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Introduction: 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.Method: 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.Results: Total MP AV was lower in crisis (1.26×106 ml−1; 0.56–2.44×106) and steady state (1.35×106 ml−1; 0.71–3.0×106) compared to transfusion (4.33×106 ml−1; 1.6–9.2×106, p0.9, p

Vascular reactivity is reflected by blood biomarkers and noninvasive vascular function measurement. The relation of biomarkers to flow-mediated dilation and peripheral arterial tonometry in the general population is little understood. In 5000 individuals (mean age, 56±11 years; age range, 35–74 years; 49% women) of the population-based Gutenberg Health Study we simultaneously assessed 6 biomarkers of cardiovascular function (midregional proadrenomedullin [MR-proADM], midregional pro atrial natriuretic peptide [MR-proANP], N-terminal pro B-type natriuretic peptide, copeptin, C-terminal proendothelin 1, and neopterin) in relation to flow-mediated dilation and peripheral arterial tonometry. Strongest partial correlations (adjusted for age and sex) were observed for baseline pulse amplitude with MR-proADM ( r =0.13) and MR-proANP ( r =−0.13); hyperemic response variables showed the highest correlation for MR-proADM and peripheral arterial tonometry ratio ( r =−0.14). In multivariable linear regression models, strongest associations with baseline vascular function were observed for MR-proANP with baseline pulse amplitude (β per SD increase [99.17%], −0.080 [−0.115 to −0.044]; P P P =0.0017) and N-terminal pro B-type natriuretic peptide (−0.027 [−0.051 to −0.003]; P =0.015) with brachial artery diameter. For hyperemic response variables, highest associations were seen for peripheral arterial tonometry ratio with MR-proADM (−0.022 [−0.043 to −0.004]; P =0.043), MR-proANP (0.016 [−0.0034 to 0.035]; P =0.18), and C-terminal proendothelin 1 (−0.025 [−0.043 to −0.008]; P =0.00094]. In our large, population-based study, we identified MR-proADM and MR-proANP as circulating biomarkers of vascular function most strongly related to noninvasive measures of conduit artery and peripheral arterial performance. Whether determination of blood biomarkers helps to better understand vascular pathology and may provide prognostic information needs to be investigated in future studies.

ObjectivesEarly identification of myocardial infarction in chest pain patients is crucial to identify patients at risk and to maintain a fast treatment initiation.BackgroundThe aim of the current investigation is to test whether determination of copeptin, an indirect marker for arginin-vasopressin, adds diagnostic information to cardiac troponin in early evaluation of patients with suspected myocardial infarction.MethodsBetween January 2007 and July 2008, patients with suspected acute coronary syndrome were consecutively enrolled in this multicenter study. Copeptin, troponin T (TnT), myoglobin, and creatine kinase-myocardial band were determined at admission and after 3 and 6 h.ResultsOf 1,386 (66.4% male) enrolled patients, 299 (21.6%) had the discharge diagnosis of acute myocardial infarction, 184 (13.3%) presented with unstable angina, and in 903 (65.2%) an acute coronary syndrome could be excluded. Combined measurement of copeptin and TnT on admission improved the c-statistic from 0.84 for TnT alone to 0.93 in the overall population and from 0.77 to 0.9 in patients presenting within 3 h after chest pain onset (CPO) (p < 0.001). In this group the combination of copeptin with a conventional TnT provided a negative predictive value of 92.4%.ConclusionsIn triage of chest pain patients, determination of copeptin in addition to troponin improves diagnostic performance, especially early after CPO. Combined determination of troponin and copeptin provides a remarkable negative predictive value virtually independent of CPO time and therefore aids in early and safe rule-out of myocardial infarction.

Background Community-acquired pneumonia (CAP) is the most important clinical infection with a high longterm 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. Methods A total of 1740 patients of mean6SD age 60618 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. Results MR-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

BACKGROUND Recently, C-terminal provasopressin (copeptin) turned out to be predictive for mortality in community-acquired pneumonia (CAP). The aim of this study was to evaluate the influence of antibiotic pre-treatment on copeptin levels in CAP. METHODS We enrolled 370 hospitalized patients (66 +/- 17 years; 42% females) with proven CAP. Venous blood samples were collected at the time of inclusion into the study and as soon as possible after the diagnosis of CAP. Copeptin (B.R.A.H.M.S. AG, Henningsdorf, Germany) levels were determined in venous blood on admission. RESULTS Eighty-five patients had antibiotic pre-treatment and 285 patients did not. Copeptin levels increased with increasing severity of CAP in patients without antibiotic pre-treatment but not in patients with antibiotic pre-treatment. Patients with prior antibiotic treatment showed significantly lower levels of copeptin [median (interquartile range): 12.8 (5.3-22.6) versus 20.8 (11.1-37.8) pmol/L, P < 0.0001] and procalcitonin [0.15 (0.07-0.38) versus 0.27 (0.10-1.52) ng/mL, P = 0.0003], but not C-reactive protein [113 (46-229) versus 122 (49-231) mg/mL, not significant] and leucocytes [12.2 x 10(3) (8.1 x 10(3)-15.4 x 10(3)) versus 12.5 x 10(3) (9.4 x 10(3)-16.3 x 10(3)) cells/mm(3), not significant] compared with those without antibiotic pre-treatment. CONCLUSIONS Copeptin serum levels are higher in patients without antibiotic pre-treatment compared with those with antibiotic pre-treatment. Copeptin serum levels increase with an increasing severity of CAP in patients without, but not in patients with, antibiotic pre-treatment. Thus, antibiotic pre-treatment has to be taken into account for the correct interpretation of copeptin levels in CAP.

