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DNA methylation is the most stable type of epigenetic modification modulating the transcriptional plasticity of mammalian genomes. Using bisulfite DNA sequencing, we report high-resolution methylation profiles of human chromosomes 6, 20 and 22, providing a resource of about 1.9 million CpG methylation values derived from 12 different tissues. Analysis of six annotation categories showed that evolutionarily conserved regions are the predominant sites for differential DNA methylation and that a core region surrounding the transcriptional start site is an informative surrogate for promoter methylation. We find that 17% of the 873 analyzed genes are differentially methylated in their 5′ UTRs and that about one-third of the differentially methylated 5′ UTRs are inversely correlated with transcription. Despite the fact that our study controlled for factors reported to affect DNA methylation such as sex and age, we did not find any significant attributable effects. Our data suggest DNA methylation to be ontogenetically more stable than previously thought.

Different biological pathways have been related to atrial fibrillation (AF). Novel biomarkers capturing inflammation, oxidative stress, and neurohumoral activation have not been investigated comprehensively in AF. In the population-based Gutenberg Health Study (n = 5000), mean age 56 ± 11 years, 51% males, we measured ten biomarkers representing inflammation (C-reactive protein, fibrinogen), cardiac and vascular function (midregional pro adrenomedullin [MR-proADM], midregional pro atrial natriuretic peptide [MR-proANP], N-terminal pro-B-type natriuretic peptide [Nt-proBNP], sensitive troponin I ultra [TnI ultra], copeptin, and C-terminal pro endothelin-1), and oxidative stress (glutathioneperoxidase-1, myeloperoxidase) in relation to manifest AF (n = 161 cases). Individuals with AF were older, mean age 64.9 ± 8.3, and more often males, 71.4%. In Bonferroni-adjusted multivariable regression analyses strongest associations per standard deviation increase in biomarker concentrations were observed for the natriuretic peptides Nt-proBNP (odds ratio [OR] 2.89, 99.5% confidence interval [CI] 2.14-3.90; P<0.0001), MR-proANP (OR 2.45, 99.5% CI 1.91-3.14; P<0.0001), the vascular function marker MR-proADM (OR 1.54, 99.5% CI 1.20-1.99; P<0.0001), TnI ultra (OR 1.50, 99.5% CI 1.19-1.90; P<0.0001) and. fibrinogen (OR 1.44, 99.5% CI 1.19-1.75; P<0.0001). Based on a model comprising known clinical risk factors for AF, all biomarkers combined resulted in a net reclassification improvement of 0.665 (99.3% CI 0.441-0.888) and an integrated discrimination improvement of >13%. In conclusion, in our large, population-based study, we identified novel biomarkers reflecting vascular function, MR-proADM, inflammation, and myocardial damage, TnI ultra, as related to AF; the strong association of natriuretic peptides was confirmed. Prospective studies need to examine whether risk prediction of AF can be enhanced beyond clinical risk factors using these biomarkers.

Background Aim of this study was to evaluate the correlation of inflammatory markers procalcitonin (PCT), C-reactive protein (CRP) and leukocyte count (WBC) with microbiological etiology of CAP. Methods We enrolled 1337 patients (62 ± 18 y, 45% f) with proven CAP. Extensive microbiological workup was performed. In all patients PCT, CRP, WBC and CRB-65 score were determined. Patients were classified according to microbial diagnosis and CRB-65 score. Results In patients with typical bacterial CAP, levels of PCT, CRP and WBC were significantly higher compared to CAP of atypical or viral etiology. There were no significant differences in PCT, CRP and WBC in patients with atypical or viral etiology of CAP. In contrast to CRP and WBC, PCT markedly increased with severity of CAP as measured by CRB-65 score (p < 0.0001). In ROC analysis for discrimination of patients with CRB-65 scores > 1, AUC for PCT was 0.69 (95% CI 0.66 to 0.71), which was higher compared to CRP and WBC (p < 0.0001). CRB-65, PCT, CRP and WBC were higher (p < 0.0001) in hospitalised patients in comparison to outpatients. Conclusion PCT, CRP and WBC are highest in typical bacterial etiology in CAP but do not allow individual prediction of etiology. In contrast to CRP and WBC, PCT is useful in severity assessment of CAP.

