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188 Publications visible to you, out of a total of 188
Alteration of Multiple Leukocyte Gene Expression Networks is Linked with Magnetic Resonance Markers of Prognosis After Acute ST-Elevation Myocardial Infarction.
LIFE Heart

Abstract (Expand)

Prognostic relevant pathways of leukocyte involvement in human myocardial ischemic-reperfusion injury are largely unknown. We enrolled 136 patients with ST-elevation myocardial infarction (STEMI) after … primary angioplasty within 12 h after onset of symptoms. Following reperfusion, whole blood was collected within a median time interval of 20 h (interquartile range: 15-25 h) for genome-wide gene expression analysis. Subsequent CMR scans were performed using a standard protocol to determine infarct size (IS), area at risk (AAR), myocardial salvage index (MSI) and the extent of late microvascular obstruction (lateMO). We found 398 genes associated with lateMO and two genes with IS. Neither AAR, nor MSI showed significant correlations with gene expression. Genes correlating with lateMO were strongly related to several canonical pathways, including positive regulation of T-cell activation (p = 3.44 x 10(-5)), and regulation of inflammatory response (p = 1.86 x 10(-3)). Network analysis of multiple gene expression alterations associated with larger lateMO identified the following functional consequences: facilitated utilisation and decreased concentration of free fatty acid, repressed cell differentiation, enhanced phagocyte movement, increased cell death, vascular disease and compensatory vasculogenesis. In conclusion, the extent of lateMO after acute, reperfused STEMI correlated with altered activation of multiple genes related to fatty acid utilisation, lymphocyte differentiation, phagocyte mobilisation, cell survival, and vascular dysfunction.

Authors: A. Teren, H. Kirsten, F. Beutner, M. Scholz, L. M. Holdt, D. Teupser, M. Gutberlet, J. Thiery, G. Schuler, I. Eitel

Date Published: 3rd Feb 2017

Publication Type: Journal article

Human Diseases: myocardial infarction

Body surface assessment with 3D laser-based anthropometry: reliability, validation, and improvement of empirical surface formulae.
Genetical Statistics and Systems Biology

Abstract (Expand)

PURPOSE Body surface area is a physiological quantity relevant for many medical applications. In clinical practice, it is determined by empirical formulae. 3D laser-based anthropometry provides an easy …y and effective way to measure body surface area but is not ubiquitously available. We used data from laser-based anthropometry from a population-based study to assess validity of published and commonly used empirical formulae. METHODS We performed a large population-based study on adults collecting classical anthropometric measurements and 3D body surface assessments (N = 1435). We determined reliability of the 3D body surface assessment and validity of 18 different empirical formulae proposed in the literature. The performance of these formulae is studied in subsets of sex and BMI. Finally, improvements of parameter settings of formulae and adjustments for sex and BMI were considered. RESULTS 3D body surface measurements show excellent intra- and inter-rater reliability of 0.998 (overall concordance correlation coefficient, OCCC was used as measure of agreement). Empirical formulae of Fujimoto and Watanabe, Shuter and Aslani and Sendroy and Cecchini performed best with excellent concordance with OCCC \textgreater 0.949 even in subgroups of sex and BMI. Re-parametrization of formulae and adjustment for sex and BMI slightly improved results. CONCLUSION In adults, 3D laser-based body surface assessment is a reliable alternative to estimation by empirical formulae. However, there are empirical formulae showing excellent results even in subgroups of sex and BMI with only little room for improvement.

