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Tzikas S.,University Medical Center Mainz | Keller T.,Goethe University Frankfurt | Ojeda F.M.,University of Hamburg | Zeller T.,University of Hamburg | And 9 more authors.
Heart | Year: 2013

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 MRproANP 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.

PubMed | University of Marburg, Federal Armed Forces Hospital and University Hospital Freiburg
Type: | Journal: Clinical oral investigations | Year: 2016

Recent studies focused on angiogenesis in the pathophysiology of bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ) and identified geranylgeraniol (GGOH) as a feasible option for BP-ONJ therapy. This study investigated the influence of GGOH on microvessel sprouting after BP-incubation in vitro.Ten experimental set-ups were randomly designed in an in vitro 3D-angiogenesis assay. Two groups included HUVEC cell spheroids with and without () GGOH substitution as controls and eight groups pairwise contained either clodronate or the nitrogen-containing bisphosphonates (N-BP) ibandronate, pamidronate, and zoledronate GGOH. The size of the cell spheroids including the outbranching sprouts (SpS) as well as the density (SpD) and length of the sprouts (SpL) were analyzed by a grid system after 0, 24, 48, and 72h.For controls and NN-BP clodronate, no significant differences at any tested parameter and any point of measurement could be detected within the experimental set-ups GGOH (p each 0.05). For N-BP ibandronate, the experimental set-ups +GGOH showed a significantly increased SpS, SpD, and SpL after 48 and 72h (p each 0.002) compared to the experimental set-ups -GGOH. For N-BPs pamidronate and zoledronate, the experimental set-ups + GGOH demonstrated a significantly increased SpS, SpD, and SpL after 24, 48, and 72h (p each 0.001) compared to the experimental set-ups -GGOH.The strong negative influence of N-BPs on microvessel sprouting could be significantly reversed by GGOH.Since supportive therapeutic options for BP-ONJ are lacking, GGOH might be a promising substitute for BP-ONJ prevention and therapy.

PubMed | University of Cologne, University of Hamburg, Aristotle University of Thessaloniki, Federal Armed Forces Hospital and 2 more.
Type: Journal Article | Journal: PloS one | Year: 2016

Common ECG criteria such as ST-segment changes are of limited value in patients with suspected acute myocardial infarction (AMI) and bundle branch block or wide QRS complex. A large proportion of these patients do not suffer from an AMI, whereas those with ST-elevation myocardial infarction (STEMI) equivalent AMI benefit from an aggressive treatment. Aim of the present study was to evaluate the diagnostic information of cardiac troponin I (cTnI) in hemodynamically stable patients with wide QRS complex and suspected AMI.In 417 out of 1818 patients presenting consecutively between 01/2007 and 12/2008 in a prospective multicenter observational study with suspected AMI a prolonged QRS duration was observed. Of these, n = 117 showed significant obstructive coronary artery disease (CAD) used as diagnostic outcome variable. cTnI was determined at admission.Patients with significant CAD had higher cTnI levels compared to individuals without (median 250ng/L vs. 11ng/L; p<0.01). To identify patients needing a coronary intervention, cTnI yielded an area under the receiver operator characteristics curve of 0.849. Optimized cut-offs with respect to a sensitivity driven rule-out and specificity driven rule-in strategy were established (40ng/L/96ng/L). Application of the specificity optimized cut-off value led to a positive predictive value of 71% compared to 59% if using the 99th percentile cut-off. The sensitivity optimized cut-off value was associated with a negative predictive value of 93% compared to 89% provided by application of the 99th percentile threshold.cTnI determined in hemodynamically stable patients with suspected AMI and wide QRS complex using optimized diagnostic thresholds improves rule-in and rule-out with respect to presence of a significant obstructive CAD.

Kuchler S.,Federal Armed Forces Hospital | Perwitz N.,University of Lübeck | Schick R.R.,Federal Armed Forces Hospital | Klein J.,University of Lübeck | Westphal S.,Federal Armed Forces Hospital
Regulatory Peptides | Year: 2010

