@article{deZeeuwAkizawaAgarwaletal.2013, author = {de Zeeuw, Dick and Akizawa, Tadao and Agarwal, Rajiv and Audhya, Paul and Bakris, George L. and Chin, Melanie and Krauth, Melissa and Lambers Heerspink, Hiddo J. and Meyer, Colin J. and McMurray, John J. and Parving, Hans-Henrik and Pergola, Pablo E. and Remuzzi, Giuseppe and Toto, Robert D. and Vaziri, Nosratola D. and Wanner, Christoph and Warnock, David G. and Wittes, Janet and Chertow, Glenn M.}, title = {Rationale and Trial Design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: The Occurrence of Renal Events (BEACON)}, series = {American Journal of Nephrology}, volume = {37}, journal = {American Journal of Nephrology}, number = {3}, issn = {0250-8095}, doi = {10.1159/000346948}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196832}, pages = {212-222}, year = {2013}, abstract = {Background: Chronic kidney disease (CKD) associated with type 2 diabetes mellitus constitutes a global epidemic complicated by considerable renal and cardiovascular morbidity and mortality, despite the provision of inhibitors of the renin-angiotensin-aldosterone system (RAAS). Bardoxolone methyl, a synthetic triterpenoid that reduces oxidative stress and inflammation through Nrf2 activation and inhibition of NF-κB was previously shown to increase estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes mellitus. To date, no antioxidant or anti-inflammatory therapy has proved successful at slowing the progression of CKD. Methods: Herein, we describe the design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON) trial, a multinational, multicenter, double-blind, randomized, placebo-controlled Phase 3 trial designed to determine whether long-term administration of bardoxolone methyl (on a background of standard therapy, including RAAS inhibitors) safely reduces renal and cardiac morbidity and mortality. Results: The primary composite endpoint is time-to-first occurrence of either end-stage renal disease or cardiovascular death. Secondary endpoints include the change in eGFR and time to occurrence of cardiovascular events. Conclusion: BEACON will be the first event-driven trial to evaluate the effect of an oral antioxidant and anti-inflammatory drug in advanced CKD.}, language = {en} } @article{LiuHuNiemannetal.2013, author = {Liu, Dan and Hu, Kai and Niemann, Markus and Herrmann, Sebastian and Cikes, Maja and St{\"o}rk, Stefan and Beer, Meinrad and Gaudron, Philipp Daniel and Morbach, Caroline and Knop, Stefan and Geissinger, Eva and Ertl, Georg and Bijnens, Bart and Weidemann, Frank}, title = {Impact of Regional Left Ventricular Function on Outcome for Patients with AL Amyloidosis}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {3}, doi = {10.1371/journal.pone.0056923}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130293}, pages = {e56923}, year = {2013}, abstract = {Objectives The aim of this study was to explore the left ventricular (LV) deformation changes and the potential impact of deformation on outcome in patients with proven light-chain (AL) amyloidosis and LV hypertrophy. Background Cardiac involvement in AL amyloidosis patients is associated with poor outcome. Detecting regional cardiac function by advanced non-invasive techniques might be favorable for predicting outcome. Methods LV longitudinal, circumferential and radial peak systolic strains (Ssys) were assessed by speckle tracking imaging (STI) in 44 biopsy-proven systemic AL amyloidosis patients with LV hypertrophy (CA) and in 30 normal controls. Patients were divided into compensated (n = 18) and decompensated (n = 26) group based on clinical assessment and followed-up for a median period of 345 days. Results Ejection fraction (EF) was preserved while longitudinal Ssys (LSsys) was significantly reduced in both compensated and decompensated groups. Survival was significantly reduced in decompensated group (35\% vs. compensated 78\%, P = 0.001). LSsys were similar in apical segments and significantly reduced in basal segments between two patient groups. LSsys at mid-segments were significantly reduced in all LV walls of decompensated group. Patients were further divided into 4 subgroups according to the presence or absence of reduced LSsys in no (normal), only basal (mild), basal and mid (intermediate) and all segments of the septum (severe). This staging revealed continuously worse prognosis in proportion to increasing number of segments with reduced LSsys (mortality: normal 14\%, mild 27\%, intermediate 67\%, and severe 64\%). Mid-septum LSsys<11\% suggested a 4.8-fold mortality risk than mid-septum LSsys≥11\%. Multivariate regression analysis showed NYHA class and mid-septum LSsys were independent predictors for survival. Conclusions Reduced deformation at mid-septum is associated with worse prognosis in systemic amyloidosis patients with LV hypertrophy.}, language = {en} } @article{PalkovitsŠebekovaKlenovicsetal.2013, author = {Palkovits, Mikl{\´o}s and Šebekov{\´a}, Katar{\´i}na and Klenovics, Kristina Simon and Kebis, Anton and Fazeli, Gholamreza and Bahner, Udo and Heidland, August}, title = {Neuronal Activation in the Central Nervous System of Rats in the Initial Stage of Chronic Kidney Disease-Modulatory Effects of Losartan and Moxonidine}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0066543}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130108}, pages = {e66543}, year = {2013}, abstract = {The effect of mild chronic renal failure (CRF) induced by 4/6-nephrectomy (4/6NX) on central neuronal activations was investigated by c-Fos immunohistochemistry staining and compared to sham-operated rats. In the 4/6 NX rats also the effect of the angiotensin receptor blocker, losartan, and the central sympatholyticum moxonidine was studied for two months. In serial brain sections Fos-immunoreactive neurons were localized and classified semiquantitatively. In 37 brain areas/nuclei several neurons with different functional properties were strongly affected in 4/6NX. It elicited a moderate to high Fos-activity in areas responsible for the monoaminergic innervation of the cerebral