR functional variants.
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Encéfalo/anomalías , Labio Leporino/genética , Fisura del Paladar/genética , Metilación de ADN , Elementos de Nucleótido Esparcido Largo , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Chile , Humanos , Lactante , Recién Nacido , Polimorfismo de Nucleótido SimpleRESUMEN
Obstructive sleep apnea (OSA), a breathing disorder featured by chronic intermittent hypoxia (CIH) is associated with pulmonary hypertension (PH). Rodents exposed to CIH develop pulmonary vascular remodeling and PH, but the pathogenic mechanisms are not well known. Overexpression of Stim-activated Transient Receptor Potential Channels (TRPC) and Calcium Release-Activated Calcium Channel Protein (ORAI) TRPC-ORAI Ca2+ channels (STOC) has been involved in pulmonary vascular remodeling and PH in sustained hypoxia. However, it is not known if CIH may change STOC levels. Accordingly, we studied the effects of CIH on the expression of STOC subunits in the lung and if these changes paralleled the progression of the vascular pulmonary remodeling and PH in a preclinical model of OSA. Male Sprague-Dawley rats (â¼200 g) were exposed to CIH (5%O2, 12 times/h for 8 h) for 14, 21, and 28 days. We measured right ventricular systolic pressure (RVSP), cardiac morphometry with MRI, pulmonary vascular remodeling, and wire-myographic arterial responses to KCl and endothelin-1 (ET-1). Pulmonary RNA and protein STOC levels of TRPC1, TRPC4, TRPC6, ORAI 1, ORAI 2, and STIM1 subunits were measured by qPCR and western blot, and results were compared with age-matched controls. CIH elicited a progressive increase of RVSP and vascular contractile responses to KCl and ET-1, leading to vascular remodeling and augmented right ventricular ejection fraction, which was significant at 28 days of CIH. The levels of TRPC1, TRPC4, TRPC 6, ORAI 1, and STIM 1 channels increased following CIH, and some of them paralleled morphologic and functional changes. Our findings show that CIH increased pulmonary STOC expression, paralleling vascular remodeling and PH.
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Clinical conditions associated with hypoxia and oxidative stress, such as fetal growth restriction (FGR), results in endothelial dysfunction. Previous reports show that changes in eNOS expression under these conditions are tightly controlled by DNA methylation and histone posttranslational modifications. However, the contribution of an orchestrating epigenetic mechanism, such as miRNAs, on the NO-related genes expression has not been addressed. We aimed to determine the levels of miRNAs highly expressed in normal endothelial cells (EC), miR-21 and miR-126, in FGR human umbilical artery EC (HUAEC), and their effects on hypoxia-dependent regulation of both, NO-related and oxidative stress-related genes. Results were validated by transcriptome analysis of HUAEC cultured under chronic low oxygen conditions. Cultured FGR-HUAEC showed decreased hsa-miR-21, DDAH1, SOD1, and NRF2, but increased miR-126, NOX4, and eNOS levels, compared with controls. MiR-21-5p levels in FGR were associated with increased hg-miR-21 gene promoter methylation, with no changes in hg-miR-126 gene promoter methylation. HUAEC exposed to hypoxia showed a transient increase in eNOS and DDAH11, paralleled by decrease miR-21-5p levels, but no changes in miR-126-3p and the other genes under study. Transcriptome profiling showed an inverse relationship among miR-21 and several transcripts targeted by miR-21 in HUAEC exposed to hypoxia, meanwhile miR-21-5p-mimic decreased eNOS and DDAH1 transcripts stability, blocking their induction by hypoxia. Consequently, FGR programs a hypoxia-related miRNA that contributes to the regulation of the NO pathway, involving a direct effect of miR-21-5p on eNOS transcript stability, not previously reported. Moreover, hypoxia downregulates miR-21-5p, contributing to increasing the expression of NO-related genes in arterial endothelial cells.
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Endotelio Vascular/metabolismo , Regulación Enzimológica de la Expresión Génica , MicroARNs/metabolismo , Óxido Nítrico Sintasa de Tipo III/biosíntesis , Arterias Umbilicales/metabolismo , Hipoxia de la Célula/fisiología , Células Cultivadas , Femenino , Humanos , Recién Nacido , Masculino , MicroARNs/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/genética , EmbarazoRESUMEN
Methylation in CpG sites of the PPARGC1A gene (encoding PGC1-α) has been associated with adiposity, insulin secretion/sensitivity indexes and type 2 diabetes. We assessed the association between the methylation profile of the PPARGC1A gene promoter gene in leukocytes with insulin secretion/sensitivity indexes in normoglycemic women. A standard oral glucose tolerance test (OGTT) and an abbreviated version of the intravenous glucose tolerance test (IVGTT) were carried out in n = 57 Chilean nondiabetic women with measurements of plasma glucose, insulin, and C-peptide. Bisulfite-treated DNA from leukocytes was evaluated for methylation levels in six CpG sites of the proximal promoter of the PPARGC1A gene by pyrosequencing (positions -816, -783, -652, -617, -521 and -515). A strong correlation between the DNA methylation percentage of different CpG sites of the PPARGC1A promoter in leukocytes was found, suggesting an integrated epigenetic control of this region. We found a positive association between the methylation levels of the CpG site -783 with the insulin sensitivity Matsuda composite index (rho = 0.31; p = 0.02) derived from the OGTT. The CpG hypomethylation in the promoter position -783 of the PPARGC1A gene in leukocytes may represent a biomarker of reduced insulin sensitivity after the ingestion of glucose.