Arginine-vasopressin (AVP) - via activation of the hypothalamic-pituitary-adrenal (HPA) axis - may play a role in the regulation of energy homeostasis and related cardiovascular complications. Brown adipose tissue (BAT) - via dissipation of energy in the form of heat - contributes to whole body energy balance. BAT expresses vasopressin receptors. We investigated direct effects of AVP on brown adipose endocrine and metabolic functions. UCP-1 protein expression in differentiated brown adipocytes was induced after acute exposure of adipocytes to AVP. This effect was time-dependent with a maximum increase after 8. h. AVP also induced a time- and dose-dependent increase in p38 MAP kinase phosphorylation. Pharmacological inhibition of p38 MAP kinase with SB 202190 abolished the induction of UCP-1 protein expression. Furthermore, while acute AVP treatment enhanced mRNA expression of MCP-1 and IL-6, adiponectin mRNA expression was reduced. Yet, on the level of intracellular glucose uptake, there was no AVP-induced change of adipose insulin-induced glucose uptake. Finally, there was no difference in lipid accumulation between control and AVP-treated cells.Taken together, our data demonstrate direct effects of AVP on thermogenic, inflammatory, and glucoregulatory gene expression in brown adipocytes, thus expanding the hitherto known spectrum of this neuropeptides's biological effects and suggesting a direct adipotropic role as a stress-promoting factor. © 2010 Elsevier B.V.

Riecke A.,University of Federal Defense Munich | Riecke A.,Federal Armed Forces Hospital | Rufa C.G.,University of Federal Defense Munich | Rufa C.G.,Helmut Schmidt University | And 4 more authors.
Radiation Research | Year: 2012

We examined the benefit of gene expression analysis on peripheral blood cellular subsets of different radiosensitivity to elucidate their utility as biodosimeters for estimation of dose in irradiated individuals. Peripheral mononucleated cells were isolated from 18 healthy volunteers employing density separation in a CPT-NH tube. Peripheral mononucleated cells were cultured in RPMI 1640 medium containing 10 autologous serum and were irradiated with 0.11 Gy (240 kV, 13 mA, X rays at 1 Gy/min). A low-dose study was performed with isolated peripheral mononucleated cells from one healthy donor in three independent experiments. Peripheral mononucleated cells were irradiated at 0 (sham), 1, 2.5 and 5 cGy (70 kV, 13 mA X rays at 1 cGy/min) and gene expression was measured 24 and 48 h after irradiation. After irradiation, CD4 or CD8 cells were isolated by magnetic beads in independent experiments. RNA from lymphocyte subsets and peripheral mononucleated cells was isolated after 24 and 48 h and converted into cDNA. Gene expression of GADD45, CDKN1A, DDB2, PCNA, BAX and ATF3 were determined using RTQ-PCR. Data were analyzed employing linear and logistic regression analysis. The same examinations were performed in 5 individuals either diagnosed using CT scans (up to 4.3 cGy) or by administering (F-18)-fluoro-2-deoxy-d-glucose (F-18 FDG, 0.6 cGy). Methodological, intra-and inter-individual variability in 9095 of measurements did not exceed the introduced twofold change over sham-irradiated control values in peripheral mononucleated cells and CD4 cells, and therefore no false positive results were observed. Dose reconstruction in peripheral mononucleated cells in opposite to CD4lymphocytes required fewer genes and appeared more efficient (R-square 84.8 compared to 51.8). In vitro samples exposed to 10 cGy could be completely discriminated from sham-irradiated samples without individual pre-exposure controls, which coincided with our preliminary in vivo results. However, in vitro differential gene expression was measured relative to control values and did not differ significantly at 24 and 48 h after irradiation in contrast to our preliminary in vivo data. In addition, below 5 cGy in vitro data did not show reproducible significant changes in gene expression, which was opposite to our preliminary in vivo data. Therefore a twofold change in gene expression over control sufficiently controls for different sources of variance, and measuring gene expression in peripheral mononucleated cell for biological dosimetry purposes appears superior over measurements in lymphocyte subsets. The increased gene expression measured after low absorbed doses in vivo and in vitro might indicate a particular applicability of this method for a low-level radiation scenario in the absence of individual pre-exposure controls. However, the constant gene expression values measured up to 48 h in our in vitro model at doses >10 cGy, and the absence of reproducible and statistically significant gene expression changes below 5 cGy contrast to the preliminary in vivo results performed at similar doses. Therefore, measurements with our in vitro models should be interpreted cautiously. © 2012 by Radiation Research Society.

Rudolph V.,University of Hamburg | Keller T.,University of Hamburg | Schulz A.,Johannes Gutenberg University Mainz | Ojeda F.,University of Hamburg | And 7 more authors.
Circulation: Cardiovascular Genetics | Year: 2012