cortex, the limbic system, the thalamus and hypothalamus (e.g. noradrenergic neurons of the locus coeruleus, serotonergic neurons in dorsal raphe, histaminergic neurons in the tuberomamillary nucleus). Other monoaminergic cell groups (A5 noradrenaline, C1 adrenaline, medullary raphe serotonin neurons) and neurons in the hypothalamic paraventricular nucleus (innervating the sympathetic preganglionic neurons and affecting the peripheral sympathetic outflow) did not show Fos-activity. Stress- and pain-sensitive cortical/subcortical areas, neurons in the limbic system, the hypothalamus and the circumventricular organs were also affected by 4/6NX. Administration of losartan and more strongly moxonidine modulated most effects and particularly inhibited Fos-activity in locus coeruleus neurons. In conclusion, 4/6NX elicits high activity in central sympathetic, stress- and pain-related brain areas as well as in the limbic system, which can be ameliorated by losartan and particularly by moxonidine. These changes indicate a high sensitivity of CNS in initial stages of CKD which could be causative in clinical disturbances.}, language = {en} } @article{NordbeckBoenhofHilleretal.2013, author = {Nordbeck, Peter and B{\"o}nhof, Leoni and Hiller, Karl-Heinz and Voll, Sabine and Arias-Loza, Paula and Seidlmaier, Lea and Williams, Tatjana and Ye, Yu-Xiang and Gensler, Daniel and Pelzer, Theo and Ertl, Georg and Jakob, Peter M. and Bauer, Wolfgang R. and Ritter, Oliver}, title = {Impact of Thoracic Surgery on Cardiac Morphology and Function in Small Animal Models of Heart Disease: A Cardiac MRI Study in Rats}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {8}, doi = {10.1371/journal.pone.0068275}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130064}, pages = {e68275}, year = {2013}, abstract = {Background Surgical procedures in small animal models of heart disease might evoke alterations in cardiac morphology and function. The aim of this study was to reveal and quantify such potential artificial early or long term effects in vivo, which might account for a significant bias in basic cardiovascular research, and, therefore, could potentially question the meaning of respective studies. Methods Female Wistar rats (n = 6 per group) were matched for weight and assorted for sham left coronary artery ligation or control. Cardiac morphology and function was then investigated in vivo by cine magnetic resonance imaging at 7 Tesla 1 and 8 weeks after the surgical procedure. The time course of metabolic and inflammatory blood parameters was determined in addition. Results Compared to healthy controls, rats after sham surgery showed a lower body weight both 1 week (267.5±10.6 vs. 317.0±11.3 g, n<0.05) and 8 weeks (317.0±21.1 vs. 358.7±22.4 g, n<0.05) after the intervention. Left and right ventricular morphology and function were not different in absolute measures in both groups 1 week after surgery. However, there was a confined difference in several cardiac parameters normalized to the body weight (bw), such as myocardial mass (2.19±0.30/0.83±0.13 vs. 1.85±0.22/0.70±0.07 mg left/right per g bw, p<0.05), or enddiastolic ventricular volume (1.31±0.36/1.21±0.31 vs. 1.14±0.20/1.07±0.17 µl left/right per g bw, p<0.05). Vice versa, after 8 weeks, cardiac masses, volumes, and output showed a trend for lower values in sham operated rats compared to controls in absolute measures (782.2±57.2/260.2±33.2 vs. 805.9±84.8/310.4±48.5 mg, p<0.05 for left/right ventricular mass), but not normalized to body weight. Matching these findings, blood testing revealed only minor inflammatory but prolonged metabolic changes after surgery not related to cardiac disease. Conclusion Cardio-thoracic surgical procedures in experimental myocardial infarction cause distinct alterations upon the global integrity of the organism, which in the long term also induce circumscribed repercussions on cardiac morphology and function. This impact has to be considered when analyzing data from respective animal studies and transferring these findings to conditions in patients.}, language = {en} } @article{PachelMathesBayeretal.2013, author = {Pachel, Christina and Mathes, Denise and Bayer, Barbara and Dienesch, Charlotte and Wangorsch, Gaby and Heitzmann, Wolfram and Lang, Isabell and Ardehali, Hossein and Ertl, Georg and Dandekar, Thomas and Wajant, Harald and Frantz, Stefan}, title = {Exogenous Administration of a Recombinant Variant of TWEAK Impairs Healing after Myocardial Infarction by Aggravation of Inflammation}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {11}, doi = {10.1371/journal.pone.0078938}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129889}, pages = {e78938}, year = {2013}, abstract = {Background: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factorinducible 14 (Fn14) are upregulated after myocardial infarction (MI) in both humans and mice. They modulate inflammation and the extracellular matrix, and could therefore be important for healing and remodeling after MI. However, the function of TWEAK after MI remains poorly defined. Methods and results: Following ligation of the left coronary artery, mice were injected twice per week with a recombinant human serum albumin conjugated variant of TWEAK (HSA-Flag-TWEAK), mimicking the activity of soluble TWEAK. Treatment with HSA-Flag-TWEAK resulted in significantly increased mortality in comparison to the placebo group due to myocardial rupture. Infarct size, extracellular matrix remodeling, and apoptosis rates were not different after MI. However, HSA-Flag-TWEAK treatment increased infiltration of proinflammatory cells into the myocardium. Accordingly, depletion of neutrophils prevented cardiac ruptures without modulating all-cause mortality. Conclusion: Treatment of mice with HSA-Flag-TWEAK induces myocardial healing defects after experimental MI. This is mediated by an exaggerated neutrophil infiltration into the myocardium.}, language = {en} } @article{FreyErtlAngermannetal.2013, author = {Frey, A. and Ertl, G. and Angermann, C. E. and Hofmann, U. and St{\"o}rk, S. and Frantz, S.