DNA methylation constitutes the most stable type of epigenetic modifications modulating the transcriptional plasticity of mammalian genomes. Using bisulfite DNA sequencing, we report high-resolution methylation reference 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 6 annotation categories, revealed evolutionary conserved regions to be the predominant sites for differential DNA methylation and a core region surrounding the transcriptional start site as informative surrogate for promoter methylation. We find 17% of the 873 analyzed genes differentially methylated in their 5′-untranslated regions (5′-UTR) and about one third of the differentially methylated 5′-UTRs to be inversely correlated with transcription. While our study was 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.

BACKGROUND: 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. METHODS AND RESULTS: 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; P13%. CONCLUSIONS: 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: Stress myocyte biomarkers are used prognostically in patients with cardiovascular disease. We examined associations between amino-terminal pro–B-type natriuretic peptide (NT-proBNP), midregional pro–A-type natriuretic peptide (MR-proANP), and midregional proadrenomedullin (MR-proADM) concentrations and cardiac chamber volumes in chest pain patients without heart failure by use of computed tomography (CT). Methods: At the time of 64-slice CT scan, we acquired plasma and serum samples for these biomarkers from 346 patients [mean (SD) age 53 (12) years, 65% men]. Left atrial volume (LAV) and left ventricular volumes at end-diastole (LVEDV) and end-systole (LVESV) were measured and indexed to body surface area (LAVI, LVEDI, LVESI). Results: Concentrations of both natriuretic peptides were correlated with LAV and LAVI (r = 0.19–0.32, all P ≤ 0.0005) and MR-proADM with LV volumes and indices (r = −0.14 to −0.21, all P ≤ 0.01). NT-proBNP and MR-proANP concentrations were higher in the top quartiles of patients than the lowest quartiles using LAV and LAVI, whereas MR-proADM concentrations were lower in the top quartiles of LV measures. In adjusted analyses, patients had 2- to 4-fold increased risk of LA enlargement for every incremental increase in log10NT-proBNP [LAV odds ratio (OR) 2.4, P = 0.03; LAVI OR 4.0, P = 0.003] and 10- to 13-fold increased risk of LA enlargement for every incremental increase in log10MR-proANP (LAV OR 10.7, P = 0.009; LAVI OR 13.1, P = 0.004). Conclusions: In patients without heart failure, both NT-proBNP and MR-proANP concentrations are independently associated with LA enlargement, whereas MR-proADM concentrations are correlated with LV volumes. This may partially explain the well-recognized value of natriuretic peptides for use in risk stratification.

Nitric Oxide (NO) and endothelin-1 (ET-1) are key modulators of endothelial vessels and actively participate in the pathophysiology of vaso-occlusive events. Sickle cell anemia (SCA) is an important model for the study of blood cells/endothelium interactions. In SCA vaso-occlusive events may be severe and cumulative. Adrenomedullin (ADM) is a strong hypotension-inducer and mediates diuresis, natriuresis and vasodilation. Adrenomedullin levels are raised in chronic cardiovascular conditions. The aim of this study was to investigate the role of adrenomedullin in SCA and its relationship to endothelin-1 and nitric oxide. A cohort of 111 children with HbSS SCA was studied with 18 age-matched controls of sub-Sahara African ethnicity. The patients were in four clinical groups: steady state (n=55, mean age 5.3 years), patients undergoing chest crisis (n=9, mean age 5.3 years), on hydroxyurea (n=30, mean age 7.2 years), on transfusion therapy (n=17, mean age 6.5 years). A third cohort of patients with HbSC genotype (n=13, mean age 6 years) all in steady state was also included. Pro-adrenomedullin and c-terminal endothelin-1 precursor (CT-proET-1) were measured by coated tube assays according to the method by Morgenthaler et al (Clin Chem.2005;51:1823–29) and Papassotiriou et al (Clin Chem.2006;52(6):1144–51), nitric oxide was quantified according to the Griess reaction. Results (median and interquartile range) are shown in table 1. Overall pro-adrenomedullin levels were raised in chest crisis: 0.38 nmol/l (0.31–0.49) vs steady state: 0.27 nmol/l (0.25–0.32; p Table 1. ADM, ET-1, NO and hematological/biochemical values in SCA patients and controls. IR= interquartile range. Figure 1. ADM and NO levels in sickle cell patients and controls. Bars indicate median and interquartile range. Figure 1. ADM and NO levels in sickle cell patients and controls. Bars indicate median and interquartile range.

Targeting gene therapy vectors to abundant receptors on airway epithelia may allow a significant enhancement of gene delivery and thereby be of particular importance for the gene therapy of cystic fibrosis. Alpha9beta1-integrins are highly expressed throughout the human airway epithelia in vivo, irrespective of any particular clinical status. Aiming to improve the targeting of our non-viral integrin-mediated gene transfer systems to airway epithelia, we searched for a short tenascin C-derived peptide which would bind to these integrins. By utilizing recombinant bacteriophages that display overlapping regions of the third fibronectin type III repeat of tenascin C (TNfn3), we were able to localize its alpha9beta1-integrin binding site to the B-C loop of TNfn3. A synthetic Pro-Leu-Ala-Glu-Ile-Asp-Gly-Ile-Glu-Leu-Thr-Tyr peptide (PLAEIDGIELTY) was shown to displace alpha9beta1-integrin-expressing cells completely from binding to TNfn3. This peptide, therefore, may prove useful both for the examination of the functional importance of alpha9beta1-integrins in vivo and the development of gene therapy vectors or drugs targeting these integrins.