Altered microRNA and target gene expression related to Tetralogy of Fallot

MicroRNAs (miRNAs) play an important role in guiding development and maintaining function of the human heart. Dysregulation of miRNAs has been linked to various congenital heart diseases including Tetralogy of Fallot (TOF), which represents the most common cyanotic heart malformation in humans. Several studies have identified dysregulated miRNAs in right ventricular (RV) tissues of TOF patients. In this study, we profiled genome-wide the whole transcriptome and analyzed the relationship of miRNAs and mRNAs of RV tissues of a homogeneous group of 22 non-syndromic TOF patients. Observed profiles were compared to profiles obtained from right and left ventricular tissue of normal hearts. To reduce the commonly observed large list of predicted target genes of dysregulated miRNAs, we applied a stringent target prediction pipeline integrating probabilities for miRNA-mRNA interaction. The final list of disease-related miRNA-mRNA pairs comprises novel as well as known miRNAs including miR-1 and miR-133, which are essential to cardiac development and function by regulating KCNJ2, FBN2, SLC38A3 and TNNI1. Overall, our study provides additional insights into post-transcriptional gene regulation of malformed hearts of TOF patients

Taking the lead for inclusion

Este estudio pionero destacó la correlación entre la presencia de mujeres en los directorios y niveles gerenciales superiores y el desempeño organizacional y financiero de las empresas. Desde entonces, este vínculo se ha confirmado muchas veces y hemos recorrido un largo camino para establecer el impacto comercial de una diversidad más amplia en la parte superior de las corporaciones.This pioneering study highlighted the correlation between the presence of women at board and top-management level and companies’ organizational and financial performance. Since then, this link has been confirmed many times, and we have come a long way in establishing the business impact of women at the top of corporations

Local Effect of Enhancer of Zeste-Like Reveals Cooperation of Epigenetic and cis-Acting Determinants for Zygotic Genome Rearrangements

International audienceIn the ciliate Paramecium tetraurelia, differentiation of the somatic nucleus from the zygotic nucleus is characterized by massive and reproducible deletion of transposable elements and of 45,000 short, dispersed, single-copy sequences. A specific class of small RNAs produced by the germline during meiosis, the scnRNAs, are involved in the epigenetic regulation of DNA deletion but the underlying mechanisms are poorly understood. Here, we show that trimethylation of histone H3 (H3K27me3 and H3K9me3) displays a dynamic nuclear localization that is altered when the endonuclease required for DNA elimination is depleted. We identified the putative histone methyltransferase Ezl1 necessary for H3K27me3 and H3K9me3 establishment and show that it is required for correct genome rearrangements. Genome-wide analyses show that scnRNA-mediated H3 trimethylation is necessary for the elimination of long, repeated germline DNA, while single copy sequences display differential sensitivity to depletion of proteins involved in the scnRNA pathway, Ezl1-a putative histone methyltransferase and Dcl5-a protein required for iesRNA biogenesis. Our study reveals cis-acting determinants, such as DNA length, also contribute to the definition of germline sequences to delete. We further show that precise excision of single copy DNA elements, as short as 26 bp, requires Ezl1, suggesting that development specific H3K27me3 and H3K9me3 ensure specific demarcation of very short germline sequences from the adjacent somatic sequences

Bimodal coupling of ripples and slower oscillations during sleep in patients with focal epilepsy.

OBJECTIVE: Differentiating pathologic and physiologic high-frequency oscillations (HFOs) is challenging. In patients with focal epilepsy, HFOs occur during the transitional periods between the up and down state of slow waves. The preferred phase angles of this form of phase-event amplitude coupling are bimodally distributed, and the ripples (80-150 Hz) that occur during the up-down transition more often occur in the seizure-onset zone (SOZ). We investigated if bimodal ripple coupling was also evident for faster sleep oscillations, and could identify the SOZ. METHODS: Using an automated ripple detector, we identified ripple events in 40-60 min intracranial electroencephalography (iEEG) recordings from 23 patients with medically refractory mesial temporal lobe or neocortical epilepsy. The detector quantified epochs of sleep oscillations and computed instantaneous phase. We utilized a ripple phasor transform, ripple-triggered averaging, and circular statistics to investigate phase event-amplitude coupling. RESULTS: We found that at some individual recording sites, ripple event amplitude was coupled with the sleep oscillatory phase and the preferred phase angles exhibited two distinct clusters (p \u3c 0.05). The distribution of the pooled mean preferred phase angle, defined by combining the means from each cluster at each individual recording site, also exhibited two distinct clusters (p \u3c 0.05). Based on the range of preferred phase angles defined by these two clusters, we partitioned each ripple event at each recording site into two groups: depth iEEG peak-trough and trough-peak. The mean ripple rates of the two groups in the SOZ and non-SOZ (NSOZ) were compared. We found that in the frontal (spindle, p = 0.009; theta, p = 0.006, slow, p = 0.004) and parietal lobe (theta, p = 0.007, delta, p = 0.002, slow, p = 0.001) the SOZ incidence rate for the ripples occurring during the trough-peak transition was significantly increased. SIGNIFICANCE: Phase-event amplitude coupling between ripples and sleep oscillations may be useful to distinguish pathologic and physiologic events in patients with frontal and parietal SOZ