}, title = {Complement C3c as a Biomarker in Heart Failure}, series = {Mediators of Inflammation}, volume = {2013}, journal = {Mediators of Inflammation}, number = {Article ID 716902}, doi = {10.1155/2013/716902}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129668}, pages = {7}, year = {2013}, abstract = {Experimental data indicates an important role of the innate immune system in cardiac remodeling and heart failure (HF). Complement is a central effector pathway of the innate immune system. Animals lacking parts of the complement system are protected from adverse remodeling. Based on these data, we hypothesized that peripheral complement levels could be a good marker for adverse remodeling and prognosis in patients with HF. Methods and Results. Since complement activation converges on the complement factor C3, we measured serum C3c, a stable C3-conversion product, in 197 patients with stable systolic HF. Subgroups with normal and elevated C3c levels were compared. C3c levels were elevated in 17\%of the cohort. Patients with elevated C3c levels exhibited a trend to better survival, slightly higher LVEF, and lower NTpro-BNP values in comparison to patients with normal C3c values. No differences were found regarding NYHA functional class. Significantly more patients with elevated C3c had preexisting diabetes. The prevalence of CAD, arterial hypertension, and atrial fibrillation was not increased in patients with elevated C3c. Conclusion. Elevated C3c levels are associated with less adverse remodeling and improved survival in patients with stable systolic heart failure.}, language = {en} } @article{HaringLengRobinsonetal.2013, author = {Haring, Bernhard and Leng, Xiaoyan and Robinson, Jennifer and Johnson, Karen C. and Jackson, Rebecca D. and Beyth, Rebecca and Wactawski-Wende, Jean and Wyler von Ballmoos, Moritz and Goveas, Joseph S. and Kuller, Lewis H. and Wassertheil-Smoller, Sylvia}, title = {Cardiovascular Disease and Cognitive Decline in Postmenopausal Women: Results From the Women's Health Initiative Memory Study}, series = {Journal of the American Heart Association}, volume = {2}, journal = {Journal of the American Heart Association}, number = {e000369}, doi = {10.1161/JAHA.113.000369}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129487}, year = {2013}, abstract = {Background-—Data on cardiovascular diseases (CVD) and cognitive decline are conflicting. Our objective was to investigate if CVD is associated with an increased risk for cognitive decline and to examine whether hypertension, diabetes, or adiposity modify the effect of CVD on cognitive functioning. Methods and Results-—Prospective follow-up of 6455 cognitively intact, postmenopausal women aged 65 to 79 years old enrolled in the Women's Health Initiative Memory Study (WHIMS). CVD was determined by self-report. For cognitive decline, we assessed the incidence of mild cognitive impairment (MCI) or probable dementia (PD) via modified mini-mental state examination (3 MS) score, neurocognitive, and neuropsychiatric examinations. The median follow-up was 8.4 years. Women with CVD tended to be at increased risk for cognitive decline compared with those free of CVD (hazard ratio [HR], 1.29; 95\% CI: 1.00, 1.67). Women with myocardial infarction or other vascular disease were at highest risk (HR, 2.10; 95\% CI: 1.40, 3.15 or HR, 1.97; 95\% CI: 1.34, 2.87). Angina pectoris was moderately associated with cognitive decline (HR 1.45; 95\% CI: 1.05, 2.01) whereas no significant relationships were found for atrial fibrillation or heart failure. Hypertension and diabetes increased the risk for cognitive decline in women without CVD. Diabetes tended to elevate the risk for MCI/PD in women with CVD. No significant trend was seen for adiposity. Conclusions-—CVD is associated with cognitive decline in elderly postmenopausal women. Hypertension and diabetes, but not adiposity, are associated with a higher risk for cognitive decline. More research is warranted on the potential of CVD prevention for preserving cognitive functioning.}, language = {en} } @article{KorbTngMilenkovicetal.2013, author = {Korb, Doreen and Tng, Priscilla Y. and Milenkovic, Vladimir M. and Reichhart, Nadine and Strauss, Olaf and Ritter, Oliver and Fischer, Tobias and Benz, Peter M. and Schuh, Kai}, title = {Identification of PDZ domain containing proteins interacting with \(Ca_v1.2\) and PMCA4b}, series = {ISRN Cell Biology}, journal = {ISRN Cell Biology}, number = {Article ID 265182}, doi = {10.1155/2013/265182}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130585}, pages = {16}, year = {2013}, abstract = {PDZ (PSD-95/Disc large/Zonula occludens-1) protein interaction domains bind to cytoplasmic protein C-termini of transmembrane proteins. In order to identify new interaction partners of the voltage-gated L-type \(Ca^{2+}\) channel Cav1.2 and the plasma membrane \(Ca^{2+}\) ATPase 4b (PMCA4b), we used PDZ domain arrays probing for 124 PDZ domains. We confirmed this byGST pulldowns and immunoprecipitations. In PDZ arrays, strongest interactionswith \(Ca_v1.2\) and PMCA4b were found for the PDZ domains of SAP-102, MAST-205, MAGI-1, MAGI-2, MAGI-3, and ZO-1. We observed binding of the \(Ca_v1.2\) C-terminus to PDZ domains of NHERF1/2, Mint-2, and CASK. PMCA4b was observed to interact with Mint-2 and its known interactions with Chapsyn-110 and CASK were confirmed. Furthermore, we validated interaction of \(Ca_v1.2\) and PMCA4b with NHERF1/2, CASK,MAST-205 and MAGI-3 viaimmunoprecipitation. We also verified the interaction of \(Ca_v1.2\) and nNOS and hypothesized that nNOS overexpression might reduce \(Ca^{2+}\) influx through \(Ca_v1.2\). To address this, we measured \(Ca^{2+}\) currents in HEK 293 cells co-expressing \(Ca_v1.2\) and nNOS and observed reduced voltage-dependent \(Ca_v1.2\) activation. Taken together, we conclude that \(Ca_v1.2\) and PMCA4b bind promiscuously to various PDZ domains, and that our data provides the basis for further investigation of the physiological consequences of these interactions.