Replication of Integrative Data Analysis for Adipose Tissue Dysfunction, Low-Grade Inflammation, Postprandial Responses and OMICs Signatures in Symptom-Free Adults.

We previously reported preliminary characterization of adipose tissue (AT) dysfunction through the adiponectin/leptin ratio (ALR) and fasting/postprandial (F/P) gene expression in subcutaneous (SQ) adipose tissue (AT) biopsies obtained from participants in the GEMM study, a precision medicine research project. Here we present integrative data replication of previous findings from an increased number of GEMM symptom-free (SF) adults (N = 124) to improve characterization of early biomarkers for cardiovascular (CV)/immunometabolic risk in SF adults with AT dysfunction. We achieved this goal by taking advantage of the rich set of GEMM F/P 5 h time course data and three tissue samples collected at the same time and frequency on each adult participant (F/P blood, biopsies of SQAT and skeletal muscle (SKM)). We classified them with the presence/absence of AT dysfunction: low (<1) or high (>1) ALR. We also examined the presence of metabolically healthy (MH)/unhealthy (MUH) individuals through low-grade chronic subclinical inflammation (high sensitivity C-reactive protein (hsCRP)), whole body insulin sensitivity (Matsuda Index) and Metabolic Syndrome criteria in people with/without AT dysfunction. Molecular data directly measured from three tissues in a subset of participants allowed fine-scale multi-OMIC profiling of individual postprandial responses (RNA-seq in SKM and SQAT, miRNA from plasma exosomes and shotgun lipidomics in blood). Dynamic postprandial immunometabolic molecular endophenotypes were obtained to move towards a personalized, patient-defined medicine. This study offers an example of integrative translational research, which applies bench-to-bedside research to clinical medicine. Our F/P study design has the potential to characterize CV/immunometabolic early risk detection in support of precision medicine and discovery in SF individuals.

Shortening in the Tp-e/QTc ratio after angioplasty in patients with acute coronary syndrome. / Acortamiento en la relación Tp-f/QTc tras angioplastia en pacientes con síndrome isquémico coronario agudo.

Objetivo: La dispersión transmural de la repolarización ventricular (DTMRV) es un factor de riesgo para muerte en pacientes con síndrome isquémico coronario agudo (SICA). Con el objetivo de conocer el efecto de la realización de angioplastia sobre la DTMRV, se estudió la relación Tp-f/QTc en pacientes con SICA sometidos a angioplastia. Método: Se diseñó un estudio observacional, retrospectivo y descriptivo. Se incluyeron 150 pacientes (N = 150) con diagnóstico de SICA. Se valoró la relación Tp-f/QTc inicial y se evaluó su acortamiento posangioplastia. Como objetivo secundario, se comparó la asociación de dichos cambios en la relación Tp-f/QTc con la mortalidad cardiovascular y los eventos adversos cardiovasculares. Resultados: El promedio en la relación Tp-f/QTc inicial fue de 0.2529, mientras que posangioplastia fue de 0.2397. Por medio de prueba de rangos de Wilcoxon se evidenció un descenso significativo en la relación Tp-f/QTc posterior a la angioplastia, con un valor Z de -2.051 y una p < 0.04. En el análisis secundario se encontró que una Tp-f/QTc ≥ 0.29 posangioplastia es factor de riesgo para presentación de los siguientes eventos adversos: muerte intrahospitalaria (7.4 vs 0%; p < 0.003), nuevo SICA en seguimiento a 1 año (25.9 vs. 18.5%; p < 0.006) y reintervención en seguimiento a 1 año (29.6 vs. 15.0%; p < 0.002). Conclusiones: Existe un acortamiento significativo en la relación Tp-f/QTc posangioplastia en pacientes con SICA. Esta medida de la DTMRV puede servir como un predictor de muerte intrahospitalaria, eventos cardiovasculares y reintervención a 1 año en pacientes con SICA tratados con angioplastia. Objective: Transmural Dispersion of Repolarization (TDR) is a Risk factor for Death in patients with Acute Coronary ­Syndrome (ACS). In order to know the effect of angioplasty on TDR, the Tp-e/QTc ratio was studied in patients with ACS undergoing angioplasty. Method: An observational, retrospective and descriptive study was designed. 150 patients (N = 150) with diagnosis of ACS were included. The initial Tp-e/QTc ratio was assessed and then its post-angioplasty shortening was evaluated. As a secondary objective, we compared the association of these Tp-e/QTc ratio changes with cardiovascular mortality and cardiovascular adverse events. Results: The average in the initial Tp-e/QTc ratio was 0.2529, while post-angioplasty was 0.2397. Through a Wilcoxon rage test, a significant decrease in the Tp-e/QTc ratio after angioplasty was observed, with a Z value of −2.051 and p < 0.04. In the secondary analysis, it was found that a Tp-e/QTc ≥ 0.29 post-angioplasty is a risk factor for presenting the following adverse events: in-hospital death (7.4 vs. 0%; p < 0.003), new ACS in 1-year follow-up (25.9 vs. 18.5%; p < 0.006), and reintervention in 1-year follow up (29.6 vs. 15%; p < 0.002). Conclusions: There is a significant shortening in the Tp-e/QTc ratio post-angioplasty in patients with ACS. This measure of TDR can serve as a predictor of in-hospital death, cardiovascular events and 1-year reintervention in patients with ACS treated initially by angioplasty.

