MBD2 contributes to developmental silencing of the human ε-globin gene

During erythroid development, the embryonic ε-globin gene becomes silenced as erythropoiesis shifts from the yolk sac to the fetal liver where γ-globin gene expression predominates. Previous studies have shown that the ε-globin gene is autonomously silenced through promoter proximal cis-acting sequences in adult erythroid cells. We have shown a role for the methylcytosine binding domain protein 2 (MBD2) in the developmental silencing of the avian embryonic ρ-globin and human fetal γ-globin genes. To determine the roles of MBD2 and DNA methylation in human ε-globin gene silencing, transgenic mice containing all sequences extending from the 5' hypersensitive site 5 (HS5) of the β-globin locus LCR to the human γ-globin gene promoter were generated. These mice show correct developmental expression and autonomous silencing of the transgene. Either the absence of MBD2 or treatment with the DNA methyltransferase inhibitor 5-azacytidine increases ε-globin transgene expression by 15-20 fold in adult mice. Adult mice containing the entire human β-globin locus also show an increase in expression of both the ε-globin gene transgene and endogenous ε(Y) and β(H1) genes in the absence of MBD2. These results indicate that the human ε-globin gene is subject to multilayered silencing mediated in part by MBD2.     

Soluble leptin receptor and leptin are associated with baseline adiposity and metabolic risk factors, and predict adiposity, metabolic syndrome, and glucose levels at 2-year follow-up: the Cyprus Metabolism Prospective Cohort Study

We examined the relationship between serum levels of leptin-binding protein (soluble leptin receptor [sOB-R]) and leptin with metabolic parameters at baseline and prospectively at 2-year follow-up in young healthy men. A total of 916 eighteen-year-old men were examined at baseline, with a subgroup of 91 participants examined again 2 years later. Anthropometric and metabolic measurements were performed at baseline and at follow-up. In the cross-sectional study, levels of sOB-R were significantly inversely correlated with all baseline measures of obesity and metabolic risk factors (blood pressure, total and low-density lipoprotein cholesterol, and fasting glucose), and significantly positively correlated with high-density lipoprotein cholesterol. After correcting for age, smoking status, and waist-to-hip ratio, the inverse correlation remained statistically significant for all measures of adiposity, fasting glucose, and the metabolic syndrome score. Correlations for leptin were similar in magnitude but opposite in direction to correlations for sOB-R. In prospective analyses, baseline levels of sOB-R were predictive at 2-year follow-up of fasting glucose, the metabolic syndrome score, and measures of adiposity in both unadjusted and adjusted models. Similarly, leptin was predictive of fasting glucose, the metabolic syndrome score, adiposity, and systolic blood pressure. We confirm correlations of leptin and sOB-R levels with measures of adiposity and metabolic risk factors at baseline, and demonstrate for the first time prospectively the role of sOB-R as an independent, although weak, predictor of metabolic syndrome and fasting glucose in young men.     

Ascending thoracic aorta dimension and outcomes in acute type B dissection (from the International Registry of Acute Aortic Dissection [IRAD])

It is not well known if the size of the ascending thoracic aorta at presentation predicts features of presentation, management, and outcomes in patients with acute type B aortic dissection. The International Registry of Acute Aortic Dissection (IRAD) database was queried for all patients with acute type B dissection who had documentation of ascending thoracic aortic size at time of presentation. Patients were categorized according to ascending thoracic aortic diameters ≤4.0, 4.1 to 4.5, and ≥4.6 cm. Four hundred eighteen patients met inclusion criteria; 291 patients (69.6%) were men with a mean age of 63.2 ± 13.5 years. Ascending thoracic aortic diameter ≤4.0 cm was noted in 250 patients (59.8%), 4.1 to 4.5 cm in 105 patients (25.1%), and ≥4.6 cm in 63 patients (15.1%). Patients with an ascending thoracic aortic diameter ≥4.6 cm were more likely to be men (p = 0.01) and have Marfan syndrome (p <0.001) and known bicuspid aortic valve disease (p = 0.003). In patients with an ascending thoracic aorta ≥4.1 cm, there was an increased incidence of surgical intervention (p = 0.013). In those with an ascending thoracic aorta ≥4.6 cm, the root, ascending aorta, arch, and aortic valve were more often involved in surgical repair. Patients with an ascending thoracic aorta ≤4.0 were more likely to have endovascular therapy than those with larger ascending thoracic aortas (p = 0.009). There was no difference in overall mortality or cause of death. In conclusion, ascending thoracic aortic enlargement in patients with acute type B aortic dissection is common. Although its presence does not appear to predict an increased risk of mortality, it is associated with more frequent open surgical intervention that often involves replacement of the proximal aorta. Those with smaller proximal aortas are more likely to receive endovascular therapy.     

Arrhythmic risk stratification in ischemic,non-ischemic and hypertrophic cardiomyopathy: A two-step multifactorial,electrophysiology study inclusive approach

Annual arrhythmic sudden cardiac death ranges from 0.6% to 4% in ischemic cardiomyopathy (ICM), 1% to 2% in non-ischemic cardiomyopathy (NICM), and 1% in hypertrophic cardiomyopathy (HCM). Towards a more effective arrhythmic risk stratification (ARS) we hereby present a two-step ARS with the usage of seven non-invasive risk factors: Late potentials presence (≥ 2/3 positive criteria), premature ventricular contractions (≥ 30/h), non-sustained ventricular tachycardia (≥ 1episode/24 h), abnormal heart rate turbulence (onset ≥ 0% and slope ≤ 2.5 ms) and reduced deceleration capacity (≤ 4.5 ms), abnormal T wave alternans (≥ 65μV), decreased heart rate variability (SDNN < 70ms), and prolonged QT_c interval (> 440 ms in males and > 450 ms in females) which reflect the arrhythmogenic mechanisms for the selection of the intermediate arrhythmic risk patients in the first step. In the second step, these intermediate-risk patients undergo a programmed ventricular stimulation (PVS) for the detection of inducible, truly high-risk ICM and NICM patients, who will benefit from an implantable cardioverter defibrillator. For HCM patients, we also suggest the incorporation of the PVS either for the low HCM Risk-score patients or for the patients with one traditional risk factor in order to improve the inadequate sensitivity of the former and the low specificity of the latter.     