Authors: Andreas Kuehnapfel, Peter Ahnert, Markus Loeffler, Markus Scholz

Date Published: 27th Jan 2017

Publication Type: Journal article

PROGRESS - prospective observational study on hospitalized community acquired pneumonia
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Community acquired pneumonia (CAP) is a high incidence disease resulting in about 260,000 hospital admissions per year in Germany, more than myocardial infarction or stroke. Worldwide, CAP …P is the most frequent infectious disease with high lethality ranging from 1.2 % in those 20-29 years old to over 10 % in patients older than 70 years, even in industrial nations. CAP poses numerous medical challenges, which the PROGRESS (Pneumonia Research Network on Genetic Resistance and Susceptibility for the Evolution of Severe Sepsis) network aims to tackle: Operationalization of disease severity throughout the course of disease, outcome prediction for hospitalized patients and prediction of transitions from uncomplicated CAP to severe CAP, and finally, to CAP with sepsis and organ failure as a life-threatening condition. It is a major aim of PROGRESS to understand and predict patient heterogeneity regarding outcome in the hospital and to develop novel treatment concepts. METHODS PROGRESS was designed as a clinical, observational, multi-center study of patients with CAP requiring hospitalization. More than 1600 patients selected for low burden of co-morbidities have been enrolled, aiming at a total of 3000. Course of disease, along with therapy, was closely monitored by daily assessments and long-term follow-up. Daily blood samples allow in depth molecular-genetic characterization of patients. We established a well-organized workflow for sample logistics and a comprehensive data management system to collect and manage data from more than 50 study centers in Germany and Austria. Samples are stored in a central biobank and clinical data are stored in a central data base which also integrates all data from molecular assessments. DISCUSSION With the PROGRESS study, we established a comprehensive data base of high quality clinical and molecular data allowing investigation of pressing research questions regarding CAP. In-depth molecular characterization will contribute to the discovery of disease mechanisms and establishment of diagnostic and predictive biomarkers. A strength of PROGRESS is the focus on younger patients with low burden of co-morbidities, allowing a more direct look at host biology with less confounding. As a resulting limitation, insights from PROGRESS will require validation in representative patient cohorts to assess clinical utility. TRIAL REGISTRATION The PROGRESS study was retrospectively registered on May 24(th), 2016 with ClinicalTrials.gov: NCT02782013.

Authors: Peter Ahnert, Petra Creutz, Markus Scholz, Hartwig Schütte, Christoph Engel, Hamid Hossain, Trinad Chakraborty, Michael Bauer, Michael Kiehntopf, Uwe Völker, Sven Hammerschmidt, Markus Loeffler, Norbert Suttorp

Date Published: 1st Dec 2016

Publication Type: Journal article

Comparing performance of modern genotype imputation methods in different ethnicities
Genetical Statistics and Systems Biology

Abstract (Expand)

A variety of modern software packages are available for genotype imputation relying on advanced concepts such as pre-phasing of the target dataset or utilization of admixed reference panels. In this … study, we performed a comprehensive evaluation of the accuracy of modern imputation methods on the basis of the publicly available POPRES samples. Good quality genotypes were masked and re-imputed by different imputation frameworks: namely MaCH, IMPUTE2, MaCH-Minimac, SHAPEIT-IMPUTE2 and MaCH-Admix. Results were compared to evaluate the relative merit of pre-phasing and the usage of admixed references. We showed that the pre-phasing framework SHAPEIT-IMPUTE2 can overestimate the certainty of genotype distributions resulting in the lowest percentage of correctly imputed genotypes in our case. MaCH-Minimac performed better than SHAPEIT-IMPUTE2. Pre-phasing always reduced imputation accuracy. IMPUTE2 and MaCH-Admix, both relying on admixed-reference panels, showed comparable results. MaCH showed superior results if well-matched references were available (Nei’s GST ≤ 0.010). For small to medium datasets, frameworks using genetically closest reference panel are recommended if the genetic distance between target and reference data set is small. Our results are valid for small to medium data sets. As shown on a larger data set of population based German samples, the disadvantage of pre-phasing decreases for larger sample sizes.

Authors: Nab Raj Roshyara, Katrin Horn, Holger Kirsten, Peter Ahnert, Markus Scholz

Date Published: 1st Dec 2016

Publication Type: Journal article

Sevoflurane and Isoflurane-Pharmacokinetics, Hemodynamic Stability, and Cardioprotective Effects During Cardiopulmonary Bypass
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVES This study aimed to evaluate the pharmacokinetic profiles of sevoflurane and isoflurane during use of minimized extracorporeal circulation to perform coronary artery bypass graft surgery. …. Furthermore, cardiovascular stability during bypass and the postoperative release of troponins were evaluated. DESIGN Prospective, randomized study. SETTING University hospital. PARTICIPANTS The study comprised 31 adult patients undergoing coronary artery bypass grafting. INTERVENTIONS The pharmacokinetic measurements of the concentration of the volatile anesthetics in the arterial and venous blood, air inlet, air outlet, and gas exhaust of the extracorporeal circulation were recorded. Secondary end-points were cardiovascular stability during bypass, amount of postoperative release of troponin, time to extubation, time to discharge from the intensive care unit and the hospital, and 30-day mortality. MEASUREMENTS AND MAIN RESULTS Thirty patients completed the protocol. The pharmacokinetics of isoflurane and sevoflurane were almost identical, with a rapid wash-in (time to reach 50% of arterial steady state) concentration of 0.87\pm0.97 minutes and 1.14\pm0.35 minutes for isoflurane and sevoflurane, respectively, and a biphasic venous elimination with a terminal half-life of approximately 10 minutes for both compounds. There was a correlation between the gas inlet and the gas exhaust of the extracorporeal circulation. No difference in cardiovascular stability was found. High-sensitivity troponin concentrations on the first postoperative morning were 0.355\pm0.312 µg/mL and 0.225\pm0.111 µg/mL in the isoflurane and sevoflurane groups, respectively (p = 0.147). CONCLUSIONS The study found similar pharmacokinetics regarding wash-in and wash-out for sevoflurane and isoflurane. In addition, no difference in cardiovascular stability was found. The markers of cardiac damage were not different between the two anesthetics. Based on these data, sevoflurane and isoflurane might be used equivalently in patients undergoing coronary artery bypass graft surgery with extracorporeal circulation.