Acortamiento en la relación Tp-f/QTc tras angioplastia en pacientes con síndrome isquémico coronario agudo / Shortening in the Tp-e/QTc ratio after angioplasty in patients with acute coronary syndrome

Resumen Objetivo: La dispersión transmural de la repolarización ventricular (DTMRV) es un factor de riesgo para muerte en pacientes con síndrome isquémico coronario agudo (SICA). Con el objetivo de conocer el efecto de la realización de angioplastia sobre la DTMRV, se estudió la relación Tp-f/QTc en pacientes con SICA sometidos a angioplastia. Método: Se diseñó un estudio observacional, retrospectivo y descriptivo. Se incluyeron 150 pacientes (N = 150) con diagnóstico de SICA. Se valoró la relación Tp-f/QTc inicial y se evaluó su acortamiento posangioplastia. Como objetivo secundario, se comparó la asociación de dichos cambios en la relación Tp-f/QTc con la mortalidad cardiovascular y los eventos adversos cardiovasculares. Resultados: El promedio en la relación Tp-f/QTc inicial fue de 0.2529, mientras que posangioplastia fue de 0.2397. Por medio de prueba de rangos de Wilcoxon se evidenció un descenso significativo en la relación Tp-f/QTc posterior a la angioplastia, con un valor Z de −2.051 y una p < 0.04. En el análisis secundario se encontró que una Tp-f/QTc ≥ 0.29 posangioplastia es factor de riesgo para presentación de los siguientes eventos adversos: muerte intrahospitalaria (7.4 vs 0%; p < 0.003), nuevo SICA en seguimiento a 1 año (25.9 vs. 18.5%; p < 0.006) y reintervención en seguimiento a 1 año (29.6 vs. 15.0%; p < 0.002). Conclusiones: Existe un acortamiento significativo en la relación Tp-f/QTc posangioplastia en pacientes con SICA. Esta medida de la DTMRV puede servir como un predictor de muerte intrahospitalaria, eventos cardiovasculares y reintervención a 1 año en pacientes con SICA tratados con angioplastia.