}, language = {en} } @article{WeidemannNiemannStorketal.2013, author = {Weidemann, F. and Niemann, M. and Stork, S. and Breunig, F. and Beer, M. and Sommer, C. and Herrmann, S. and Ertl, G. and Wanner, C.}, title = {Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications}, series = {Journal of Internal Medicine}, volume = {247}, journal = {Journal of Internal Medicine}, number = {4}, doi = {10.1111/joim.12077}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132075}, pages = {331-4}, year = {2013}, abstract = {The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards 'hard' clinical end-points in comparison with the natural course of the disease. METHODS: A total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain. RESULTS: During a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7\%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min(-1) per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry. CONCLUSION: Despite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease.}, language = {en} } @article{DrechslerRitzTomaschitzetal.2013, author = {Drechsler, Christiane and Ritz, Eberhard and Tomaschitz, Andreas and Pilz, Stefan and Sch{\"o}nfeld, Stephan and Blouin, Katja and Bidlingmaier, Martin and Hammer, Fabian and Krane, Vera and M{\"a}rz, Winfried and Allolio, Bruno and Fassnacht, Martin and Wanner, Christoph}, title = {Aldosterone and cortisol affect the risk of sudden cardiac death in haemodialysis patients}, series = {European Heart Journal}, volume = {34}, journal = {European Heart Journal}, doi = {10.1093/eurheartj/ehs361}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132562}, pages = {578-585}, year = {2013}, abstract = {Background: Sudden cardiac death is common and accounts largely for the excess mortality of patients on maintenance dialysis. It is unknown whether aldosterone and cortisol increase the incidence of sudden cardiac death in dialysis patients. Methods and results: We analysed data from 1255 diabetic haemodialysis patients participating in the German Diabetes and Dialysis Study (4D Study). Categories of aldosterone and cortisol were determined at baseline and patients were followed for a median of 4 years. By Cox regression analyses, hazard ratios (HRs) were determined for the effect of aldosterone, cortisol, and their combination on sudden death and other adjudicated cardiovascular outcomes. The mean age of the patients was 66 ± 8 years (54\% male). Median aldosterone was <15 pg/mL (detection limit) and cortisol 16.8 µg/dL. Patients with aldosterone levels >200 pg/mL had a significantly higher risk of sudden death (HR: 1.69; 95\% CI: 1.06-2.69) compared with those with an aldosterone <15 pg/mL. The combined presence of high aldosterone (>200 pg/mL) and high cortisol (>21.1 µg/dL) levels increased the risk of sudden death in striking contrast to patients with low aldosterone (<15 pg/mL) and low cortisol (<13.2 µg/dL) levels (HR: 2.86, 95\% CI: 1.32-6.21). Furthermore, all-cause mortality was significantly increased in the patients with high levels of both hormones (HR: 1.62, 95\% CI: 1.01-2.62). Conclusions: The joint presence of high aldosterone and high cortisol levels is strongly associated with sudden cardiac death as well as all-cause mortality in haemodialysed type 2 diabetic patients. Whether a blockade of the mineralocorticoid receptor decreases the risk of sudden death in these patients must be examined in future trials.}, language = {en} } @article{DrechslerSchmiedekeNiemannetal.2013, author = {Drechsler, Christiane and Schmiedeke, Benjamin and Niemann, Markus and Schmiedeke, Daniel and Kr{\"a}mer, Johannes and Turkin, Irina and Blouin, Katja and Emmert, Andrea and Pilz, Stefan and Obermayer-Pietsch, Barbara and Wiedemann, Frank and Breunig, Frank and Wanner, Christoph}, title = {Potential role of vitamin D deficiency on Fabry cardiomyopathy}, series = {Journal of Inherited Metabolic Disease}, volume = {37}, journal = {Journal of Inherited Metabolic Disease}, number = {2}, doi = {10.1007/s10545-013-9653-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132102}, pages = {289-295}, year = {2013}, abstract = {Patients with Fabry disease frequently develop left ventricular (LV) hypertrophy and renal fibrosis. Due to heat intolerance and an inability to sweat, patients tend to avoid exposure to sunlight. We hypothesized that subsequent vitamin D deficiency may contribute to Fabry cardiomyopathy. This study investigated the vitamin D status and its association with LV mass and adverse clinical symptoms in patients with Fabry disease. 25-hydroxyvitamin D (25[OH]D) was measured in 111 patients who were genetically proven to have Fabry disease. LV mass and cardiomyopathy were assessed by magnetic resonance imaging and echocardiography. In cross-sectional analyses, associations with adverse clinical outcomes were determined by linear and binary logistic regression analyses, respectively, and were adjusted for age, sex, BMI and season. Patients had a mean age of 40 ± 13 years (42 \% males), and a mean 25(OH)D of 23.5 ± 11.4 ng/ml. Those with overt vitamin D deficiency (25[OH]D ≤ 15 ng/ml) had an adjusted six fold higher risk of cardiomyopathy, compared to those with sufficient 25(OH)D levels >30 ng/ml (p = 0.04). The mean LV mass was distinctively different with 170 ± 75 g in deficient, 154 ± 60 g in moderately deficient and 128 ± 58 g in vitamin D sufficient patients (p = 0.01). With increasing severity of vitamin D deficiency, the median levels of proteinuria increased, as well as the prevalences of depression, edema, cornea verticillata and the need for medical pain therapy. In conclusion, vitamin D deficiency was strongly associated with cardiomyopathy and adverse clinical symptoms in patients with Fabry disease. Whether vitamin D supplementation improves complications of Fabry disease, requires a randomized controlled trial.