Hemodialysis access placement with preoperative noninvasive vascular mapping: comparison between patients with and without diabetes

We retrospectively analyzed data on preoperative vascular mapping in 195 consecutive patients to investigate the common belief that patients with diabetes are poor candidates to have an arteriovenous fistula placed as dialysis access because they lack suitable blood vessels. There was no difference in venous diameter, arterial diameter, and arterial peak systolic velocity measurements between patients with and without diabetes. Patients with diabetes had a greater prevalence of vascular calcifications and greater cuff measurements of systolic segmental arterial pressure. In 140 of 195 patients, subsequent vascular access surgery had been performed in our institution, and 127 of these patients were on hemodialysis therapy at the end of the study period. There was no difference in the prevalence of fistula placement (66% versus 60%; chi-square = 2.6; df = 2; P = 0.28, not significant [NS]) and percentage of functioning fistulae between patients with and without diabetes (67% versus 62%; chi-square = 0.27; df = 1; P = 0.61, NS). The percentage of patients dialyzed through a temporary catheter was equal in patients with and without diabetes (18%). In summary, patients with diabetes seem to be as good candidates for arteriovenous fistula placement as patients without diabetes. Additional studies are required to determine the long-term outcome of fistulae in patients with diabetes.     

The role of advanced glycation end products in the development of atherosclerosis

Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Atherosclerosis constitutes the main pattern of cardiovascular disease and leads to thickening of the intima with plaque formation and eventual occlusion of the arterial lumen. A large amount of evidence links advanced glycation end products (AGEs) with the development or progression of atherosclerosis, regardless of the diabetic status. AGEs are a heterogenous group of compounds formed by the nonenzymatic reaction of reducing sugars with proteins, lipids, and nucleic acids. Although AGEs are formed endogenously in the body, diet has recently been recognized as an important exogenous source. An increased understanding of the mechanisms of formation and interaction of AGEs has allowed the development of several potential anti-AGE approaches.     

Proangiogenic role of tumor-activated hepatic stellate cells in experimental melanoma metastasis

Myofibroblasts infiltrate malignant liver tumors, although their pathogenic implications are unclear. Immunohistochemical detection of alpha-smooth muscle actin, glial fibrillary acidic protein (GFAP), and CD31 and CD34 expression was used to analyze the contribution of myofibroblasts to angiogenesis in hepatic metastasis produced by intrasplenically-injected B16 melanoma (B16M). Because activated hepatic stellate cells (HSCs) are oxygen-sensing myofibroblasts producing vascular endothelial growth factor (VEGF), the effect of B16M and human A375 melanoma supernatants on VEGF production by immortalized rat HSC line T6 and primary cultured human HSCs also was studied under an hypoxic atmosphere mimicking a tumor microenvironment. Myofibroblast infiltration preceded endothelium recruitment in avascular micrometastasis and generated specific stroma for sinusoidal-type and portal-type angiogeneses. Thereafter, myofibroblasts and endothelial cells colocalized within both angiogenic patterns and their numerical densities correlated with metastasis development. Myofibroblasts often were GFAP-positive, suggesting an HSC origin. Melanoma supernatants stimulated VEGF messenger RNA and protein synthesis by HSCs. These effects were potentiated by hypoxia. VEGF up-regulation was accompanied by increased expression of cyclooxygenase type 2 (COX-2) and PGE2 synthesis. HSC production of VEGF decreased under COX-2 inhibition, whereas it was increased by exogenous PGE2. The high VEGF expression in HSCs induced by melanoma factors and hypoxia resulted in mitogenic, antiapoptotic, and motogenic stimulation of both murine hepatic sinusoidal endothelium and human umbilical vein endothelium. In conclusion, temporal and positional relationships evolve between myofibroblast and endothelium recruitment during metastasis development. Mechanistically, hypoxic induction of VEGF in tumor-activated HSCs may create a proangiogenic microenvironment, facilitating endothelial cell recruitment and survival during hepatic metastasis transition from an avascular to a vascular stage.     

