@article{AllignolSchumacherWanneretal.2011, author = {Allignol, Arthur and Schumacher, Martin and Wanner, Christoph and Drechsler, Christiane and Beyersmann, Jan}, title = {Understanding competing risks: a simulation point of view}, series = {BMC Medical Research Methodology}, volume = {11}, journal = {BMC Medical Research Methodology}, number = {86}, doi = {10.1186/1471-2288-11-86}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142811}, pages = {1-13}, year = {2011}, abstract = {Background: Competing risks methodology allows for an event-specific analysis of the single components of composite time-to-event endpoints. A key feature of competing risks is that there are as many hazards as there are competing risks. This is not always well accounted for in the applied literature. Methods: We advocate a simulation point of view for understanding competing risks. The hazards are envisaged as momentary event forces. They jointly determine the event time. Their relative magnitude determines the event type. 'Empirical simulations' using data from a recent study on cardiovascular events in diabetes patients illustrate subsequent interpretation. The method avoids concerns on identifiability and plausibility known from the latent failure time approach. Results: The 'empirical simulations' served as a proof of concept. Additionally manipulating baseline hazards and treatment effects illustrated both scenarios that require greater care for interpretation and how the simulation point of view aids the interpretation. The simulation algorithm applied to real data also provides for a general tool for study planning. Conclusions: There are as many hazards as there are competing risks. All of them should be analysed. This includes estimation of baseline hazards. Study planning must equally account for these aspects.}, language = {en} } @article{EdelmannWachterDuengenetal.2011, author = {Edelmann, Frank and Wachter, Rolf and D{\"u}ngen, Hans-Dirk and St{\"o}rk, Stefan and Richter, Annette and Stahrenberg, Raoul and Neumann, Till and L{\"u}ers, Claus and Angermann, Christiane E. and Mehrhof, Felix and Gelbrich, G{\"o}tz and Pieske, Burkert}, title = {Heart failure therapy in diabetic patients-comparison with the recent ESC/EASD guideline}, series = {Cardiovascular Diabetology}, volume = {10}, journal = {Cardiovascular Diabetology}, number = {15}, doi = {10.1186/1475-2840-10-15}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140397}, pages = {1-8}, year = {2011}, abstract = {Background: To assess heart failure therapies in diabetic patients with preserved as compared to impaired systolic ventricular function. Methods: 3304 patients with heart failure from 9 different studies were included (mean age 63 +/- 14 years); out of these, 711 subjects had preserved left ventricular ejection fraction (>= 50\%) and 994 patients in the whole cohort suffered from diabetes. Results: The majority (>90\%) of heart failure patients with reduced ejection fraction (SHF) and diabetes were treated with an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB) or with beta-blockers. By contrast, patients with diabetes and preserved ejection fraction (HFNEF) were less likely to receive these substance classes (p < 0.001) and had a worse blood pressure control (p < 0.001). In comparison to patients without diabetes, the probability to receive these therapies was increased in diabetic HFNEF patients (p < 0.001), but not in diabetic SHF patients. Aldosterone receptor blockers were given more often to diabetic patients with reduced ejection fraction (p < 0.001), and the presence and severity of diabetes decreased the probability to receive this substance class, irrespective of renal function. Conclusions: Diabetic patients with HFNEF received less heart failure medication and showed a poorer control of blood pressure as compared to diabetic patients with SHF. SHF patients with diabetes were less likely to receive aldosterone receptor blocker therapy, irrespective of renal function.