}, language = {en} } @article{FrantzKlaiberBabaetal.2013, author = {Frantz, Stefan and Klaiber, Michael and Baba, Hideo A. and Oberwinkler, Heinz and V{\"o}lker, Katharina and Gaßner, Birgit and Bayer, Barbara and Abeßer, Marco and Schuh, Kai and Feil, Robert and Hofmann, Franz and Kuhn, Michaela}, title = {Stress-dependent dilated cardiomyopathy in mice with cardiomyocyte-restricted inactivation of cyclic GMP-dependent protein kinase I}, series = {European Heart Journal}, volume = {34}, journal = {European Heart Journal}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134693}, pages = {1233-1244}, year = {2013}, abstract = {Aims: Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. Elevation of myocyte cyclic GMP levels by local actions of endogenous atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) or by pharmacological inhibition of phosphodiesterase-5 was shown to counter-regulate pathological hypertrophy. It was suggested that cGMP-dependent protein kinase I (cGKI) mediates this protective effect, although the role in vivo is under debate. Here, we investigated whether cGKI modulates myocyte growth and/or function in the intact organism. Methods and results: To circumvent the systemic phenotype associated with germline ablation of cGKI, we inactivated the murine cGKI gene selectively in cardiomyocytes by Cre/loxP-mediated recombination. Mice with cardiomyocyte-restricted cGKI deletion exhibited unaltered cardiac morphology and function under resting conditions. Also, cardiac hypertrophic and contractile responses to β-adrenoreceptor stimulation by isoprenaline (at 40 mg/kg/day during 1 week) were unaltered. However, angiotensin II (Ang II, at 1000 ng/kg/min for 2 weeks) or transverse aortic constriction (for 3 weeks) provoked dilated cardiomyopathy with marked deterioration of cardiac function. This was accompanied by diminished expression of the \([Ca^{2+}]_i\)-regulating proteins SERCA2a and phospholamban (PLB) and a reduction in PLB phosphorylation at Ser16, the specific target site for cGKI, resulting in altered myocyte \(Ca^{2+}_i\) homeostasis. In isolated adult myocytes, CNP, but not ANP, stimulated PLB phosphorylation, \(Ca^{2+}_i\)-handling, and contractility via cGKI. Conclusion: These results indicate that the loss of cGKI in cardiac myocytes compromises the hypertrophic program to pathological stimulation, rendering the heart more susceptible to dysfunction. In particular, cGKI mediates stimulatory effects of CNP on myocyte \(Ca^{2+}_i\) handling and contractility.}, language = {en} } @article{BloemerPachelHofmannetal.2013, author = {Bl{\"o}mer, Nadja and Pachel, Christina and Hofmann, Urlich and Nordbeck, Peter and Bauer, Wolfgang and Mathes, Denise and Frey, Anna and Bayer, Barbara and Vogel, Benjamin and Ertl, Georg}, title = {5-Lipoxygenase facilitates healing after myocardial infarction}, series = {Basic Research in Cardiology}, volume = {108}, journal = {Basic Research in Cardiology}, number = {4}, doi = {10.1007/s00395-013-0367-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132602}, year = {2013}, abstract = {Early healing after myocardial infarction (MI) is characterized by a strong inflammatory reaction. Most leukotrienes are pro-inflammatory and are therefore potential mediators of healing and remodeling after myocardial ischemia. The enzyme 5-lipoxygenase (5-LOX) has a key role in the transformation of arachidonic acid in leukotrienes. Thus, we tested the effect of 5-LOX on healing after MI. After chronic coronary artery ligation, early mortality was significantly increased in 5-LOX\(^{-/-}\) when compared to matching wildtype (WT) mice due to left ventricular rupture. This effect could be reproduced in mice treated with the 5-LOX inhibitor Zileuton. A perfusion mismatch due to the vasoactive potential of leukotrienes is not responsible for left ventricular rupture since local blood flow assessed by magnetic resonance perfusion measurements was not different. However, after MI, there was an accentuation of the inflammatory reaction with an increase of pro-inflammatory macrophages. Yet, mortality was not changed in chimeric mice (WT vs. 5-LOX\(^{-/-}\) bone marrow in 5-LOX\(^{-/-}\) animals), indicating that an altered function of 5-LOX\(^{-/-}\) inflammatory cells is not responsible for the phenotype. Collagen production and accumulation of fibroblasts were significantly reduced in 5-LOX\(^{-/-}\) mice in vivo after MI. This might be due to an impaired migration of 5-LOX\(^{-/-}\) fibroblasts, as shown in vitro to serum. In conclusion, a lack or inhibition of 5-LOX increases mortality after MI because of healing defects. This is not mediated by a change in local blood flow, but through an altered inflammation and/or fibroblast function.}, language = {en} } @article{HofmannFrantz2013, author = {Hofmann, Ulrich and Frantz, Stefan}, title = {How can we cure a heart "in flame"? A translational view on inflammation in heart failure}, series = {Basic Research in Cardiology}, volume = {108}, journal = {Basic Research in Cardiology}, number = {356}, doi = {10.1007/s00395-013-0356-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134497}, year = {2013}, abstract = {The prevalence of chronic heart failure is still increasing making it a major health issue in the 21st century. Tremendous evidence has emerged over the past decades that heart failure is associated with a wide array of mechanisms subsumed under the term "inflammation". Based on the great success of immuno-suppressive treatments in auto-immunity and transplantation, clinical trials were launched targeting inflammatory mediators in patients with chronic heart failure. However, they widely lacked positive outcomes. The failure of the initial study program directed against tumor necrosis factor-a led to the search for alternative therapeutic targets involving a broader spectrum of mechanisms besides cytokines. We here provide an overview of the current knowledge on immune activation in chronic heart failure of different etiologies, summarize clinical studies in the field, address unresolved key questions, and highlight some promising novel therapeutic targets for clinical trials from a translational basic science and clinical perspective.}, language = {en} } @article{QuinklerBeuschleinHahneretal.2013, author = {Quinkler, Marcus and Beuschlein, Felix and Hahner, Stefanie and Meyer, Gesine and Sch{\"o}fl, Christof and Stalla, G{\"u}nter K.