Prioritizing cardiovascular disease-associated variants altering NKX2-5 and TBX5 binding through an integrative computational approach.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide and are heavily influenced by genetic factors. Genome-wide association studies have mapped >90% of CVD-associated variants within the noncoding genome, which can alter the function of regulatory proteins, such as transcription factors (TFs). However, due to the overwhelming number of single-nucleotide polymorphisms (SNPs) (>500,000) in genome-wide association studies, prioritizing variants for in vitro analysis remains challenging. In this work, we implemented a computational approach that considers support vector machine (SVM)-based TF binding site classification and cardiac expression quantitative trait loci (eQTL) analysis to identify and prioritize potential CVD-causing SNPs. We identified 1535 CVD-associated SNPs within TF footprints and putative cardiac enhancers plus 14,218 variants in linkage disequilibrium with genotype-dependent gene expression in cardiac tissues. Using ChIP-seq data from two cardiac TFs (NKX2-5 and TBX5) in human-induced pluripotent stem cell-derived cardiomyocytes, we trained a large-scale gapped k-mer SVM model to identify CVD-associated SNPs that altered NKX2-5 and TBX5 binding. The model was tested by scoring human heart TF genomic footprints within putative enhancers and measuring in vitro binding through electrophoretic mobility shift assay. Five variants predicted to alter NKX2-5 (rs59310144, rs6715570, and rs61872084) and TBX5 (rs7612445 and rs7790964) binding were prioritized for in vitro validation based on the magnitude of the predicted change in binding and are in cardiac tissue eQTLs. All five variants altered NKX2-5 and TBX5 DNA binding. We present a bioinformatic approach that considers tissue-specific eQTL analysis and SVM-based TF binding site classification to prioritize CVD-associated variants for in vitro analysis.

Infection of porcine small intestinal enteroids with human and pig rotavirus A strains reveals contrasting roles for histo-blood group antigens and terminal sialic acids.

Rotaviruses (RVs) are a leading cause of acute viral gastroenteritis in young children and livestock worldwide. Growing evidence suggests that host cellular glycans, such as histo-blood group antigens (HBGAs) and sialic acids (SA), are recognized by the RV surface protein VP4. However, a mechanistic understanding of these interactions and their effects on RV infection and pathogenesis is lacking. Here, we established a porcine crypt-derived 3D intestinal enteroids (PIEs) culture system which contains all intestinal epithelial cells identified in vivo and represents a unique physiologically functional model to study RV-glycan interactions in vitro. PIEs expressing different HBGAs (A+, H+, and A+/H+) were established and isolation, propagation, differentiation and RV infection conditions were optimized. Differentiated PIEs were infected with human RV (HRV) G1P[8] Wa, porcine RV (PRV) G9P[13], PRV Gottfried G4P[6] or PRV OSU G5P[7] virulent and attenuated strains and virus replication was measured by qRT-PCR. Our results indicated that virulent HRV G1P[8] Wa replicated to the highest titers in A+ PIEs, while a distinct trend was observed for PRV G9P[13] or G5P[7] with highest titers in H+ PIEs. Attenuated Wa and Gottfried strains replicated poorly in PIEs while the replication of attenuated G9P[13] and OSU strains in PIEs was relatively efficient. However, the replication of all 4 attenuate strains was less affected by the PIE HBGA phenotypes. HBGA synthesis inhibitor 2-F-Peracetyl-Fucose (2F) treatment demonstrated that HBGAs are essential for G1P[8] Wa replication; however, they may only serve as a cofactor for PRVs G9P[13] and OSU G5P[7]. Interestingly, contrasting outcomes were observed following sialidase treatment which significantly enhanced G9P[13] replication, but inhibited the growth of G5P[7]. These observations suggest that some additional receptors recognized by G9P[13] become unmasked after removal of terminal SA. Overall, our results confirm that differential HBGAs-RV and SA-RV interactions determine replication efficacy of virulent group A RVs in PIEs. Consequently, targeting individual glycans for development of therapeutics may not yield uniform results for various RV strains.

Congenital Absence of the Pericardium: A Systematic Approach to Diagnosis and Management.

Congenital absence of the pericardium (CAP) is a rare condition. Failure to recognize the clinical features of this condition can lead to incorrect and delayed diagnosis. Limited data are available regarding the optimal approach to diagnose and manage patients with suspected CAP. Due to the rare nature of CAP, this condition can present diagnostic and management dilemmas for clinicians. Using 3 cases of CAP as a framework, a clinically focused review on the diagnosis and management of CAP is presented. Clinicians will be provided with a systematic approach to evaluating patients with suspected CAP, incorporating key history, examination, and multimodality cardiovascular imaging investigations.

