The involvement of Kidney DNA methylation in blood pressure regulation

Background and aims: Increasing evidence suggests that epigenetic modifications such as DNA methylation (5mC) is important to the development of essential hypertension, and that changes in DNA methylation of blood cells is associated to blood pressure (BP). So far there has been no studies of epigenetic changes in the kidney - an important effector organ in BP regulation. The aim of this study was to compare the global and gene specific methylation status in the kidney between normal and hypertensive subjects. Methods and results: We used 96 human renal tissue samples from the TRANScriptome of RenaL HumAN TissueE (TRANSLATE) Study to measure DNA methylation. TRANSLATE consists of carefully characterised collections of “apparently healthy” specimens of human kidneys. DNA was extracted from peripheral blood leukocytes and kidney tissue using the DNeasy blood and tissue Qiagen kit. Global methylation was measured by ELISA assay to determine the percentage of 5mC and loci specific methylation status was determined using Infinium HumanMethylation 450K array (Illumina®, Australia). A significant negative relationship was found in the renal samples between 5mC% and systolic (SBP) and diastolic (DBP) blood pressure readings (SBP r=-0.25, P=<0.05), DBP r=-0.32, P=<0.01). This correlation was also evident when BP is adjusted for hypertensive medication effects (adjusted SBP P=<0.05, adjusted DBP P=<0.01). There was no significant relationship in DNA extracted from peripheral blood leukocytes between 5mC% and BP reading. We found 275 loci differentially methylated between hypertensive and normotensive individuals. Conclusions: DNA methylation is an important molecular mechanism for BP and hypertension in humans Maciej D Tomaszewski3, Fadi J Charchar4

The Acute Effects of Cardiorespiratory Exercise on Telomere-Associated Genes and MicroRNA Expression in Immune Cell Subsets.

The acute effects of cardiorespiratory exercise on telomere-associated genes and microRNA expression in immune cell subsets. CHILTON WL, MARQUES FZ, O’BRIEN BJ, and CHARCHAR F. School of Health Sciences; University of Ballarat; Victoria, Australia. ABSTRACT Telomeres are specialized nucleoprotein structures that protect the ends of linear chromosomes from degradation. Habitual physical activity is positively associated with longer leukocyte telomere length; however the molecular mechanisms underpinning the association are unclear. Human telomerase reverse transcriptase (hTERT) is the rate-limiting component of the telomere extending enzyme telomerase. The effective functioning of the adaptive immune system depends heavily upon the replicative potential of T cells, which is largely determined by telomere length and hTERT expression. Sirtuin 6 (SIRT6) also serves important pro-telomeric functions via an interaction with telomeric chromatin and regulatory roles in genome stabilization and DNA repair. It is unknown if cardiorespiratory exercise acutely regulates mRNA levels of hTERT, SIRT6 or other telomere-associated genes in white blood cells in general and T cell subsets in particular. Additionally, the exercise-induced regulation of microRNAs (short, non-coding RNA molecules that negatively regulate gene expression) with potential telomeric functions is unknown. Twenty-three healthy males (mean age=23.96 ±1.49 years) undertook 30min of treadmill running at 80% of previously determined VO2peak. Blood samples were taken before exercise, immediately post-exercise and 60min post-exercise. White blood cells and flow cytometry-sorted T cell subsets were assessed via quantitative polymerase chain reaction for differential regulation of telomeric genes and microRNAs. Expression levels of hTERT and SIRT6 mRNA were up-regulated following exercise in white blood cells and various T cell subsets (CD4+ naïve, CD4+ memory, CD8+ naïve, and CD8+ memory). Additionally, exercise differentially regulated several genes associated with telomere structure. A total of 56 microRNAs were differentially regulated post-exercise, six of which were investigated for potential telomeric functions. MicroRNAs-186, 636, 15a, and 96 showed significant up-regulation 60min post-exercise. MicroRNAs-186 and 636 showed detectable differential regulation in naïve and memory subsets. Intense cardiorespiratory exercise differentially regulated a host of telomeric genes in white blood cells and T cell subsets. Furthermore, it resulted in differential regulation of 56 microRNAs, some of which have binding potential to telomeric genes. Importantly, we demonstrated cell type-specific expression patterns in telomeric genes and microRNA. These results could have important implications for T cell-dependent immune functions and telomere homeostasis