}, title = {Adrenal Cortical Insufficiency-a Life Threatening Illness With Multiple Etiologies}, series = {Deutsches {\"A}rzteblatt International}, volume = {110}, journal = {Deutsches {\"A}rzteblatt International}, doi = {10.3238/arztebl.2013.0882}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131662}, pages = {51-52}, year = {2013}, abstract = {Background: The clinical signs of adrenal cortical insufficiency (incidence, ca. 25 per million per year; prevalence, ca. 400 per million) are nonspecific, and misdiagnoses are therefore common. Glucocorticoid substitution therapy has been in use for 50 years but is not a wholly adequate treatment. Our understanding of this disease remains incomplete in many ways. Methods: We selectively searched the Medline database for publications on adrenal cortical insufficiency, with particular attention to studies from the year 2000 onward (search terms: "adrenal insufficiency" or "Addison's disease" or "hypopituitarism"). Results: Hydrocortisone substitution therapy is often given in doses of 10-25 mg/day, timed according to the circadian rhythm. Gastrointestinal and other, febrile infections account for 30-50\% of life-threatening adrenocortical crises. Such crises affect 8 of 100 persons with adrenal cortical insufficiency per year and must be treated by the immediate administration of glucocorticoids and fluids. When persons with adrenal cortical insufficiency are acutely ill or are otherwise under unusual stress, they may need additional amounts of hydrocortisone, often in the range of 5-10 mg but occasionally as high as 200 mg. The sustained administration of excessive amounts of steroid can shorten patients' lives by several years. Inappropriate substitution therapy can cause other major medical conditions, such as metabolic syndrome and osteoporosis. Conclusion: Important measures for the prevention of adrenocortical crises include improved care by treating physicians, education of patients and their families, the provision of emergency identifying documents, and the prescription of glucocorticoid emergency kits.}, language = {en} } @article{DrechslerKolleritzMeinitzeretal.2013, author = {Drechsler, Christiane and Kolleritz, Barbara and Meinitzer, Andreas and M{\"a}rz, Winfried and Ritz, Eberhard and K{\"o}nig, Paul and Neyer, Ulrich and Pilz, Stefan and Wanner, Christoph and Kronenberg, Florian}, title = {Homoarginine and Progression of Chronic Kidney Disease: Results from the Mild to Moderate Kidney Disease Study}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {5}, organization = {MMKD Study Group}, doi = {10.1371/journal.pone.0063560}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130979}, pages = {e63560}, year = {2013}, abstract = {Background: Homoarginine is an amino acid derivative mainly synthesized in the kidney. It is suggested to increase nitric oxide availability, enhance endothelial function and to protect against cardiovascular diseases. We aimed to investigate the relation between homoarginine, kidney function and progression of chronic kidney disease (CKD). Methods: We measured plasma homoarginine concentrations in baseline samples of the Mild to Moderate Kidney Disease (MMKD) Study, a prospective cohort study of 227 patients with CKD in Europe. Homoarginine concentrations were available in 182 of the baseline samples and in 139 of the prospectively-followed patients. We correlated homoarginine concentrations to parameters of kidney function. The association between homoarginine and progression of CKD was assessed during a follow-up of up to seven years (median 4.45 years, interquartile range 2.54-5.19) using Cox regression analysis. Progression of CKD was defined as doubling of baseline serum creatinine and/or end-stage renal disease. Results: Study participants were at baseline on average 47 \(\pm\)13 years old and 65\% were male. Mean \(\pm\) standard deviation of homoarginine concentrations were \(2.5 \pm 1.1 \mu mol/L\) and concentrations were incrementally lower at lower levels of GFR with mean concentrations of \(2.90 \pm 1.02 \mu mol/L\) (GFR. 90 ml/min), \(2.64 \pm 1.06 \mu mol/L\) (GFR 60-90 ml/min), \(2.52 \pm 1.24 \mu mol/L\) (GFR 30-60 ml/min) and \(2.05 \pm 0.78 \mu mol/L\) (GFR, 30 ml/min), respectively (p = 0.002). The age-and sex-adjusted risk to reach the renal endpoint was significantly higher by 62\% with each decrease by one standard deviation (\(1.1 \mu mol/L\)) of homoarginine (HR 1.62, 95\% CI 1.16-2.27, p = 0.005). This association was independent of proteinuria (HR 1.56, 95\% CI 1.11-2.20, p = 0.01), and was slightly attenuated when adjusting for GFR (HR 1.40 (95\% CI 0.98-1.98, p = 0.06). Conclusions: Homoarginine concentrations are directly correlated with kidney function and are significantly associated with the progression of CKD. Low homoarginine concentrations might be an early indicator of kidney failure and a potential target for the prevention of disease progression which needs further investigations.}, language = {en} } @article{SchneiderSchneiderScharnagletal.2013, author = {Schneider, Andreas and Schneider, Markus P. and Scharnagl, Hubert and Jardine, Alan G. and Wanner, Christoph and Drechsler, Christiane}, title = {Predicting erythropoietin resistance in hemodialysis patients with type 2 diabetes}, series = {BMC Nephrology}, volume = {14}, journal = {BMC Nephrology}, number = {67}, doi = {10.1186/1471-2369-14-67}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128695}, year = {2013}, abstract = {Background: Resistance to ESAs (erythropoietin stimulating agents) is highly prevalent in hemodialysis patients with diabetes and associated with an increased mortality. The aim of this study was to identify predictors for ESA resistance and to develop a prediction model for the risk stratification in these patients. Methods: A post-hoc analysis was conducted of the 4D study, including 1015 patients with type 2 diabetes undergoing hemodialysis. Determinants of ESA resistance were identified by univariate logistic regression analyses. Subsequently, multivariate models were