Induced pluripotent stem cells of patients with Tetralogy of Fallot reveal transcriptional alterations in cardiomyocyte differentiation

Patient-specific induced pluripotent stem cells (ps-iPSCs) and their differentiated cell types are a powerful model system to gain insight into mechanisms driving early developmental and disease-associated regulatory networks. In this study, we use ps-iPSCs to gain insights into Tetralogy of Fallot (TOF), which represents the most common cyanotic heart defect in humans. iPSCs were generated and further differentiated to cardiomyocytes (CMs) using standard methods from two well-characterized TOF patients and their healthy relatives serving as controls. Patient-specific expression patterns and genetic variability were investigated using whole genome and transcriptome sequencing data. We first studied the clonal mutational burden of the derived iPSCs. In two out of three iPSC lines of patient TOF-01, we found a somatic mutation in the DNA-binding domain of tumor suppressor P53, which was not observed in the genomic DNA from blood. Further characterization of this mutation showed its functional impact. For patient TOF-02, potential disease-relevant differential gene expression between and across cardiac differentiation was shown. Here, clear differences at the later stages of differentiation could be observed between CMs of the patient and its controls. Overall, this study provides first insights into the complex molecular mechanisms underlying iPSC-derived cardiomyocyte differentiation and its transcriptional alterations in TOF

Secuelas por Accidente Cerebrovascular Isquémico en pacientes de 40-90 años, del servicio de Medicina Interna, Hospital Roberto Calderón Gutiérrez, de enero 2011 a diciembre 2014

Las secuelas neurológicas después del accidente cerebrovascular isquémico pueden impactar negativamente en la calidad de vida de las personas y ser factor determinante en la mortalidad de estas, existiendo datos limitados y variables en cuanto a la frecuencia de su desarrollo, siendo preponderante la investigación de este tópico. El presente estudio es de tipo descriptivo, retrospectivo y de corte transversal, en el cual se abordaron las Secuelas por Accidente Cerebrovascular Isquémico en pacientes de 40 – 90 años, del servicio de Medicina Interna, del Hospital Roberto Calderón Gutiérrez, de enero 2011 a diciembre 2014, que persigue describir las secuelas por esta patología en el grupo de estudio definido. El universo se conformó por 138 expedientes de pacientes con la patología, siendo la muestra de 103 expedientes, la fuente fue secundaria, conformada por la revisión de expedientes clínico, recopilando los datos por medio de la Ficha de recolección elaborada en base a los objetivos propuestos en el estudio. Los principales resultados reflejaron que el sexo predominante fue el femenino, entre el grupo etario de 71 a 80 años. La Hipertensión Arterial representó el antecedente patológico más frecuente, siendo la arteria cerebral media la más afectada. La parálisis / paresia de las extremidades contralaterales fue la secuela predominante. Por tanto, se recomienda hacer insistencia en la atención integral en salud brindada a los usuarios, logrando reconocer factores de riesgo patológico y no patológico incidiendo así en su control o eliminación y de esta forma mitigando el desarrollo de esta enfermedad. Palabras Claves: Secuelas, accidente cerebrovascular, isquemia

Tracking Cardiac Rehabilitation Utilization in Medicare Beneficiaries: 2017 UPDATE

PURPOSE: This study updates cardiac rehabilitation (CR) utilization data in a cohort of Medicare beneficiaries hospitalized for CR-eligible events in 2017, including stratification by select patient demographics and state of residence. METHODS: We identified Medicare fee-for-service beneficiaries who experienced a CR-eligible event and assessed their CR participation (≥1 CR sessions in 365 d), engagement, and completion (≥36 sessions) rates through September 7, 2019. Measures were assessed overall, by beneficiary characteristics and state of residence, and by primary (myocardial infarction; coronary artery bypass surgery; heart valve repair/replacement; percutaneous coronary intervention; or heart/heart-lung transplant) and secondary (angina; heart failure) qualifying event type. RESULTS: In 2017, 412 080 Medicare beneficiaries had a primary CR-eligible event and 28.6% completed ≥1 session of CR within 365 d after discharge from a qualifying event. Among beneficiaries who completed ≥1 CR session, the mean total number of sessions was 25 ± 12 and 27.6% completed ≥36 sessions. Nebraska had the highest enrollment rate (56.1%), with four other states also achieving an enrollment rate \u3e50% and 23 states falling below the overall rate for the United States. CONCLUSIONS: The absolute enrollment, engagement, and program completion rates remain low among Medicare beneficiaries, indicating that many patients did not benefit or fully benefit from a class I guideline-recommended therapy. Additional research and continued widespread adoption of successful enrollment and engagement initiatives are needed, especially among identified populations

The Polycomb protein Ezl1 mediates H3K9 and H3K27 methylation to repress transposable elements in Paramecium.

