Reduced prognostic power of ventricular late potentials in post-infarction patients of the reperfusion era.

AIMS: To test the prognostic value of ventricular late potentials (LPs) in a large cohort of post-infarction patients in the modern reperfusion era. METHODS AND RESULTS: 1800 consecutive survivors of acute myocardial infarction in sinus rhythm and under 76 years of age were enrolled. Many (99%) of the patients received reperfusion/revascularization therapy (91% percutaneous coronary intervention) and up-to-date pharmacological treatment (99% aspirin, 93% beta-blockers, 90% ACE-inhibitors, and 85% statins). LPs were calculated in 968 patients and found to be present in 90 (9.3%). The primary endpoint was the composite of cardiac death and serious arrhythmic events. The secondary endpoint was the composite of sudden cardiac death and serious arrhythmic events. During follow-up (median 34 months), 26 patients reached the primary endpoint. The presence of LPs was not significantly associated with the primary endpoint in univariable or multivariable analysis. In contrast, low (< or = 30%) left ventricular ejection fraction (hazard ratio 9.6, 95% confidence interval 4.1-22.4), heart rate turbulence category 2 (7.5, 2.4-23.9) and category 1 (5.3, 1.9-14.9) were significant predictors in both univariable and multivariable analysis. CONCLUSION: Ventricular LPs are of limited use for risk stratification in unselected post-infarction patients in the modern reperfusion era.     

Chronic Total Left Main Coronary Artery Occlusion— A Case Report

We report on the clinical and angiographic data of a patient suffering from total chronic occlusion of the left main coronary artery. For many years the patient’s only complaint was of mild stable angina (CCS I). He had a history of a previous acute myocardial infarction 20 years ago, possibly caused by the occlusion of the left main coronary artery. The anatomic and clinical findings of chronic total occlusion of the left main coronary artery during his life are discussed.     

Histological patterns of synovitis and serum chemokines in patients with rheumatoid arthritis

OBJECTIVE: Studies indicate the genetic, biological, and clinical heterogeneity of rheumatoid arthritis (RA). Recently the histological diversity of RA has been postulated. We investigated whether serum concentrations of interleukin 8 (IL-8), RANTES (regulated upon activation normal T cell expressed and secreted), and monocyte chemoattractant protein-1 (MCP-1) are correlated with histological appearance of the rheumatoid synovitis. METHODS: Using ELISA we assessed IL-8, RANTES, and MCP-1 concentrations in serum of 47 patients with RA and 30 patients with osteoarthritis (OA). RESULTS: Morphological analysis of synovial specimens distinguished 2 types of rheumatoid synovitis. Twenty-eight RA samples presented diffuse infiltrates of mononuclear cells with no specific microanatomical organization and were categorized as diffuse synovitis. In the remaining 19 specimens, classified as follicular synovitis, formation of lymphocytic follicles with germinal center-like structures was observed. Serum levels of studied chemokines were increased in patients with RA compared to the OA control group (p < 0.001 for all comparisons). Concentrations of IL-8, RANTES, and MCP-1 were highest in serum of RA patients with follicular synovitis in comparison with patients with diffuse synovitis (p < 0.01, p < 0.01, and p < 0.05, respectively) and could distinguish RA patients with these 2 histological disease patterns. Serum levels of chemokines correlated with markers of disease activity such as erythrocyte sedimentation rate, C-reactive protein concentrations, and Disease Activity Score. CONCLUSION: Distinct histological variants of rheumatoid synovitis associated with different serum levels of IL-8, RANTES, and MCP-1 reflect clinical activity of the disease and confirm the concept of RA heterogeneity.     

Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells

Mouse embryonic stem (ES) cells differentiate into cells of all three primary germ layers including endodermal cells that produce insulin in vitro. We show that constitutive expression of Pax4 (Pax4(+)), and to a lesser extent Pdx1 (Pdx1(+)), affects the differentiation of ES cells and significantly promote the development of insulin-producing cells. In Pax4 overexpressing R1 ES cells, isl-1, ngn3, insulin, islet amyloid polypeptide, and glucose transporter 2 (Glut-2) mRNA levels increase significantly. The number of nestin-expressing (nestin+) cells also increases. Constitutive Pax4 expression combined with selection of nestin+ cells and histotypic culture conditions give rise to spheroids containing insulin-positive granules typical of embryonal and adult beta cells. In response to glucose, Pax4(+) and wild-type ES-derived cells release insulin. Transplantation of these cells into streptozotocin-treated diabetic mice results in a normalization of blood glucose levels. We conclude that constitutive expression of Pax4 in combination with histotypic cultivation facilitates ES cell differentiation into the pancreatic lineage, which leads to the formation of islet-like spheroid structures that produce increased levels of insulin.     