Fasting triglycerides are positively associated with cardiovascular mortality risk in people with diabetes

Aims: We investigated the association of fasting triglycerides with cardiovascular disease (CVD) mortality. Methods and results: This cohort study included US adults from the National Health and Nutrition Examination Surveys from 1988 to 2014. CVD mortality outcomes were ascertained by linkage to the National Death Index records. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of triglycerides for CVD mortality. The cohort included 26 570 adult participants, among which 3978 had diabetes. People with higher triglycerides had a higher prevalence of diabetes at baseline. The cohort was followed up for a mean of 12.0 years with 1492 CVD deaths recorded. A 1-natural-log-unit higher triglyceride was associated with a 30% higher multivariate-adjusted risk of CVD mortality in participants with diabetes (HR, 1.30; 95% CI, 1.08–1.56) but not in those without diabetes (HR, 0.95; 95% CI, 0.83–1.07). In participants with diabetes, people with high triglycerides (200–499 mg/dL) had a 44% (HR, 1.44; 95% CI, 1.12–1.85) higher multivariate-adjusted risk of CVD mortality compared with those with normal triglycerides (<150 mg/dL). The findings remained significant when diabetes was defined by fasting glucose levels alone, or after further adjustment for the use of lipid-lowering medications, or after the exclusion of those who took lipid-lowering medications. Conclusion: This study demonstrates that fasting triglycerides of ≥200 mg/dL are associated with an increased risk of CVD mortality in patients with diabetes but not in those without diabetes. Future clinical trials of new treatments to lower triglycerides should focus on patients with diabetes

Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity

Dietary fatty acids and mortality risk from heart disease in US adults: an analysis based on NHANES

We investigated the association of dietary intake of major types of fatty acids with heart disease mortality in a general adult cohort with or without a prior diagnosis of myocardial infarction (MI). This cohort study included US adults who attended the National Health and Nutrition Examination Surveys from 1988 to 2014. Heart disease mortality was ascertained by linkage to the National Death Index records through 31 December 2015. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of fatty acid intake for heart disease mortality. This cohort included 45,820 adults among which 1,541 had a prior diagnosis of MI. Participants were followed up for 532,722 person-years (mean follow-up, 11.6 years), with 2,313 deaths recorded from heart disease being recorded. Intake of saturated (SFAs) and monounsaturated fatty acids (MUFAs) was associated with heart disease mortality after adjustment for all the tested confounders. In contrast, a 5% higher calorie intake from polyunsaturated fatty acids (PUFAs) was associated with a 9% (HR, 0.91; 95% CI 0.83–1.00; P = 0.048) lower multivariate-adjusted risk of heart disease mortality. Sub-analyses showed that this inverse association was present in those without a prior diagnosis of MI (HR,0.89; 95% CI 0.80–0.99) but not in those with the condition (HR, 0.94; 95% CI 0.75–1.16). The lack of association in the MI group could be due to a small sample size or severity and procedural complications (e.g., stenting and medication adherence) of the disease. Higher PUFA intake was associated with a favourable lipid profile. However, further adjustment for plasma lipids did not materially change the inverse association between PUFAs and heart disease mortality. Higher intake of PUFAs, but not SFAs and MUFAs, was associated with a lower adjusted risk of heart disease mortality in a large population of US adults supporting the need to increase dietary PUFA intake in the general public