Authors: David Freiermuth, Berend Mets, Daniel Bolliger, Oliver Reuthebuch, Thomas Doebele, Markus Scholz, Michael Gregor, Matthias Haschke, Manfred Daniel Seeberger, Jens Fassl

Date Published: 1st Dec 2016

Publication Type: Journal article

Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans
Genetical Statistics and Systems Biology

Abstract (Expand)

Circular RNAs (circRNAs) are broadly expressed in eukaryotic cells, but their molecular mechanism in human disease remains obscure. Here we show that circular antisense non-coding RNA in the INK4 locus … (circANRIL), which is transcribed at a locus of atherosclerotic cardiovascular disease on chromosome 9p21, confers atheroprotection by controlling ribosomal RNA (rRNA) maturation and modulating pathways of atherogenesis. CircANRIL binds to pescadillo homologue 1 (PES1), an essential 60S-preribosomal assembly factor, thereby impairing exonuclease-mediated pre-rRNA processing and ribosome biogenesis in vascular smooth muscle cells and macrophages. As a consequence, circANRIL induces nucleolar stress and p53 activation, resulting in the induction of apoptosis and inhibition of proliferation, which are key cell functions in atherosclerosis. Collectively, these findings identify circANRIL as a prototype of a circRNA regulating ribosome biogenesis and conferring atheroprotection, thereby showing that circularization of long non-coding RNAs may alter RNA function and protect from human disease.

Authors: Lesca M. Holdt, Anika Stahringer, Kristina Sass, Garwin Pichler, Nils A. Kulak, Wolfgang Wilfert, Alexander Kohlmaier, Andreas Herbst, Bernd H. Northoff, Alexandros Nicolaou, Gabor Gäbel, Frank Beutner, Markus Scholz, Joachim Thiery, Kiran Musunuru, Knut Krohn, Matthias Mann, Daniel Teupser

Date Published: 1st Nov 2016

Publication Type: Journal article

No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis.
Genetical Statistics and Systems Biology, LIFE Heart

Abstract (Expand)

In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X … chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.

Authors: C. Loley, M. Alver, T. L. Assimes, A. Bjonnes, A. Goel, S. Gustafsson, J. Hernesniemi, J. C. Hopewell, S. Kanoni, M. E. Kleber, K. W. Lau, Y. Lu, L. P. Lyytikainen, C. P. Nelson, M. Nikpay, L. Qu, E. Salfati, M. Scholz, T. Tukiainen, C. Willenborg, H. H. Won, L. Zeng, W. Zhang, S. S. Anand, F. Beutner, E. P. Bottinger, R. Clarke, G. Dedoussis, R. Do, T. Esko, M. Eskola, M. Farrall, D. Gauguier, V. Giedraitis, C. B. Granger, A. S. Hall, A. Hamsten, S. L. Hazen, J. Huang, M. Kahonen, T. Kyriakou, R. Laaksonen, L. Lind, C. Lindgren, P. K. Magnusson, E. Marouli, E. Mihailov, A. P. Morris, K. Nikus, N. Pedersen, L. Rallidis, V. Salomaa, S. H. Shah, A. F. Stewart, J. R. Thompson, P. A. Zalloua, J. C. Chambers, R. Collins, E. Ingelsson, C. Iribarren, P. J. Karhunen, J. S. Kooner, T. Lehtimaki, R. J. Loos, W. Marz, R. McPherson, A. Metspalu, M. P. Reilly, S. Ripatti, D. K. Sanghera, J. Thiery, H. Watkins, P. Deloukas, S. Kathiresan, N. J. Samani, H. Schunkert, J. Erdmann, I. R. Konig

Date Published: 12th Oct 2016

Publication Type: Journal article

Human Diseases: coronary artery disease

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