performed with stepwise inclusion of significant predictors from clinical parameters, routine laboratory and specific biomarkers. Results: In the model restricted to clinical parameters, male sex, shorter dialysis vintage, lower BMI, history of CHF, use of ACE-inhibitors and a higher heart rate were identified as independent predictors of ESA resistance. In regard to routine laboratory markers, lower albumin, lower iron saturation, higher creatinine and higher potassium levels were independently associated with ESA resistance. With respect to specific biomarkers, higher ADMA and CRP levels as well as lower Osteocalcin levels were predictors of ESA resistance. Conclusions: Easily obtainable clinical parameters and routine laboratory parameters can predict ESA resistance in diabetic hemodialysis patients with good discrimination. Specific biomarkers did not meaningfully further improve the risk prediction of ESA resistance. Routinely assessed data can be used in clinical practice to stratify patients according to the risk of ESA resistance, which may help to assign appropriate treatment strategies.}, language = {en} } @article{WeidemannSanchezNinoPoliteietal.2013, author = {Weidemann, Frank and Sanchez-Nino, Maria D. and Politei, Juan and Oliveira, Jo{\~a}o-Paulo and Wanner, Christoph and Warnock, David G. and Oritz, Alberto}, title = {Fibrosis: a key feature of Fabry disease with potential therapeutic implications}, series = {Orphanet Journal of Rare Diseases}, volume = {8}, journal = {Orphanet Journal of Rare Diseases}, number = {116}, issn = {1750-1172}, doi = {10.1186/1750-1172-8-116}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124773}, year = {2013}, abstract = {Fabry disease is a rare X-linked hereditary disease caused by mutations in the AGAL gene encoding the lysosomal enzyme alpha-galactosidase A. Enzyme replacement therapy (ERT) is the current cornerstone of Fabry disease management. Involvement of kidney, heart and the central nervous system shortens life span, and fibrosis of these organs is a hallmark of the disease. Fibrosis was initially thought to result from tissue ischemia secondary to endothelial accumulation of glycosphingolipids in the microvasculature. However, despite ready clearance of endothelial deposits, ERT is less effective in patients who have already developed fibrosis. Several potential explanations of this clinical observation may impact on the future management of Fabry disease. Alternative molecular pathways linking glycosphingolipids and fibrosis may be operative; tissue injury may recruit secondary molecular mediators of fibrosis that are unresponsive to ERT, or fibrosis may represent irreversible tissue injury that limits the therapeutic response to ERT. We provide an overview of Fabry disease, with a focus on the assessment of fibrosis, the clinical consequences of fibrosis, and recent advances in understanding the cellular and molecular mechanisms of fibrosis that may suggest novel therapeutic approaches to Fabry disease.}, language = {en} } @article{BrandenburgKramannKoosetal.2013, author = {Brandenburg, Vincent M. and Kramann, Rafael and Koos, Ralf and Krueger, Thilo and Schurgers, Leon and M{\"u}hlenbruch, Georg and H{\"u}bner, Sinah and Gladziwa, Ulrich and Drechler, Christiane and Ketteler, Markus}, title = {Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: a cross-sectional study}, series = {BMC Nephrology}, volume = {14}, journal = {BMC Nephrology}, number = {219}, issn = {1471-2369}, doi = {10.1186/1471-2369-14-219}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122070}, year = {2013}, abstract = {Background: Sclerostin is a Wnt pathway antagonist regulating osteoblast activity and bone turnover. Here, we assessed the potential association of sclerostin with the development of coronary artery (CAC) and aortic valve calcifications (AVC) in haemodialysis (HD) patients. Methods: We conducted a cross-sectional multi-slice computed tomography (MS-CT) scanning study in 67 chronic HD patients (59.4 +/- 14.8 yrs) for measurement of CAC and AVC. We tested established biomarkers as well as serum sclerostin (ELISA) regarding their association to the presence of calcification. Fifty-four adults without relevant renal disease served as controls for serum sclerostin levels. Additionally, sclerostin expression in explanted aortic valves from 15 dialysis patients was analysed ex vivo by immunohistochemistry and mRNA quantification (Qt-RT-PCR). Results: CAC (Agatston score > 100) and any AVC were present in 65\% and in 40\% of the MS-CT patient group, respectively. Serum sclerostin levels (1.53 +/- 0.81 vs 0.76 +/- 0.31 ng/mL, p < 0.001) were significantly elevated in HD compared to controls and more so in HD patients with AVC versus those without AVC (1.78 +/- 0.84 vs 1.35 +/- 0.73 ng/mL, p = 0.02). Multivariable regression analysis for AVC revealed significant associations with higher serum sclerostin. Ex vivo analysis of uraemic calcified aortic valves (n = 10) revealed a strong sclerostin expression very close to calcified regions (no sclerostin staining in non-calcified valves). Correspondingly, we observed a highly significant upregulation of sclerostin mRNA in calcified valves compared to non-calcified control valves. Conclusion: We found a strong association of sclerostin with calcifying aortic heart valve disease in haemodialysis patients. Sclerostin is locally produced in aortic valve tissue adjacent to areas of calcification.}, language = {en} } @article{DoerhoeferLammertKraneetal.2013, author = {D{\"o}rh{\"o}fer, Lena and Lammert, Alexander and Krane, Vera and Gorski, Mathias and Banas, Bernhard and Wanner, Christoph and Kr{\"a}mer, Bernhard K. and Heid, Iris M. and B{\"o}ger, Carsten A.