}, language = {en} } @article{DrechslerMeinitzerPilzetal.2011, author = {Drechsler, Christiane and Meinitzer, Andreas and Pilz, Stefan and Krane, Vera and Tomaschitz, Andreas and Ritz, Eberhard and M{\"a}rz, Winfried and Wanner, Christoph}, title = {Homoarginine, heart failure, and sudden cardiac death in haemodialysis patients}, series = {European Journal of Heart Failure}, volume = {13}, journal = {European Journal of Heart Failure}, number = {8}, doi = {10.1093/eurjhf/hfr056}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140495}, pages = {852-859}, year = {2011}, abstract = {Aims Sudden cardiac death (SCD) is a major contributor to the excess mortality of patients on maintenance dialysis. Homoarginine deficiency may lead to decreased nitric oxide availability and endothelial dysfunction. Based on this rationale we assessed whether homoarginine deficiency is a risk factor for SCD in dialysis patients. Methods and results This study examined the association of homoarginine with cardiovascular outcomes in 1255 diabetic haemodialysis patients from the German diabetes and dialysis study. During a median of 4 years of follow-up, hazard ratios (HR) (95\% CI) for reaching the following pre-specified, adjudicated endpoints were determined: SCD, myocardial infarction, stroke, death due to heart failure, and combined cardiovascular events. There was a strong association of low homoarginine concentrations with the presence of congestive heart failure and left ventricular hypertrophy as well as increased levels of brain natriuretic peptide. Per unit decrease in homoarginine, the risk of SCD increased three-fold (HR 3.1, 95\% CI 2.0-4.9), attenuating slightly in multivariate models (HR 2.4; 95\% CI 1.5-3.9). Patients in the lowest homoarginine quintile experienced a more than two-fold increased risk of SCD, and more than three-fold increased risk of heart failure death than patients in the highest quintile, which accounted for the high incidence of combined cardiovascular events. Low homoarginine showed a trend towards increased risk of stroke, however, myocardial infarction was not meaningfully affected. Conclusion Low homoarginine is a strong risk factor for SCD and death due to heart failure in haemodialysis patients. Further studies are needed to elucidate the underlying mechanisms, offering the potential to develop new interventional strategies.}, language = {en} } @article{SbieraDexneitReichardtetal.2011, author = {Sbiera, Silviu and Dexneit, Thomas and Reichardt, Sybille D. and Michel, Kai D. and van den Brandt, Jens and Schmull, Sebastian and Kraus, Luitgard and Beyer, Melanie and Mlynski, Robert and Wortmann, Sebastian and Allolio, Bruno and Reichardt, Holger M. and Fassnacht, Martin}, title = {Influence of Short-Term Glucocorticoid Therapy on Regulatory T Cells \(In\) \(Vivo\)}, series = {PLoS One}, volume = {6}, journal = {PLoS One}, number = {9}, doi = {10.1371/journal.pone.0024345}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140822}, pages = {e24345}, year = {2011}, abstract = {Background: Pre- and early clinical studies on patients with autoimmune diseases suggested that induction of regulatory T(T(reg)) cells may contribute to the immunosuppressive effects of glucocorticoids(GCs). Objective: We readdressed the influence of GC therapy on T(reg) cells in immunocompetent human subjects and naive mice. Methods: Mice were treated with increasing doses of intravenous dexamethasone followed by oral taper, and T(reg) cells in spleen and blood were analyzed by FACS. Sixteen patients with sudden hearing loss but without an inflammatory disease received high-dose intravenous prednisolone followed by stepwise dose reduction to low oral prednisolone. Peripheral blood T(reg) cells were analyzed prior and after a 14 day GC therapy based on different markers. Results: Repeated GC administration to mice for three days dose-dependently decreased the absolute numbers of T(reg) cells in blood (100 mg dexamethasone/kg body weight: 2.8 +/- 1.8 x 10(4) cells/ml vs. 33 +/- 11 x 10(4) in control mice) and spleen (dexamethasone: 2.8 +/- 1.9 x 10(5)/spleen vs. 95 +/- 22 x 10(5)/spleen in control mice), which slowly recovered after 14 days taper in spleen but not in blood. The relative frequency of FOXP3(+) T(reg) cells amongst the CD4(+) T cells also decreased in a dose dependent manner with the effect being more pronounced in blood than in spleen. The suppressive capacity of T(reg) cells was unaltered by GC treatment in vitro. In immunocompetent humans, GCs induced mild T cell lymphocytosis. However, it did not change the relative frequency of circulating T(reg) cells in a relevant manner, although there was some variation depending on the definition of the T(reg) cells (FOXP3(+): 4.0 +/- 1.5\% vs 3.4 +/- 1.5\%*; AITR(+): 0.660.4 vs 0.5 +/- 0.3\%, CD127(low): 4.0 +/- 1.3 vs 5.0 +/- 3.0\%* and CTLA4+: 13.8 +/- 11.5 vs 15.6 +/- 12.5\%; * p < 0.05). Conclusion: Short-term GC therapy does not induce the hitherto supposed increase in circulating T(reg) cell frequency, neither in immunocompetent humans nor in mice. Thus, it is questionable that the clinical efficacy of GCs is achieved by modulating T(reg) cell numbers.