QT-interval dispersion in acute myocardial infarction is only shortened by thrombolysis in myocardial infarction grade 2/3 reperfusion

BACKGROUND: Increased QT interval dispersion (QTd) has been found in patients with acute myocardial infarction (AMI). In previous studies this has been shown to decrease with thrombolysis. HYPOTHESIS: The aim of this study was to compare the effects of reperfusion by primary percutaneous transluminal coronary angioplasty (PTCA) and by thrombolysis on QTd and correlate these results with the degree of reperfusion. METHODS: We studied 60 patients with a first AMI. The study cohort included 40 consecutive patients who had received thrombolysis (streptokinase or rt-PA); 20 additional consecutive patients with successful primary PTCA, all with preselected Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow by predefined selection criteria (12 stents); and 20 controls. A 12-lead ECG for QTd calculation was recorded before thrombolysis or PTCA and immediately after the procedure. All values were corrected according to Bazett's formula (QTcd). QTd and QTcd values before and after each procedure in three groups and the respective percent changes of deltaQTd and deltaQTcd were compared separately. RESULTS: QTd and QTcd were significantly increased before thrombolysis/PTCA versus normals. An angiogram performed after thrombolysis showed adequate reperfusion (TIMI grade 2/3) in 20 patients, while in the other 20 only TIMI 0/1 reperfusion was achieved. Thrombolysis-TIMI flow 2/3 and PTCA significantly reduced QTd (from 68 +/- 10 to 35 +/- 8 ms, p < 0.001, deltaQTd = 48 +/- 11%, in the Thr-TIMI flow 2/3 group,and from 79 +/- 11 to 38 +/- 9 ms, p < 0.001, deltaQTd = 52 +/- 9%, in the PTCA group), while in the Thr-TIMI flow 0/1 group no significant changes were recorded. A percent QTd decrease > 30 s had 96% sensitivity, 85% specificity, and 93% positive and 94% negative predictive value, respectively, for TIMI 2/3 flow. CONCLUSIONS: A significant decrease in QT dispersion may provide an additional electrocardiographic index for successful (TIMI 2/3) reperfusion.     

Prospective surveillance of hypertension in firefighters

The authors evaluated blood pressure and antihypertensive medication use in 334 firefighters in an occupational medical surveillance program. Firefighters received written summaries of their examination results, including blood pressures, and were encouraged to see their personal physicians for any abnormal results. The mean age of the participants was 39 years, and the vast majority were men (n=330). The prevalence of hypertension was 20% at baseline (1996), 23% in 1998, and 23% in 2000. Among firefighters with high blood pressure readings, only 17%, 25%, and 22% were taking antihypertensive medications at the baseline, 1998, and 2000 examinations, respectively. Medical surveillance was effective in detecting hypertension in firefighters; however, after 4 years of follow-up, only 42% of hypertensives were receiving treatment with medications, including only 22% of firefighters with hypertensive readings. Overall, 74% of hypertensives were not adequately controlled. Possible reasons for low treatment rates may be the inadequate recognition among primary care physicians that mild hypertension is a significant risk factor for cardiovascular disease.     

Continuous 12-lead electrocardiographic ST monitoring adds prognostic information to the thrombolysis in myocardial infarction risk score in patients with non-ST-elevation acute coronary syndromes

BACKGROUND: Continuous 12-lead electrocardiographic (ECG) ST monitoring and the Thrombolysis In Myocardial Infarction Risk Score (TIMI-RS), both have been shown to be useful for early risk stratification in patients with non-ST elevation acute coronary syndromes (NSTACS). HYPOTHESIS: Transient ST ischemic events, detected by continuous 12-lead ECG ST monitoring, early in the course of NSTACS, may add prognostic information to the TIMI-RS. METHODS: In all, 567 consecutive patients with a NSTACS underwent 24-h continuous 12-lead ECG ST monitoring. An ST ischemic event was defined as a transient ST shift in any lead of > or = 0.10 mV compared with the reference ECG, lasting for > or = 1 min. RESULTS: The incidence of the composite of death, nonfatal myocardial infarction (or reinfarction) and recurrent ischemia by Day 14 was 22.2%. By Day 30, the incidence of the composite of death and nonfatal myocardial infarction (or reinfarction) was 14.7%. There was a significantly increased risk of 14-day (p value for trend < 0.001) or 30-day (p value for trend <0.001) composite endpoint with increasing of TIMI-RS. Moreover, the occurrence of > or = 1 ST shifts during ST monitoring was associated with a significantly increased risk of 14- (p value < 0.001) or 30-day (p value < 0.001) composite endpoint, and this was true throughout the groups of TIMI-RS. CONCLUSIONS: The present study suggests that continuous 12-lead ECG ST monitoring, early in the course of NSTACS, may serve as an affordable tool to add prognostic information to the TIMI-RS.