Circulating microparticles (MP) have been described in sickle cell anaemia (SCA); however, their interaction with endothelial markers remains unclear. We investigated the relationship between MP, protein C (PC), free protein S (PS), nitric oxide (NO), endothelin-1 (ET-1) and adrenomedullin (ADM) in a large cohort of paediatric patients. A total of 111 children of African ethnicity with SCA: 51 in steady state; 15 in crises; 30 on hydroxyurea (HU) therapy; 15 on transfusion; 17 controls (HbAA) of similar age/ethnicity. MP were analysed by flow cytometry using: Annexin V (AV), CD61, CD42a, CD62P, CD235a, CD14, CD142 (tissue factor), CD201 (endothelial PC receptor), CD62E, CD36 (TSP-1), CD47 (TSP-1 receptor), CD31 (PECAM), CD144 (VE-cadherin). Protein C, free PS, NO, pro-ADM and C-terminal ET-1 were also measured. Total MP AV was lower in crisis (1.26×10 6 ml −1 ; 0.56-2.44×10 6 ) and steady state (1.35×10 6 ml −1 ; 0.71-3.0×10 6 ) compared to transfusion (4.33×10 6 ml −1 ; 1.6-9.2×10 6 , p<0.01). Protein C levels were significantly lower in crisis (median 0.52 IU ml −1 ; interquartile range 0.43-0.62) compared with all other groups: HbAA (0.72 IU ml −1 ; 0.66-0.82, p<0.001); HU (0.67 IU ml −1 ; 0.58-0.77, p<0.001); steady state (0.63 IU ml −1 ; 0.54-0.70, p<0.05) and transfusion (0.60 IU ml −1 ; 0.54-0.70, p<0.05). In addition, levels were significantly reduced in steady state (0.63 IU ml −1 ; 0.54-0.70) compared with HbAA (0.72 IU ml −1 ; 0.66-0.80, p<0.01). PS levels were significantly higher in HbAA (0.85 IU ml −1 ; 0.72-0.97) compared with crisis (0.49 IU ml −1 ; 0.42-0.64, p<0.001), HU (0.65 IU ml −1 ; 0.56-0.74, p<0.01) and transfusion (0.59 IU ml −1 ; 0.47-0.71, p<0.01). There was also a significant difference in crisis patients compared with steady state (0.49 IU ml −1 ; 0.42-0.64 vs. 0.68 IU ml −1 ; 0.58-0.79, p<0.05). There was high correlation (R>0.9, p<0.05) between total numbers of AV-positive MP (MP AV) and platelet MP expressing non-activation platelet markers. There was a lower correlation between MP AV and MP CD62P (R=0.73, p<0.05) (platelet activation marker), and also a lower correlation between percentage of MP expressing CD201 (%MP CD201) and %MP CD14 (R=0.627, p<0.001). %MP CD201 was higher in crisis (11.6%) compared with HbAA (3.2%, p<0.05); %MP CD144 was higher in crisis (7.6%) compared with transfusion (2.1%, p<0.05); %CD14 (0.77%) was higher in crisis compared with transfusion (0.0%, p<0.05) and steady state (0.0%, p<0.01); MP CD14 was detectable in a higher number of samples (92%) in crisis compared with the rest (40%); %MP CD235a was higher in crisis (17.9%) compared with transfusion (8.9%), HU (8.7%) and steady state (9.9%, p<0.05); %CD62E did not differ significantly across the groups and CD142 was undetectable. Pro-ADM levels were raised in chest crisis: 0.38 nmol L −1 (0.31-0.49) versus steady state: 0.27 nmol L −1 (0.25-0.32; p<0.01) and control: 0.28 nmol L −1 (0.27-0.31; p<0.01). CT-proET-1 levels were reduced in patients on HU therapy: 43.6 pmol L −1 (12.6-49.6) versus control: 55.1 pmol L −1 (45.2-63.9; p<0.05). NO levels were significantly lower in chest crisis (19.3 mmol L −1 plasma; 10.7-19.9) compared with HU (22.2 mmol L −1 plasma; 18.3-28.4; p<0.05), and HbSC (30.6 mmol L −1 plasma; 20.8-39.5; p<0.05) and approach significance when compared with steady state (22.5mmol L −1 plasma; 16.9-28.2; p=0.07). Protein C and free PS are reduced in crisis with lower numbers of platelet MP and higher percentage of markers of endothelial damage and of red cell origin. During chest crisis, ADM and ET-1 were elevated suggesting a role for therapy inhibiting ET-1 in chest crisis.