Catalogue of Stone ScuIpture from the Area of Kula Atlagića

U radu se obrađuje problematika atribucije pojedinih kamenih ulomaka s lokaliteta Sv. Petar i Sv. Nikola u Kuli Atlagića. Većina se ulomaka čuva u Muzeju hrvatskih arheoloških spomenika u Splitu, a onamo su dospjeli u nekoliko etapa. Osim činjenice da pripadaju različitim stilskim epohama, postavlja se problem kako odrediti pripadnost ulomaka određenim objektima. U članku je priložen katalog kamenih ulomaka te njihova interpretacija. Rezultati rekognosciranja ponudili su nekoliko mogućih lokacija na kojima bi mogli biti objekti kojima pripadaju ulomci skulpture priloženi u katalogu, no tek sustavna arheološka iskopavanja mogu ponuditi sigurniju atribuciju.The village of Kula Atlagića is located 4km north-west of Benkovac in the direction of the medieval road via Magna which passed through the Zadar hinterland. The name of the village was first mentioned as late as the 17th century, while older documents mention two Croatian villages in that area: TihIići and Bojište (Bojišće). In today\u27s village stand three churches: two Orthodox dedicated to St Nicholas and one Catholic dedicated to St Peter. The two churches are mentioned in the archaeological literature at the beginning of the 20lh century. The church of St Nicholas in the Orthodox graveyard was completed in 1447 as witnessed by the inscription on the transom of the side portal, while the church of St Peter bears early Romanesque features, although it was destroyed several times during its turbulent history. The stone fragments which are presented in the catalogue were gathered over a long period of time. Some were brought to Knin on the prompting of Fra Lujo Marun while most of the sculptures were gathered after the Homeland War from the ruins of the church of St Peter, into which they had been incorporated as building material, and brought to the Museum of Croatian Archaeological Monuments in Split. According to their stylistic characteristics, the sculptures are divided into different groups: ancient, early medieval and early Romanesque. The problem which arose during the work on the sculptures was the attribution of individual groups to a particular object. The ancient sculptures could have belonged to a temple or shrine to the Roman god Liber which was probably located in the area around the church of St Nicholas as evidenced by entries in the diary of Fra Lujo Marun, who on several occasions made notes on both churches and the areas around them. The early medieval sculpture shows different characteristics and we could suppose that the earlier sculptures in this group were replaced by new furniture donated by some worthy benefactor. The question remains open as to where the early medieval church to which this furniture belonged was located. Numerous authors suppose that an early medieval church, which was in the 15\u27h century or earlier replaced by a new one, was situated on the site of today\u27s church of St Nicholas in the Orthodox graveyard. Because the investigations on this site have not been completed, we are left only with suppositions which could be confirmed by archaeological work. The fragments of early Romanesque sculpture are very specific and it is not possible to find close parallel s for them. The sculpture could be connected to the church of St Peter which was founded prior to the 12\u27b century, but investigations carried out in 1997 showed that this building had only one building phase and we cannot therefore talk of the possibility of the existence of an earlier church, at least not in the investigated area inside the church and in its immediate area. Translation: Nicholas Philip Saywel

The prevalence of cardiovascular risk factors and cardiovascular disease among primary care patients in Poland:results from the LIPIDOGRAM2015 study

BACKGROUND AND AIM: To estimate the prevalence of cardiovascular (CV) disease and CV risk factors among Polish patients. METHODS: A nationwide cross-sectional study, LIPIDOGRAM2015, was carried out in Poland in the 4th quarter of 2015 and 1st and 2nd quarters of 2016; 438 primary care physicians enrolled 13,724 adult patients that sought medical care in primary health care practices. RESULTS: Nearly 19% of men and approximately 12% of women had cardiovascular disease (CVD). Over 60% of the recruited patients had hypertension (HTN), >80% had dyslipidaemia and <15% of patients were diagnosed with diabetes (DM). All of these disorders were more frequent in men. In 80% of patients the waist circumference exceed norm for the European population. Less than half of the patients were current smokers or had smoked in the past. Patients with CVD had significantly higher blood pressure and glucose levels but lower low density lipoprotein-cholesterol level. CONCLUSIONS: The prevalence of CVD and CV risk factors among patients in Poland is high. CVD is more common in men than in women. The most common CV risk factors are excess waist circumference, dyslipidaemia and HTN. Family physicians should conduct activities to prevent, diagnose early and treat CVD in the primary health care population