Background: Activation of leukocytes with release of myeloperoxidase (MPO) has been linked to acute coronary disease. To date, studies investigating the diagnostic and prognostic performance of circulating MPO in patients with chest pain (CP) are mainly retrospective, of low size, and lack a cut-off value for MPO. Herein, we prospectively assess the diagnostic and prognostic properties of MPO compared with sensitive troponin I (sTNI) in patients admitted to the emergency room with CP. Methods and Results: One thousand, eight hundred and eighteen consecutive patients (mean age, 61.4±13.5 years;33.6% female) admitted for CP underwent determination of MPO, sTnI, and B-natriuretic peptide plasma levels at admission and 3 hours and 6 hours thereafter. A cut-off for MPO was defined in 5000 population-based subjects. Baseline MPO levels were elevated in patients with acute myocardial infarction compared with patients with noncoronary C P. For all time-points accuracy of MPO was inferior to sTNI for predicting AMI. The sensitivity of MPO to diagnose AMI at presentation was 73.5% compared with 90.7% for sTNI, and the specificity of MPO was 45.5% as opposed to 90.2%. B-natriuretic peptide levels also failed to demonstrate independent diagnostic information. Both MPO and B-natriuretic peptide were predictive for increased risk of adverse events at 30 days and 6 months, whereas their predictive value was weakened after covariate adjustment. Conclusions: The data demonstrate that MPO and B-natriuretic peptide fail to provide incremental information for patients with acute onset CP when added to sensitive troponin. However, there is a potential value for both biomarkers as prognostic markers. © 2012 American Heart Association, Inc.

Nastaly P.,University of Hamburg | Ruf C.,University of Hamburg | Ruf C.,Helmut Schmidt University | Becker P.,Helmut Schmidt University | And 13 more authors.
Clinical Cancer Research | Year: 2014

Purpose: Germ cell tumors (GCTs) represent the most frequent malignancies among young men, but little is known about circulating tumor cells (CTCs) in these tumors. Considering their heterogeneity, CTCs were investigated using two independent assays targeting germ cell tumor and epithelial cell-specific markers, and results were correlated with disease stage, histology, and serum tumor markers. Experimental Design: CTCs were enriched from peripheral blood (n = 143 patients) and testicular vein blood (TVB, n = 19 patients) using Ficoll density gradient centrifugation. For CTC detection, a combination of germ cell tumor (anti-SALL4, anti-OCT3/4) and epithelial cell-specific (anti-keratin, anti-EpCAM) antibodies was used. In parallel, 122 corresponding peripheral blood samples were analyzed using the CellSearch system. Results: In total, CTCs were detected in 25 of 143 (17.5%) peripheral blood samples, whereas only 11.5% of patients were CTC-positive when considering exclusively the CellSearch assay. The presence of CTCs in peripheral blood correlated with clinical stage (P < 0.001) with 41% of CTC positivity in patients with metastasized tumors and 100% in patients with relapsed and chemotherapy-refractory disease. Histologically, CTC-positive patients suffered more frequently from nonseminomatous primary tumors (P < 0.001), with higher percentage of yolk sac (P < 0.001) and teratoma (P = 0.004) components. Furthermore, CTC detection was associated with elevated serum levels of α-fetoprotein (AFP; P = 0.025), β-human chorionic gonadotropin (βHCG; P = 0.002), and lactate dehydrogenase (LDH; P = 0.002). Incidence and numbers of CTCs in TVB were much higher than in peripheral blood. Conclusions: The inclusion of germ cell tumor-specific markers improves CTC detection in GCTs. CTCs occur frequently in patients with more aggressive disease, and there is a gradient of CTCs with decreasing numbers from the tumor-draining vein to the periphery. ©2014 AACR.

PubMed | University of Leipzig, Federal Armed Forces Hospital and Innsbruck Medical University
Type: | Journal: BioMed research international | Year: 2016

Background. Emergency airway management (AM) is a priority when resuscitating critically ill or severely injured patients. The goal of this study was to determine the success rates of LT insertion during AM. Methods. Studies that included LT first-pass insertion (FPI) and overall-pass insertion (OPI) success by emergency medical services and in-hospital providers performing AM for emergency situations as well as for scheduled surgery published until July 2014 were searched systematically in Medline. Results. Data of 36 studies (n = 1,897) reported a LT FPI success by physicians of 82.5% with an OPI success of 93.6% (p < 0.001). A cumulative analysis of all 53 studies (n = 3,600) led to FPI and OPI success of 80.1% and 92.6% (p < 0.001), respectively. The results of 26 studies (n = 2,159) comparing the LT with the laryngeal mask airway (LMA) demonstrated a FPI success of 77.0 versus 78.7% (p = 0.36) and an OPI success of 92.2 versus 97.7% (p < 0.001). Conclusion. LT insertion failed in the first attempt in one out of five patients, with an overall failure rate in one out of 14 patients. When compared with the LT, the LMA had a cumulative 5.5% better OPI success rate.