Objectives The purpose of this study was to evaluate complement activation in a heart failure cohort. Based on their powerful biological activity, we hypothesized that the levels of anaphylatoxin C3a are related to pathological signs and outcomes in heart failure. Design, setting and patients Complement activation products C3a and SC5b9 were determined in 182 consecutive CHF patients (single centre, prospective cohort study), with a left ventricular ejection fraction <45%. Mortality and re-hospitalisation due to the progression of CHF were assessed after a median follow-up of 14 months. Interventions None. Results In the univariate analysis, high level of anaphylatoxin C3a was significantly associated with clinical events ( p  < 0.0001), whereas SC5b9 showed a tendency of association ( p  = 0.094). In multivariable Cox analysis, adjusted for age, NT-proBNP, diastolic blood pressure, body mass index (BMI), haemoglobin and creatinine levels, C3a was a significant predictor of HF-related re-hospitalization or death (HR 1.189 per 1-SD increase, 95% CI 1.023–1.383), and of cardiovascular events or death (HR 1.302, CI 1.083–1.566). C3a was strongly associated with the presence of peripheral oedema, inflammatory markers (CRP, prealbumin, IL-6, sTNFRI, sTNFRII), heat-shock protein 70 levels and endothelial activation markers (von-Willebrand factor and endothelin-1). Conclusions Results of the present study showed that complement activation is strongly linked to unfavourable outcomes in heart failure. High levels of anaphylatoxin C3a predicted re-hospitalization, cardiovascular events and mortality in adjusted survival model. Increased C3a levels were associated with biomarkers of acute-phase reaction, inflammation, cellular stress response, endothelial-cell activation and oedematous complications independently from disease severity.

Quality of life (QoL) is impaired in diastolic heart failure. Little is known about QoL in diastolic dysfunction (DD) without heart failure. In the DIAST-CHF observational study, outpatients with risk factors for or a history of heart failure were included. In a cross-sectional analysis, we classified patients with preserved systolic function as having normal diastolic function (N, n = 264) or DD without (DD−, n = 957) or with (DD+, n = 321) elevated filling pressures according to echocardiography. Quality of life was evaluated by the Short Form 36 (SF-36) questionnaire. Short Form 36 physical function (SF-36-PF) was worse in DD+ (mean ± SD 67.2 ± 25.6) than in DD− (76.2 ± 22.7, P < .05) than in N (mean ± SD 81.1 ± 23.5, P < .01). Other physical dimensions and the physical component score were also lower in DD, whereas the mental component score did not differ. The SF-36-PF correlated weakly with echocardiographic indicators of diastolic function. In multivariate linear regression controlling for age, sex, body mass index, depressiveness as assessed by Patient Health Questionnaire 9, N-terminal probrain-type natriuretic peptide, and midregional proadrenomedullin (MR-proADM), individual echocardiographic parameters or grade of DD was not independently associated with SF-36-PF, whereas the presence of DD+ was. Both N-terminal probrain-type natriuretic peptide and MR-proADM were independently associated with SF-36-PF, with MR-proADM showing the stronger association. Physical dimensions of QoL are reduced in DD. Impaired SF-36-PF is only weakly associated with DD per se but rather seems to be contingent on the presence of elevated filling pressures. Biomarkers are more strongly and independently associated with SF-36-PF and may be more adequate surrogate markers of QoL in DD than echocardiographic measurements.

BackgroundCommunity-acquired pneumonia (CAP) is the most important clinical infection with a high long-term mortality rate. The aim of this study was to evaluate the value of biomarkers for the prediction of short-term and long-term mortality in CAP.MethodsA total of 1740 patients of mean±SD age 60±18 years (45% female) with proven CAP were enrolled in the study. Mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-atrial vasopressin (CT-proAVP), procalcitonin, C-reactive protein, leucocyte count (WBC) and CRB-65 score were determined on admission. Patients were followed up for 180 days.ResultsMR-proANP and CT-proAVP levels increased with increasing severity of CAP, classified according to CRB-65 score. In patients who died within 28 and 180 days, median MR-proANP (313.9 vs 80.0 and 277.8 vs 76.0 pmol/l, each p<0.0001) and CT-proAVP (42.6 vs 11.2 and 33.2 vs 10.7 pmol/l, each p<0.0001) levels were significantly higher than the levels in survivors. In receiver operating characteristics analysis for survival at 28 and 180 days, the areas under the curves (AUCs) for CT-proAVP (0.84, 95% CI 0.82 to 0.86 and 0.78, 95% CI 0.76 to 0.80) and MR-proANP (0.81, 95% CI 0.79 to 0.83 and 0.81, 95% CI 0.79 to 0.83) were superior to the AUC of CRB-65 (0.74, 95% CI 0.71 to 0.76 and 0.71, 95% CI 0.69 to 0.74, p<0.05), procalcitonin, C-reactive protein and WBC. In multivariable Cox proportional hazards regression analyses adjusted for comorbidity and pneumonia severity, MR-proANP and CT-proAVP were independent and the strongest predictors of short-term and long-term mortality.ConclusionsMR-proANP and CT-proAVP are powerful tools for the prediction of short-term and long-term risk stratification of patients with CAP.