}, language = {en} } @article{FassnachtSbieraDexneitetal.2011, author = {Fassnacht, Martin and Sbiera, Silviu and Dexneit, Thomas and Reichardt, Sybille D. and Michel, Kai D. and van den Brandt, Jens and Schmull, Sebastian and Kraus, Luitgard and Beyer, Melanie and Mlynski, Robert and Wortmann, Sebastian and Allolio, Bruno and Reichardt, Holger M.}, title = {Influence of Short-Term Glucocorticoid Therapy on Regulatory T Cells In Vivo}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-74749}, year = {2011}, abstract = {Background: Pre- and early clinical studies on patients with autoimmune diseases suggested that induction of regulatory T(Treg) cells may contribute to the immunosuppressive effects of glucocorticoids(GCs). Objective: We readdressed the influence of GC therapy on Treg cells in immunocompetent human subjects and na{\i}¨ve mice. Methods: Mice were treated with increasing doses of intravenous dexamethasone followed by oral taper, and Treg cells in spleen and blood were analyzed by FACS. Sixteen patients with sudden hearing loss but without an inflammatory disease received high-dose intravenous prednisolone followed by stepwise dose reduction to low oral prednisolone. Peripheral blood Treg cells were analyzed prior and after a 14 day GC therapy based on different markers. Results: Repeated GC administration to mice for three days dose-dependently decreased the absolute numbers of Treg cells in blood (100 mg dexamethasone/kg body weight: 2.861.86104 cells/ml vs. 336116104 in control mice) and spleen (dexamethasone: 2.861.96105/spleen vs. 956226105/spleen in control mice), which slowly recovered after 14 days taper in spleen but not in blood. The relative frequency of FOXP3+ Treg cells amongst the CD4+ T cells also decreased in a dose dependent manner with the effect being more pronounced in blood than in spleen. The suppressive capacity of Treg cells was unaltered by GC treatment in vitro. In immunocompetent humans, GCs induced mild T cell lymphocytosis. However, it did not change the relative frequency of circulating Treg cells in a relevant manner, although there was some variation depending on the definition of the Treg cells (FOXP3+: 4.061.5\% vs 3.461.5\%*; AITR+: 0.660.4 vs 0.560.3\%, CD127low: 4.061.3 vs 5.063.0\%* and CTLA4+: 13.8611.5 vs 15.6612.5\%; * p,0.05). Conclusion: Short-term GC therapy does not induce the hitherto supposed increase in circulating Treg cell frequency, neither in immunocompetent humans nor in mice. Thus, it is questionable that the clinical efficacy of GCs is achieved by modulating Treg cell numbers.}, subject = {Medizin}, language = {en} } @article{KasangKalluvyaMajingeetal.2011, author = {Kasang, Christa and Kalluvya, Samuel and Majinge, Charles and Stich, August and Bodem, Jochen and Kongola, Gilbert and Jacobs, Graeme B. and Mlewa, Mathias and Mildner, Miriam and Hensel, Irina and Horn, Anne and Preiser, Wolfgang and van Zyl, Gert and Klinker, Hartwig and Koutsilieri, Eleni and Rethwilm, Axel and Scheller, Carsten and Weissbrich, Benedikt}, title = {HIV Drug Resistance (HIVDR) in Antiretroviral Therapy-Na{\"i}ve Patients in Tanzania Not Eligible for WHO Threshold HIVDR Survey Is Dramatically High}, series = {PLoS One}, volume = {6}, journal = {PLoS One}, number = {8}, doi = {10.1371/journal.pone.0023091}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137988}, pages = {e23091}, year = {2011}, abstract = {Background The World Health Organization (WHO) has recommended guidelines for a HIV drug resistance (HIVDR) survey for resource-limited countries. Eligibility criteria for patients include age below 25 years in order to focus on the prevalence of transmitted HIVDR (tHIVDR) in newly-infected individuals. Most of the participating sites across Africa have so far reported tHIVDR prevalences of below 5\%. In this study we investigated whether the rate of HIVDR in patients <25 years is representative for HIVDR in the rest of the therapy-na{\"i}ve population. Methods and Findings HIVDR was determined in 88 sequentially enrolled ART-na{\"i}ve patients from Mwanza, Tanzania (mean age 35.4 years). Twenty patients were aged <25 years and 68 patients were aged 25-63 years. The frequency of HIVDR in the study population was 14.8\% (95\%; CI 0.072-0.223) and independent of NVP-resistance