Abstract Objective: Transmural Dispersion of Repolarization (TDR) is a Risk factor for Death in patients with Acute Coronary Syndrome (ACS). In order to know the effect of angioplasty on TDR, the Tp-e/QTc ratio was studied in patients with ACS undergoing angioplasty. Method: An observational, retrospective and descriptive study was designed. 150 patients (N = 150) with diagnosis of ACS were included. The initial Tp-e/QTc ratio was assessed and then its post-angioplasty shortening was evaluated. As a secondary objective, we compared the association of these Tp-e/QTc ratio changes with cardiovascular mortality and cardiovascular adverse events. Results: The average in the initial Tp-e/QTc ratio was 0.2529, while post-angioplasty was 0.2397. Through a Wilcoxon rage test, a significant decrease in the Tp-e/QTc ratio after angioplasty was observed, with a Z value of −2.051 and p < 0.04. In the secondary analysis, it was found that a Tp-e/QTc ≥ 0.29 post-angioplasty is a risk factor for presenting the following adverse events: in-hospital death (7.4 vs. 0%; p < 0.003), new ACS in 1-year follow-up (25.9 vs. 18.5%; p < 0.006), and reintervention in 1-year follow up (29.6 vs. 15%; p < 0.002). Conclusions: There is a significant shortening in the Tp-e/QTc ratio post-angioplasty in patients with ACS. This measure of TDR can serve as a predictor of in-hospital death, cardiovascular events and 1-year reintervention in patients with ACS treated initially by angioplasty.

Towards precision medicine: defining and characterizing adipose tissue dysfunction to identify early immunometabolic risk in symptom-free adults from the GEMM family study.

Interactions between macrophages and adipocytes are early molecular factors influencing adipose tissue (AT) dysfunction, resulting in high leptin, low adiponectin circulating levels and low-grade metaflammation, leading to insulin resistance (IR) with increased cardiovascular risk. We report the characterization of AT dysfunction through measurements of the adiponectin/leptin ratio (ALR), the adipo-insulin resistance index (Adipo-IRi), fasting/postprandial (F/P) immunometabolic phenotyping and direct F/P differential gene expression in AT biopsies obtained from symptom-free adults from the GEMM family study. AT dysfunction was evaluated through associations of the ALR with F/P insulin-glucose axis, lipid-lipoprotein metabolism, and inflammatory markers. A relevant pattern of negative associations between decreased ALR and markers of systemic low-grade metaflammation, HOMA, and postprandial cardiovascular risk hyperinsulinemic, triglyceride and GLP-1 curves was found. We also analysed their plasma non-coding microRNAs and shotgun lipidomics profiles finding trends that may reflect a pattern of adipose tissue dysfunction in the fed and fasted state. Direct gene differential expression data showed initial patterns of AT molecular signatures of key immunometabolic genes involved in AT expansion, angiogenic remodelling and immune cell migration. These data reinforce the central, early role of AT dysfunction at the molecular and systemic level in the pathogenesis of IR and immunometabolic disorders.

Deep Multi-OMICs and Multi-Tissue Characterization in a Pre- and Postprandial State in Human Volunteers: The GEMM Family Study Research Design.

Cardiovascular disease (CVD) and type 2 diabetes (T2D) are increasing worldwide. This is mainly due to an unhealthy nutrition, implying that variation in CVD risk may be due to variation in the capacity to manage a nutritional load. We examined the genomic basis of postprandial metabolism. Our main purpose was to introduce the GEMM Family Study (Genetics of Metabolic Diseases in Mexico) as a multi-center study carrying out an ongoing recruitment of healthy urban adults. Each participant received a mixed meal challenge and provided a 5-hours' time course series of blood, buffy coat specimens for DNA isolation, and adipose tissue (ADT)/skeletal muscle (SKM) biopsies at fasting and 3 h after the meal. A comprehensive profiling, including metabolomic signatures in blood and transcriptomic and proteomic profiling in SKM and ADT, was performed to describe tendencies for variation in postprandial response. Our data generation methods showed preliminary trends indicating that by characterizing the dynamic properties of biomarkers with metabolic activity and analyzing multi-OMICS data it could be possible, with this methodology and research design, to identify early trends for molecular biology systems and genes involved in the fasted and fed states.

Palliative Care Needs in an Acute Internal Medicine Ward in Mexico.