Serum antinuclear autoantibodies are associated with measures of oxidative stress and lifestyle factors:analysis of LIPIDOGRAM2015 and LIPIDOGEN2015 studies

Introduction: Oxidative stress is one of many factors suspected to promote antinuclear autoantibody (ANA) formation. Reactive oxygen species can induce changes in the antigenic structure of macromolecules, causing the immune system to treat them as “neo-antigens” and start production of autoantibodies. This study was designed to evaluate the relationship between oxidative stress markers, lifestyle factors and the detection of ANA. Material and methods: We examined measures of oxidative stress indices of free-radical damage to lipids and proteins, such as total oxidant status (TOS), concentration of protein thiol groups (PSH), and malondialdehyde (MDA), activity of superoxide dismutase (SOD) in 1731 serum samples. The parameters of the non-enzymatic antioxidant system, such as total antioxidant status (TAS) and uric acid (UA) concentration, were also measured and the oxidative stress index (OSI-index) was calculated. All samples were tested for the presence of ANA using an indirect immunofluorescence assay (IIFA). Results: The presence of ANA in women was associated with lower physical activity (p = 0.036), less frequent smoking (p = 0.007) and drinking of alcohol (p = 0.024) accompanied by significant changes in SOD isoenzymes activity (p &lt; 0.001) and a higher uric acid (UA) concentration (p &lt; 0.001). In ANA positive males we observed lower concentrations of PSH (p = 0.046) and increased concentrations of MDA (p = 0.047). Conclusions: The results indicate that local oxidative stress may be associated with increased probability of ANA formation in a sex-specific manner.</p

Relationship Between Anti-DFS70 Autoantibodies and Oxidative Stress

Background: The anti-DFS70 autoantibodies are one of the most commonly and widely described agent of unknown clinical significance, frequently detected in healthy individuals. It is not known whether the DFS70 autoantibodies are protective or pathogenic. One of the factors suspected of inducing the formation of anti-DFS70 antibodies is increased oxidative stress. We evaluated the coexistence of anti-DFS70 antibodies with selected markers of oxidative stress and investigated whether these antibodies could be considered as indirect markers of oxidative stress.Methods: The intensity of oxidative stress was measured in all samples via indices of free-radical damage to lipids and proteins such as total oxidant status (TOS), concentrations of lipid hydroperoxides (LPH), lipofuscin (LPS), and malondialdehyde (MDA). The parameters of the non-enzymatic antioxidant system, such as total antioxidant status (TAS) and uric acid concentration (UA), were also measured, as well as the activity of superoxide dismutase (SOD). Based on TOS and TAS values, the oxidative stress index (OSI) was calculated. All samples were also tested with indirect immunofluorescence assay (IFA) and 357 samples were selected for direct monospecific anti DFS70 enzyme-linked immunosorbent assay (ELISA) testing.Results: The anti-DFS70 antibodies were confirmed by ELISA test in 21.29% of samples. Compared with anti-DFS70 negative samples we observed 23% lower concentration of LPH (P = .038) and 11% lower concentration of UA (P = .005). TOS was 20% lower (P = .014). The activity of SOD was up to 5% higher (P = .037). The Pearson correlation showed weak negative correlation for LPH, UA, and TOS and a weak positive correlation for SOD activity.Conclusion: In samples positive for the anti-DFS70 antibody a decreased level of oxidative stress was observed, especially in the case of samples with a high antibody titer. Anti-DFS70 antibodies can be considered as an indirect marker of reduced oxidative stress or a marker indicating the recent intensification of antioxidant processes.</p