induced by prevention of mother-to-child transmission programs. Patients >25 years had a significantly higher HIVDR frequency than younger patients (19.1\%; 95\% CI 0.095-0.28) versus 0\%, P = 0.0344). In 2 out of the 16 patients with HIVDR we found traces of antiretrovirals (ARVs) in plasma. Conclusions ART-na{\"i}ve patients aged over 25 years exhibited significantly higher HIVDR than younger patients. Detection of traces of ARVs in individuals with HIVDR suggests that besides transmission, undisclosed misuse of ARVs may constitute a significant factor in the generation of the observed high HIVDR rate. The current WHO tHIVDR survey that is solely focused on the transmission of HIVDR and that excludes patients over 25 years of age may therefore result in substantial underestimation of the prevalence of HIVDR in the therapy-na{\"i}ve population. Similar studies should be performed also in other areas to test whether the so far reported optimistic picture of low HIVDR prevalence in young individuals is really representative for the rest of the ART-na{\"i}ve HIV-infected population.}, language = {en} } @article{KistlerSiwyFranketal.2011, author = {Kistler, Andreas D. and Siwy, Justyna and Frank, Breunig and Jeevaratnam, Praveen and Scherl, Alexander and Mullen, William and Warnock, David G. and Wanner, Christoph and Hughes, Derralynn A. and Mischak, Harald and W{\"u}thrich, Rudolf P. and Serra, Andreas L.}, title = {A Distinct Urinary Biomarker Pattern Characteristic of Female Fabry Patients That Mirrors Response to Enzyme Replacement Therapy}, series = {PLoS ONE}, volume = {6}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0020534}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133526}, pages = {e20534}, year = {2011}, abstract = {Female patients affected by Fabry disease, an X-linked lysosomal storage disorder, exhibit a wide spectrum of symptoms, which renders diagnosis, and treatment decisions challenging. No diagnostic test, other than sequencing of the alpha-galactosidase A gene, is available and no biomarker has been proven useful to screen for the disease, predict disease course and monitor response to enzyme replacement therapy. Here, we used urine proteomic analysis based on capillary electrophoresis coupled to mass spectrometry and identified a biomarker profile in adult female Fabry patients. Urine samples were taken from 35 treatment-naive female Fabry patients and were compared to 89 age-matched healthy controls. We found a diagnostic biomarker pattern that exhibited 88.2\% sensitivity and 97.8\% specificity when tested in an independent validation cohort consisting of 17 treatment-naive Fabry patients and 45 controls. The model remained highly specific when applied to additional control patients with a variety of other renal, metabolic and cardiovascular diseases. Several of the 64 identified diagnostic biomarkers showed correlations with measures of disease severity. Notably, most biomarkers responded to enzyme replacement therapy, and 8 of 11 treated patients scored negative for Fabry disease in the diagnostic model. In conclusion, we defined a urinary biomarker model that seems to be of diagnostic use for Fabry disease in female patients and may be used to monitor response to enzyme replacement therapy.}, language = {en} } @article{EdelmannStahrenbergGelbrichetal.2011, author = {Edelmann, Frank and Stahrenberg, Raoul and Gelbrich, G{\"o}tz and Durstewitz, Kathleen and Angermann, Christiane E. and D{\"u}ngen, Hans-Dirk and Scheffold, Thomas and Zugck, Christian and Maisch, Bernhard and Regitz-Zagrosek, Vera and Hasenfuß, Gerd and Pieske, Burkert M. and Wachter, Rolf}, title = {Contribution of comorbidities to functional impairment is higher in heart failure with preserved than with reduced ejection fraction}, series = {Clinical Research in Cardiology}, volume = {100}, journal = {Clinical Research in Cardiology}, number = {9}, doi = {10.1007/s00392-011-0305-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134354}, pages = {755-764}, year = {2011}, abstract = {Background Comorbidities negatively affect prognosis more strongly in heart failure with preserved (HFpEF) than with reduced (HFrEF) ejection fraction. Their comparative impact on physical impairment in HFpEF and HFrEF has not been evaluated so far. Methods and results The frequency of 12 comorbidities and their impact on NYHA class and SF-36 physical functioning score (SF-36 PF) were evaluated in 1,294 patients with HFpEF and 2,785 with HFrEF. HFpEF