In animals and plants, the H3K9me3 and H3K27me3 chromatin silencing marks are deposited by different protein machineries. H3K9me3 is catalyzed by the SET-domain SU(VAR)3-9 enzymes, while H3K27me3 is catalyzed by the SET-domain Enhancer-of-zeste enzymes, which are the catalytic subunits of Polycomb Repressive Complex 2 (PRC2). Here, we show that the Enhancer-of-zeste-like protein Ezl1 from the unicellular eukaryote Paramecium tetraurelia, which exhibits significant sequence and structural similarities with human EZH2, catalyzes methylation of histone H3 in vitro and in vivo with an apparent specificity toward K9 and K27. We find that H3K9me3 and H3K27me3 co-occur at multiple families of transposable elements in an Ezl1-dependent manner. We demonstrate that loss of these histone marks results in global transcriptional hyperactivation of transposable elements with modest effects on protein-coding gene expression. Our study suggests that although often considered functionally distinct, H3K9me3 and H3K27me3 may share a common evolutionary history as well as a common ancestral role in silencing transposable elements

Dementia in Latin America:Assessing the present and envisioning the future

The demographic structure of Latin American countries (LAC) is fast approaching that of developing countries, and the predicted prevalence of dementia in the former already exceeds the latter. Dementia has been declared a global challenge, yet regions around the world show differences in both the nature and magnitude of such a challenge. This article provides evidence and insights on barriers which, if overcome, would enable the harmonization of strategies to tackle the dementia challenge in LAC. First, we analyze the lack of available epidemiologic data, the need for standardizing clinical practice and improving physician training, and the existing barriers regarding resources, culture, and stigmas. We discuss how these are preventing timely care and research. Regarding specific health actions, most LAC have minimal mental health facilities and do not have specific mental health policies or budgets specific to dementia. In addition, local regulations may need to consider the regional context when developing treatment and prevention strategies. The support needed nationally and internationally to enable a smooth and timely transition of LAC to a position that integrates global strategies is highlighted. We focus on shared issues of poverty, cultural barriers, and socioeconomic vulnerability. We identify avenues for collaboration aimed to study unique populations, improve valid assessment methods, and generate opportunities for translational research, thus establishing a regional network. The issues identified here point to future specific actions aimed at tackling the dementia challenge in LAC.Alzheimer's Society UK grants AS-R42303 AS-SF-14-008 CONICYT-Fondecyt 117001

Gender Differences in Interpersonal Problems of Alcohol-Dependent Patients and Healthy Controls

Alcohol dependence is a heavy burden on patients, their families, and society. Epidemiological studies indicate that alcohol dependence will affect many individuals at some time in their lives, with men affected more frequently than women. Since alcohol-dependent patients often exhibit a lack of social skills and suffer from interpersonal problems, the aim of this study is to elucidate whether men and women experience the same interpersonal problems. Eighty-five alcohol-dependent patients (48 men; 37 women) after detoxification and 62 healthy controls (35 men; 27 women) were recruited. Interpersonal problems were measured with the Inventory of Interpersonal Problems (IIP-64). Additionally, alcohol-dependent patients were interviewed with the Alcohol Use Disorders Identification Test (AUDIT) and were subtyped according to Lesch’s Alcohol Typology (LAT). There were no significant gender differences in the AUDIT and LAT between alcohol-dependent men and women. Interpersonal problems of alcohol-dependent men differed significantly in one out of eight dimensions from controls; alcohol-dependent men perceive themselves as colder than male controls. Alcohol-dependent women differed in four out of eight interpersonal dimensions from female controls. Alcohol-dependent women rated themselves as significantly more vindictive, more introverted, more overly accommodating and more intrusive than female controls. Results suggest that alcohol-dependent men and women suffer from different interpersonal problems and furthermore alcohol-dependent women perceive more interpersonal problems, whereas the severity of alcohol dependence did not differ between the groups. Our findings indicate that alcohol-dependent women may profit more from a gender-specific treatment approach aimed at improving treatment outcome than alcohol-dependent men