Totally epicardial cardiac resynchronization therapy system implantation in patients with heart failure undergoing CABG

BACKGROUND: Systolic dyssynchrony is present in a considerable number of patients with heart failure (HF) undergoing coronary artery bypass grafting (CABG). Surgical revascularization offers an optimal setting for totally epicardial cardiac resynchronization therapy (CRT) system implantation. AIM: To assess the efficacy of totally epicardial CRT implantation during CABG, in patients with HF. METHODS: Twenty three patients with HF and dyssynchrony underwent totally epicardial CRT system implantation during CABG. This randomised, single-blind, cross-over study compared clinical and echocardiographic parameters during two periods: 3 months of active CRT (CRT+) and 3 months of inactive CRT (CRT-) pacing. RESULTS: Twenty two patients underwent randomisation and completed both study periods. In the CRT+ group more patients improved by two NYHA classes (p=0.028), had a longer 6-minute walk test distance (p=0.047) and better quality of life (p=0.003) compared with the CRT- group. Echocardiography revealed an improved LV ejection fraction (p<0.001), smaller LV end-systolic volume (p=0.04), reduced mitral regurgitation (p=0.026) and improved LV synchrony in the CRT+ group compared with the CRT- group. CONCLUSION: CRT delivered by a totally epicardial system implanted during CABG is associated with additional improvement of clinical and echocardiographic parameters in patients with HF and systolic dyssynchrony.     

The Long Noncoding RNA Landscape of Cardiac Regeneration in Zebrafish

BackgroundNovel therapeutic targets of heart failure (HF) are needed. Long noncoding RNAs (lncRNAs) are engaged during cardiac regeneration. Unlike in humans, zebrafish naturally undergo cardiac regeneration after HF. We aimed to describe the landscape of lncRNAs during regeneration in a zebrafish model of HF and to investigate their human homologs.MethodsHF was established in adult zebrafish through thrice-weekly incubations with an anemia-inducing drug, phenylhydrazine hydrochloride (PHZ). After 5 weeks, PHZ treatment ceased and the fish were followed through a regeneration period of 14 days. Total RNA was extracted from the hearts of adult zebrafish after establishment of HF and at 2, 5, and 9 days after treatment cessation (9 hearts per condition at each time point). Gene regulation patterns were characterized with the use of bioinformatics and validated with the use of quantitative polymerase chain reaction.ResultsWe obtained 14,340 lncRNAs from the reannotated Affymetrix zebrafish microarray. Of these, 187 lncRNAs were found to be differentially expressed (false discovery rate < 0.05 and fold change ≥ 2) at at least 1 time point. 85% of differentially expressed lncRNAs overlapped or were close to (distance < 10 kb) protein-coding genes which were mostly related to muscle development in Gene Ontology analyses. Fifty-seven lncRNAs had human homologs, according to orientation relative to their conserved protein-coding neighbours.ConclusionsLncRNAs are differentially expressed during regeneration after HF in adult zebrafish and could be potential future therapeutic targets. The extent to which lncRNAs contribute to cardiac regeneration is a worthy avenue for future research.     

Comparison of high‐resolution melting analysis with direct sequencing for the detection of recurrent mutations in DNA methyltransferase 3A and isocitrate dehydrogenase 1 and 2 genes in acute myeloid leukemia patients

Acute myeloid leukemia (AML) cells harbor frequent mutations in genes responsible for epigenetic modifications. Increasing evidence of clinical role of DNMT3A and IDH1/2 mutations highlights the need for a robust and inexpensive test to identify these mutations in routine diagnostic work‐up. Herein, we compared routinely used direct sequencing method with high‐resolution melting (HRM) assay for screening DNMT3A and IDH1/2 mutations in patients with AML. We show very high concordance between HRM and Sanger sequencing (100% samples for IDH2‐R140 and DNMT3‐R882 mutations, 99% samples for IDH1‐R132 and IDH2‐R172 mutations). HRM method reported no false‐negative results, suggesting that it can be used for mutations screening. Moreover, HRM displayed much higher sensitivity in comparison with DNA sequencing in all assessed loci. With Sanger sequencing, robust calls were observed when the sample contained 50% of mutant DNA in the background of wild‐type DNA. In marked contrast, the detection limit of HRM improved down to 10% of mutated DNA. Given the ubiquitous presence of wild‐type DNA background in bone marrow aspirates and clonal variations regarding mutant allele burden, these results favor HRM as a sensitive, specific, labor‐, and cost‐effective tool for screening and detection of mutations in IDH1/2 and DNMT3A genes in patients with AML.     

Control of bud activation by an auxin transport switch

In many plant species only a small proportion of buds yield branches. Both the timing and extent of bud activation are tightly regulated to produce specific branching architectures. For example, the primary shoot apex can inhibit the activation of lateral buds. This process is termed apical dominance and is dependent on the plant hormone auxin moving down the main stem in the polar auxin transport stream. We use a computational model and mathematical analysis to show that apical dominance can be explained in terms of an auxin transport switch established by the temporal precedence between competing auxin sources. Our model suggests a mechanistic basis for the indirect action of auxin in bud inhibition and captures the effects of diverse genetic and physiological manipulations. In particular, the model explains the surprising observation that highly branched Arabidopsis phenotypes can exhibit either high or low auxin transport.     

Massive J-waves in the context of intracranial hemorrhage

Transient ST-segment elevation may be caused by conditions other than myocardial ischemia, among them intracranial hemorrhage. Recognition of the underlying etiology of these ST-segment changes is key because of the vastly different therapies used to treat them. We describe the case of a patient with massive transient J-waves and ST-segment elevation in the context of an intracranial hemorrhage.