patients had lower NYHA class (2.0 ± 0.6 vs. 2.4 ± 0.6, p < 0.001) and higher SF-36 PF score (54.4 ± 28.3 vs. 54.4 ± 27.7, p < 0.001). All comorbidities were significantly (p < 0.05) more frequent in HFrEF, except hypertension and obesity, which were more frequent in HFpEF (p < 0.001). Adjusting for age and gender, COPD, anemia, hyperuricemia, atrial fibrillation, renal dysfunction, cerebrovascular disease and diabetes had a similar (p for interaction > 0.05) negative effect in both groups. Obesity, coronary artery disease and peripheral arterial occlusive disease exerted a significantly (p < 0.05) more adverse effect in HFpEF, while hypertension and hyperlipidemia were associated with fewer (p < 0.05) symptoms in HFrEF only. The total impact of comorbidities on NYHA (AUC for prediction of NYHA III/IV vs. I/II) and SF-36 PF (r 2) in multivariate analyses was approximately 1.5-fold higher in HFpEF, and also much stronger than the impact of a 10\% decrease in ejection fraction in HFrEF or a 5 mm decrease in left ventricular end-diastolic diameter in HFpEF. Conclusion The impact of comorbidities on physical impairment is higher in HFpEF than in HFrEF. This should be considered in the differential diagnosis and in the treatment of patients with HFpEF.}, language = {en} } @article{CarstenAGorskiLietal.2011, author = {Carsten A., B{\"o}ger and Gorski, Mathias and Li, Man and Hoffmann, Michael M. and Huang, Chunmei and Yang, Qiong and Teumer, Alexander and Krane, Vera and O'Seaghdha, Conall M. and Kutalik, Zolt{\´a}n and Wichmann, H.-Erich and Haak, Thomas and Boes, Eva and Coassin, Stefan and Coresh, Josef and Kollerits, Barbara and Haun, Margot and Paulweber, Bernhard and K{\"o}ttgen, Anna and Li, Guo and Shlipak, Michael G. and Powe, Neil and Hwang, Shih-Jen and Dehghan, Abbas and Rivadeneira, Fernando and Uitterlinden, Andr{\´e} and Hofman, Albert and Beckmann, Jacques S. and Kr{\"a}mer, Bernhard K. and Witteman, Jacqueline and Bochud, Murielle and Siscovick, David and Rettig, Rainer and Kronenberg, Florian and Wanner, Christoph and Thadhani, Ravi I. and Heid, Iris M. and Fox, Caroline S. and Kao, W.H.}, title = {Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD}, series = {PLoS Genetics}, volume = {7}, journal = {PLoS Genetics}, number = {9}, doi = {10.1371/journal.pgen.1002292}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133758}, pages = {e1002292}, year = {2011}, abstract = {Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR < 60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.}, language = {en} } @article{BauerNadler2010, author = {Bauer, Wolfgang R. and Nadler, Walter}, title = {Thermodynamics of Competitive Molecular Channel Transport: Application to Artificial Nuclear Pores}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68484}, year = {2010}, abstract = {In an analytical model channel transport is analyzed as a function of key parameters, determining efficiency and selectivity of particle transport in a competitive molecular environment. These key parameters are the concentration of particles, solvent-channel exchange dynamics, as well as particle-in-channel- and interparticle interaction. These parameters are explicitly related to translocation dynamics and channel occupation probability. Slowing down the exchange dynamics at the channel ends, or elevating the particle concentration reduces the in-channel binding strength necessary to maintain maximum transport. Optimized in-channel interaction may even shift from binding to repulsion. A simple equation gives the interrelation of access dynamics and concentration at this transition point. The model is readily transferred to competitive transport of different species, each of them having their individual in-channel affinity. Combinations of channel affinities are determined which differentially favor selectivity of certain species on the cost of others. Selectivity for a species increases if its in-channel binding enhances the species' translocation probablity when compared to that of the other species. Selectivity increases particularly for a wide binding site, long channels, and fast access dynamics. Recent experiments on competitive transport of in-channel binding and inert molecules through artificial nuclear pores serve as a paradigm for our model. It explains qualitatively and quantitatively how binding molecules are favored for transport at the cost of the transport of inert molecules.}, subject = {Thermodynamik}, language = {en} }