DNA methylation clocks for dogs and humans

DNA methylation profiles have been used to develop biomarkers of aging known as epigenetic clocks, which predict chronological age with remarkable accuracy and show promise for inferring health status as an indicator of biological age. Epigenetic clocks were first built to monitor human aging, but their underlying principles appear to be evolutionarily conserved, as they have now been successfully developed for many mammalian species. Here, we describe reliable and highly accurate epigenetic clocks shown to apply to 93 domestic dog breeds. The methylation profiles were generated using the mammalian methylation array, which utilizes DNA sequences that are conserved across all mammalian species. Canine epigenetic clocks were constructed to estimate age and also average time to death. We also present two highly accurate human–dog dual species epigenetic clocks (R = 0.97), which may facilitate the ready translation from canine to human use (or vice versa) of antiaging treatments being developed for longevity and preventive medicine. Finally, epigenome-wide association studies here reveal individual methylation sites that may underlie the inverse relationship between breed weight and lifespan. Overall, we describe robust biomarkers to measure aging and, potentially, health status in canines.

Ideally, model species for antiaging research should be representative of human characteristics such as size and genetic diversity, as well as shared environment. Domestic dogs (Canis lupus familiaris) fulfill most of these criteria, offering a unique opportunity to evaluate the effectiveness of emerging antiaging interventions (1–5). There is also a significant need to develop health-monitoring tools for dogs, as there are more than 76 million companion dogs in the United States alone (6).Over 340 dog breeds are recognized worldwide, which are each a closed breeding population under strong selection for morphologic and behavioral traits. As a result, dogs share extensive phenotypic and genetic homogeneity within breeds and increased heterogeneity between breeds (7). Small breeds live considerably longer than large breeds (8), offering the rare chance to understand the relationship between size and lifespan within a single mammalian species. Dogs also share a similar yet accelerated trajectory of development as humans including infancy, puberty, adulthood, and senescence in about 20% of the human lifespan (5, 9). As a result, dogs represent an ideal system for studies of comparative aging, where intrabreed studies can be conducted on a background of limited diversity.Our previous work on DNA-methylation-based age estimators (i.e., epigenetic clocks) for dogs and wolves (10) described one of the first nonhuman epigenetic clocks. We determined that the age dependence of DNA methylation (DNAm) is conserved at syntenic sites in the genomes of multiple mammalian species including humans. However, a small sample size (n < 150) and technical limitations associated with the measurement platform (reduced representation bisulfite sequencing) limited the generalizability of the results. Furthermore, our initial study utilized only a few canine breeds, which prevented testing the relationship between epigenetic aging and breed lifespan. Here, we report the development of a canine epigenetic clock based on 93 recognized dog breeds (11) using a mammalian array (HorvathMammalMethylChip40) that profiles highly conserved cytosines across mammalian species (12).In this study, we present dual-species epigenetic clocks that apply to both humans and dogs. We test whether short-lived breeds exhibit faster epigenetic aging than long-lived breeds and develop epigenetic predictors of the average time to death. Finally, we investigate the relationship between breed size and lifespan and characterize 5''-C-phosphate-G-3'' regions (CpGs) that are correlated with age or breed characteristics such as median lifespan or average adult weight.     

Electrocardiographic Characteristics and Associated Outcomes in Patients with Takotsubo Syndrome. Insights from the RETAKO Registry

Electrocardiographic disturbances in Takotsubo syndrome have been previously partially described but their consequences remain mostly unknown. Our aim was to describe the prevalence and prognostic significance of different electrocardiographic features in patients with Takotsubo syndrome. Our data come from the Spanish multicenter REgistry of TAKOtsubo syndrome (RETAKO). All patients with an available 12-lead surface electrocardiogram at admission and 48 hours post-admission were included. A total of 246 patients were studied, mean age was 71.3 ± 11.5 and 215 (87.4%) were women. ST-segment elevation was seen in 143 patients (59.1%) and was present in ≥2 wall leads in 97 (39.8%). Exclusive elevation in inferior leads was infrequent (5% - 2.0%). After 48 hours, 198 patients (88.0%) developed negative T waves in a median of 8 leads with a mean amplitude of 0.7 ± 0.5 mV and 137 (60.9%) had pathological Q waves. The mean corrected QT interval was 520 ± 72 ms. Corrected QT interval was independently associated with the primary endpoint of all-cause death and nonfatal cardiovascular events (P = 0.002) and all-cause death (P = 0.008). A higher heart rate at admission was an independent predictor of the primary endpoint (P = 0.001) and of acute pulmonary edema (P = 0.04). ST-segment elevation with reciprocal depression was an independent predictor of all-cause death (P = 0.04). Absence of ST-segment deviation was a protective factor (P = 0.005) for the primary endpoint. Tachyarrhythmias were independently associated with cardiogenic shock (P< 0.001). Takotsubo syndrome patients present with distinct electrocardiographic features. Prolonged corrected QT interval, tachyarrhythmias, heart rate at admission, and more extensive repolarization alterations are associated with poor outcomes.