Prioritizing Cardiovascular Disease-Associated Variants Altering NKX2-5 Binding through an Integrative Computational Approach.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide and are heavily influenced by genetic factors. Genome-wide association studies (GWAS) have mapped > 90% of CVD-associated variants within the non-coding genome, which can alter the function of regulatory proteins, like transcription factors (TFs). However, due to the overwhelming number of GWAS single nucleotide polymorphisms (SNPs) (>500,000), prioritizing variants for in vitro analysis remains challenging. In this work, we implemented a computational approach that considers support vector machine (SVM)-based TF binding site classification and cardiac expression quantitative trait loci (eQTL) analysis to identify and prioritize potential CVD-causing SNPs. We identified 1,535 CVD-associated SNPs that occur within human heart footprints/enhancers and 9,309 variants in linkage disequilibrium (LD) with differential gene expression profiles in cardiac tissue. Using hiPSC-CM ChIP-seq data from NKX2-5 and TBX5, two cardiac TFs essential for proper heart development, we trained a large-scale gapped k-mer SVM (LS-GKM-SVM) predictive model that can identify binding sites altered by CVD-associated SNPs. The computational predictive model was tested by scoring human heart footprints and enhancers in vitro through electrophoretic mobility shift assay (EMSA). Three variants (rs59310144, rs6715570, and rs61872084) were prioritized for in vitro validation based on their eQTL in cardiac tissue and LS-GKM-SVM prediction to alter NKX2-5 DNA binding. All three variants altered NKX2-5 DNA binding. In summary, we present a bioinformatic approach that considers tissue-specific eQTL analysis and SVM-based TF binding site classification to prioritize CVD-associated variants for in vitro experimental analysis.

Reactive hemophagocytic syndrome associated with disseminated histoplasmosis in a heart transplant recipient.

We describe a patient who developed multi-organ failure with reactive hemophagocytic syndrome secondary to disseminated histoplasmosis 8 months after orthotopic heart transplantation. The patient responded fully to a prolonged course of therapy with amphotericin B and remains free of recurrence. Disseminated histoplasmosis and reactive hemophagocytic syndrome have rarely been described in the setting of cardiac transplantation and never before in combination.

Metabolic syndrome and its components are underdiagnosed in cardiology clinics.

BACKGROUND: Although metabolic syndrome (MetS) is an important clinical condition, evidence is scarce on how often doctors successfully diagnose this syndrome. AIMS: To assess the extent of doctors' diagnosis of MetS and its components in cardiology outpatient setting and whether such diagnosis affects the way patients are counselled on lifestyle modification. METHODS: This is a multicentre cross-sectional study on randomly selected clinical notes at ambulatory cardiology clinics in three academic centres in the USA. We abstracted data on cardiovascular risk factors, and examined whether doctors documented a diagnosis of MetS and its components. RESULTS: Of 511 participants who satisfied our inclusion criteria, the MetS was present in 246 participants (48%). The proportions with which a doctor correctly documented diagnoses were: MetS 9.3% (23/246), obesity 60% (119/197), elevated blood pressure 74% (305/412), elevated fasting glucose 17% (49/291), reduced high density lipoprotein cholesterol 10% (18/190) and elevated triglycerides 20% (32/164). This pattern of diagnoses, less frequent with dyslipidaemia and elevated fasting glucose compared with the rest, was persistently observed regardless of sex, age, and presence or absence of MetS. Those diagnosed were more likely to receive a recommendation of weight loss or increase in physical activity than those undiagnosed: 91% (21/23) versus 37% (82/223) for weight loss, and 83% (19/23) versus 26% (58/223) for increase in physical activity (P < 0.001 for both). CONCLUSIONS: Our data indicate that MetS and its components are commonly underdiagnosed in cardiology outpatient setting. Better diagnosis may lead to better counselling on lifestyle changes and improvement in the quality of care.

Tumor neuroendocrino gástrico / Gastric neuroendocrine tumor

Es a partir de las células similares a las enterocromafines (ECL) que se forman tumores neuroendocrinos gástricos, con una incidencia muy variable según la literatura, pudiendo ser de 2 por ciento a 41 por ciento de todos los tumores neuroendocrinos y representando hasta un 0.3 por ciento de las neoplasias malignas de estómago, siendo más frecuentes en pacientes mayores de 60 años y afectando por igual a ambos sexos. Estos tumores se forman a partir de una proliferación acelerada de las células ECL que se da como respuesta a la hipersecreción de gastrina, situación que se observa en las gastritis atróficas y el síndrome de Zollinger-Ellison. Por lo anterior se informa el caso de una mujer de 51 años con epigastralgia de tres meses de evolución, acompañada de distensión abdominal y constipación ocasional, para la cual recibió ranitidina y metoclopramida. Ante la persistencia del cuadro se le realizó una endoscopia alta con reporte de gastritis atrófica y pólipos gástricos, realizándose resección y estudio histopatológico compatible con tumor neuroendocrino, con tinciones para serotonina y gastrina levemente positivas y glucagon negativas. Se realizó la determinación de hormonas luteinizante, foliculoestimulante, estradiol, ACTH, progesterona, clacitonina y cortisol, todos con resultados normales. Se reportó elevado el nivel sérico de gastrina con 500 pg/mL. El rastreo gamagráfico con octreotida fue negativo para metástasis