Objective To evaluate mid-regional pro-adrenomedullin (MR-proADM) and mid-regional pro-atrial natriuretic peptide (MR-proANP) as prognostic biomarkers in a representative ‘real world’ cohort of patients with suspected acute coronary syndrome (ACS). Design Prospective observational multicentre cohort study. Setting Chest pain units of three major hospitals in Germany from 2007 to 2008. Patients Patients presenting with signs and symptoms suggestive of an ACS. Main outcome measures Primary end point was death or non-fatal myocardial infarction (MI), and secondary end point was death, non-fatal MI, stroke, need for coronary revascularisation, and hospital admission for cardiovascular cause or acute heart failure within 6 months after enrolment. Results 1386 patients (male/female=920/466) were enrolled. Follow-up information was available for 97.8% of patients (median follow-up time 183 days). Forty-three patients reached the primary end point, and 132 the secondary end point. Patients who reached a primary end point had significantly higher MR-proANP (271 vs 101 pmol/l, p<0.001) and MR-proADM (0.86 vs 0.59 nmol/l, p<0.001) concentrations than those who did not. Cox regression analysis revealed a 2.55-fold risk of death or non fatal MI (95% CI 1.48 to 2.46, p<0.001) for an increment of the log-transformed MR-proANP concentration by 1 SD after adjustment for cardiovascular risk factors, and a 1.91-fold risk (95% CI 1.48 to 2.46, p<0.001) for MR-proADM. Both peptides could result in significant reclassification of patients when added to the Global Registry of Acute Coronary Events risk score, with an overall net reclassification improvement of 41.2% for MR-proADM and 35.7% for MR-proANP. Conclusions MR-proADM and MR-proANP are predictors of future cardiovascular events in patients presenting with acute chest pain and might facilitate the choice of treatment in those patients complementary to established risk scores.

Quality of life (QoL) is impaired in diastolic heart failure. Little is known about QoL in diastolic dysfunction (DD) without heart failure. In the DIAST-CHF observational study, outpatients with risk factors for or a history of heart failure were included. In a cross-sectional analysis, we classified patients with preserved systolic function as having normal diastolic function (N, n = 264) or DD without (DD-, n = 957) or with (DD+, n = 321) elevated filling pressures according to echocardiography. Quality of life was evaluated by the Short Form 36 (SF-36) questionnaire. Short Form 36 physical function (SF-36-PF) was worse in DD+ (mean ± SD 67.2 ± 25.6) than in DD- (76.2 ± 22.7, P < .05) than in N (mean ± SD 81.1 ± 23.5, P < .01). Other physical dimensions and the physical component score were also lower in DD, whereas the mental component score did not differ. The SF-36-PF correlated weakly with echocardiographic indicators of diastolic function. In multivariate linear regression controlling for age, sex, body mass index, depressiveness as assessed by Patient Health Questionnaire 9, N-terminal probrain-type natriuretic peptide, and midregional proadrenomedullin (MR-proADM), individual echocardiographic parameters or grade of DD was not independently associated with SF-36-PF, whereas the presence of DD+ was. Both N-terminal probrain-type natriuretic peptide and MR-proADM were independently associated with SF-36-PF, with MR-proADM showing the stronger association. Physical dimensions of QoL are reduced in DD. Impaired SF-36-PF is only weakly associated with DD per se but rather seems to be contingent on the presence of elevated filling pressures. Biomarkers are more strongly and independently associated with SF-36-PF and may be more adequate surrogate markers of QoL in DD than echocardiographic measurements.

Background The bradykinin pathway in the pathomechanism of hereditary angioedema due to C1-inhibitor deficiency (henceforward “hereditary angioedema”) has been thoroughly studied; however, much less is known about endothelial cell function. Enhanced endothelial cell permeability is obvious during edematous attacks, but not during inter-attack periods. Our knowledge about other endothelial characteristics is even more incomplete. Objective Therefore the aim of this study was to characterize endothelial cell function in hereditary angioedema patients during symptom-free, inter-attack periods. Methods We measured the serum levels of soluble E-selectin, endothelin-1, and von Willebrand factor along with collagen-binding activity in 49 hereditary angioedema patients and in 50 healthy controls. Results Endothelin-1 and von Willebrand factor level, as well as its collagen-binding activity, were similar in hereditary angioedema patients and in controls; however, we found elevated soluble E-selectin levels in the patients. Interestingly, soluble E-selectin concentration did not correlate with any of the inflammatory markers or smoking, and it is not the consequence of the known E-selectin/C1-inhibitor interaction (an analytical phenomenon). In a multiple logistic regression model, the difference in soluble E-selectin between hereditary angioedema patients and controls remained highly significant when adjusted for age, gender, smoking, C-reactive protein, and AB0 blood groups. Conclusion These results demonstrate that in hereditary angioedema, the majority of endothelial functions are normal during inter-attack periods; however, soluble E-selectin levels are elevated. The higher soluble E-selectin plasma concentration is unlikely to result from inflammation; rather, it reflects enhanced shedding mechanisms.