BACKGROUND: Palliative care is an evolving but underdeveloped practice in Mexico. OBJECTIVE: The primary end point of this prospective observational study was to identify internal medicine inpatients fulfilling advanced criteria within a second-level hospital. Secondary end points were symptom burden, treatment, resource utilization, and one-year survival. DESIGN AND MEASUREMENTS: The 390-sample size calculation was based on previous studies where 15% of inpatients fulfilled palliative care needs. Consecutive admissions were assessed to identify patients with any of the following: cancer, cardiac, renal, hepatic insufficiency, COPD, AIDS, stroke, or fragility until sample size was completed. After obtaining informed consent, interview to patient, attending physician, and chart review was completed to identify any of the following advanced disease criteria in each patient: (1) Surprise question to attending physician of the possibility of the patient dying in the following year, (2) Palliative Performance Scale (PPS) <50, and (3) Advanced disease specific criteria. Interview also included presence of symptoms, functional capacity, and previous resource utilization. Treatment offered was analyzed only on day of admission. One-year follow-up to assess survival was done through the state death certificates. RESULTS: Out of 390 patients, 131 (34%) had any of the diseases studied. Out of 131 patients, 86 (66%) had at least one of the three inclusion criteria for advanced disease. Out of 86 patients, 70 (81%) advanced disease patients died after one-year follow-up. Comparison between patients with no advanced disease (no criteria) versus advanced disease (at least one criteria) showed a significant difference in mean PPS, nutrition status, survival days, inhospital death, weight loss, dependency on activities of daily living, and previous multiple emergency room visits. Advanced disease patients with no death at one year follow-up had significantly more new admissions to that hospital. CONCLUSIONS: The number of patients requiring palliative care in internal medicine wards may be excessive to the current palliative care structures available.

Integrating genomic analysis with the genetic basis of gene expression: preliminary evidence of the identification of causal genes for cardiovascular and metabolic traits related to nutrition in Mexicans.

Whole-transcriptome expression profiling provides novel phenotypes for analysis of complex traits. Gene expression measurements reflect quantitative variation in transcript-specific messenger RNA levels and represent phenotypes lying close to the action of genes. Understanding the genetic basis of gene expression will provide insight into the processes that connect genotype to clinically significant traits representing a central tenet of system biology. Synchronous in vivo expression profiles of lymphocytes, muscle, and subcutaneous fat were obtained from healthy Mexican men. Most genes were expressed at detectable levels in multiple tissues, and RNA levels were correlated between tissue types. A subset of transcripts with high reliability of expression across tissues (estimated by intraclass correlation coefficients) was enriched for cis-regulated genes, suggesting that proximal sequence variants may influence expression similarly in different cellular environments. This integrative global gene expression profiling approach is proving extremely useful for identifying genes and pathways that contribute to complex clinical traits. Clearly, the coincidence of clinical trait quantitative trait loci and expression quantitative trait loci can help in the prioritization of positional candidate genes. Such data will be crucial for the formal integration of positional and transcriptomic information characterized as genetical genomics.

Glucotoxicidad en la diabetes mellitus no dependiente de insulina / Glucose toxic effect upon non insuline dependent diabetes mellitus

Se ha encontrado defecto específico en el glucorreceptor de pacientes con diabetes mellitus no insulino dependiente (DMNID), aunque existe poca información de los efectos tóxicos de la glucosa sobre la función de la célula beta cuando ésta es estimulada por un agente diferente de la glucos. En el presente informe se analiza la respuesta de insulina en seis pacientes con DMNID crónicamente descompensados a una carga oral de 75 g de glucosa, y posteriormente a 1 mg de glucagon endovenoso, una vez compensados los pacientes, se repitió el mismo protocolo. La concentración de insulina sérica antes de la compensasión fue de 96 96 ñ 32 uU/mL, con una relación glucosa/insulina de 0.343 (p=NS); después de la compensación la concentración de insulina alcanzó 154 ñ 67 uU/mL, (