Ruf C.G.,Helmut Schmidt University | Ruf C.G.,University of Federal Defense Munich | Linbecker M.,Helmut Schmidt University | Port M.,Hannover Medical School | And 6 more authors.
BJU International | Year: 2012

Objective To evaluate the usefulness of gene expression profiling for predicting metastatic status in testicular seminoma at the time of first diagnosis compared with established clinical and pathological parameters. Patients and Methods Total RNA was isolated from testicular tumours of metastasized patients (12 patients, clinical stage IIa-III), non-metastasized patients (40, clinical stage I) and adjacent 'normal' tissue (n= 36). The RNA was then converted into cDNA and real-time quantitative polymerase chain reaction was run on 94 candidate genes selected from previous work. Normalised gene expression of these genes and histological variables, e.g. tumour size and rete testis infiltration, were analysed using logistic regression analysis. Results Expression of two genes (dopamine receptor D1 [DRD1] and family with sequence similarity 71, member F2 [FAM71F2], P= 0.005 and 0.024 in separate analysis and P= 0.004 and 0.016 when combining both genes, respectively) made it possible to significantly discriminate the metastasis status. Concordance increased from 77.9% (DRD1) and 72.3% (FAM71F2) in separate analysis and up to 87.7% when combining both genes in one model. Only primary tumour size in separate analysis (continuous or categorical with tumour size >6 cm) was significantly associated with metastasis (P= 0.039/P= 0.02), but concordance was lower (61%). When we combined tumour size with our two genes in one model there was no further statistical improvement or increased concordance. Conclusion Based on gene expression analysis our study provides suggestions for improved individual decision making either in favour of early adjuvant therapy or increased surveillance. © 2012 BJU INTERNATIONAL.

PubMed | University of Federal Defense Munich and Federal Armed Forces Hospital
Type: Journal Article | Journal: Radiation research | Year: 2016

The purpose of this work was to adapt a more advanced form of the cytokinesis-block micronucleus (CBMN) cytome assay for triage biodosimetry in the event of a mass casualty radiation incident. We modified scoring procedures for the CBMN cytome assay to optimize field deployability, dose range, accuracy, speed, economy, simplicity and stability. Peripheral blood of 20 donors was irradiated in vitro (0-6 Gy X ray, maximum photon energy 240 keV) and processed for CBMN. Initially, we assessed two manual scoring strategies for accuracy: 1. Conventional scoring, comprised of micronucleus (MN) frequency per 1,000 binucleated (BN) cells (MN/1,000 BN cells); and 2. Evaluation of 1,000, 2,000 and 3,000 cells in total and different cellular subsets based on MN formation and proliferation (e.g., BN cells with and without MN, mononucleated cells). We used linear and logistic regression models to identify the cellular subsets related closest to dose with the best discrimination ability among different doses/dose categories. We validated the most promising subsets and their combinations with 16 blind samples covering a dose range of 0-8.3 Gy. Linear dose-response relationships comparable to the conventional CBMN assay (r(2) = 0.86) were found for BN cells with MN (r(2) = 0.84) and BN cells without MN (r(2) = 0.84). Models of combined cell counts (CCC) of BN cells with and without MN (BN(+MN) and BN(-MN)) with mononucleated cells (Mono) improved this relationship (r(2) = 0.92). Conventional CBMN discriminated dose categories up to 3 Gy with a concordance between 0.96-1.0 upon scoring 1,000 total cells. In 1,000 BN cells, concordances were observed for conventional CBMN up to 4 Gy as well as BN(+MN) or BN(-MN) (about 0.85). At doses of 4-6 Gy, the concordance of conventional CBMN, BN(+MN) and BN(-MN) declined (about 0.55). We found about 20% higher concordance and more precise dose estimates of irradiated and blinded samples for CCC (Mono + BN(+MN)) after scoring 1,000 total cells. Blinded sample analysis revealed that the mean absolute difference (MAD) of dose estimates and the number of dose estimates outside the 0.5 Gy interval based on CCC (Mono + BN(+MN)) was comparable to conventional CBMN for doses 4 Gy when scoring 3,000 total cells or more. At doses >4-8.3 Gy, the MAD of CCC (Mono + BN(+MN)) declined to half of the MADs observed for conventional CBMN, suggesting that the combined cell counts approach improved the discrimination ability. Conventional CBMN at 1,000 total-cell counts performed as efficiently as counting 1,000 BN cells. Discriminating and counting only BN cells with and without MN after 1,000 BN cells at 4 Gy revealed performances similar to conventional CBMN. After 3,000 total cells were scored, CCC (Mono + BN(+MN)) was superior to conventional CBMN at >4 Gy up to about 8 Gy. Our modification of CBMN evaluations saved time compared to the widely established semiautomated MN scoring and extended the dose range up to approximately 6 Gy for triage biodosimetry.

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