}, title = {Study design of DIACORE (DIAbetes COhoRtE) - a cohort study of patients with diabetes mellitus type 2}, series = {BMC Medical Genetics}, volume = {14}, journal = {BMC Medical Genetics}, number = {25}, issn = {1471-2350}, doi = {10.1186/1471-2350-14-25}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122040}, year = {2013}, abstract = {Background: Diabetes mellitus type 2 (DM2) is highly associated with increased risk for chronic kidney disease (CKD), end stage renal disease (ESRD) and cardiovascular morbidity. Epidemiological and genetic studies generate hypotheses for innovative strategies in DM2 management by unravelling novel mechanisms of diabetes complications, which is essential for future intervention trials. We have thus initiated the DIAbetes COhoRtE study (DIACORE). Methods: DIACORE is a prospective cohort study aiming to recruit 6000 patients of self-reported Caucasian ethnicity with prevalent DM2 for at least 10 years of follow-up. Study visits are performed in University-based recruiting clinics in Germany using standard operating procedures. All prevalent DM2 patients in outpatient clinics surrounding the recruiting centers are invited to participate. At baseline and at each 2-year follow-up examination, patients are subjected to a core phenotyping protocol. This includes a standardized online questionnaire and physical examination to determine incident micro-and macrovascular DM2 complications, malignancy and hospitalization, with a primary focus on renal events. Confirmatory outcome information is requested from patient records. Blood samples are obtained for a centrally analyzed standard laboratory panel and for biobanking of aliquots of serum, plasma, urine, mRNA and DNA for future scientific use. A subset of the cohort is subjected to extended phenotyping, e. g. sleep apnea screening, skin autofluorescence measurement, non-mydriatic retinal photography and non-invasive determination of arterial stiffness. Discussion: DIACORE will enable the prospective evaluation of factors involved in DM2 complication pathogenesis using high-throughput technologies in biosamples and genetic epidemiological studies.}, language = {en} } @article{EiseleBlozikStoerketal.2013, author = {Eisele, Marion and Blozik, Eva and St{\"o}rk, Stefan and Tr{\"a}der, Jens-Martin and Herrmann-Lingen, Christoph and Scherer, Martin}, title = {Recognition of depression and anxiety and their association with quality of life, hospitalization and mortality in primary care patients with heart failure - study protocol of a longitudinal observation study}, series = {BMC Family Practice}, volume = {14}, journal = {BMC Family Practice}, number = {180}, issn = {1471-2296}, doi = {10.1186/1471-2296-14-180}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121881}, year = {2013}, abstract = {Background: International disease management guidelines recommend the regular assessment of depression and anxiety in heart failure patients. Currently there is little data on the effect of screening for depression and anxiety on the quality of life and the prognosis of heart failure (HF). We will investigate the association between the recognition of current depression/anxiety by the general practitioner (GP) and the quality of life and the patients' prognosis. Methods/Design: In this multicenter, prospective, observational study 3,950 patients with HF are recruited by general practices in Germany. The patients fill out questionnaires at baseline and 12-month follow-up. At baseline the GPs are interviewed regarding the somatic and psychological comorbidities of their patients. During the follow-up assessment, data on hospitalization and mortality are provided by the general practice. Based on baseline data, the patients are allocated into three observation groups: HF patients with depression and/or anxiety recognized by their GP (P+/+), those with depression and/or anxiety not recognized (P+/-) and patients without depression and/or anxiety (P-/-). We will perform multivariate regression models to investigate the influence of the recognition of depression and/or anxiety on quality of life at 12 month follow-up, as well as its influences on the prognosis (hospital admission, mortality). Discussion: We will display the frequency of GP-acknowledged depression and anxiety and the frequency of installed therapeutic strategies. We will also describe the frequency of depression and anxiety missed by the GP and the resulting treatment gap. Effects of correctly acknowledged and missed depression/anxiety on outcome, also in comparison to the outcome of subjects without depression/anxiety will be addressed. In case results suggest a treatment gap of depression/anxiety in patients with HF, the results of this study will provide methodological advice for the efficient planning of further interventional research.}, language = {en} } @phdthesis{Steigenberger2013, author = {Steigenberger, Jana Su}, title = {Kosten der Nierentransplantation in Abh{\"a}ngigkeit von der Transplantatfunktion}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116499}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Die Nierentransplantation ist neben den verschiedenen Formen der Dialyse die wichtigste Therapieform f{\"u}r Patienten mit terminaler Niereninsuffizienz. In dieser retrospektiven, monozentrischen Analyse wurden 204 Patienten erfasst, die von 2000 bis 2007 eine Nierentransplantation im Universit{\"a}tsklinikum W{\"u}rzburg erhalten hatten. Die Patienten wurden an Hand ihrer Nierenfunktion in vier Gruppen eingeteilt und miteinander verglichen. Ziel dieser Studie war es, Einflussfaktoren auf die Nierenfunktion, Komplikationen und Kosten im ersten Jahr nach Nierentransplantation zu untersuchen. Wir konnten zeigen, dass eine l{\"a}ngere Wartezeit auf ein Spenderorgan und ein hoher pr{\"a}operativer BMI mit einer schlechteren Nierenfunktion nach Transplantation assoziiert waren. Außerdem fiel auf, dass in den Gruppen mit besserer Nierenfunktion nach Transplantation h{\"a}ufiger Lebendspenden durchgef{\"u}hrt worden waren. Zu den h{\"a}ufigsten Komplikationen im ersten Jahr nach Nierentransplantation geh{\"o}rten An{\"a}mien, akute Abstoßungsreaktionen, die verz{\"o}gerte Funktionsaufnahme des Organs, Infektionen, arterielle Hypertonie und Verschlechterungen der Transplantatfunktion. Eine h{\"o}here Komplikationsrate war mit einer schlechteren Nierenfunktion und h{\"o}heren Kosten assoziiert. Der Kostenmehraufwand ergab sich aus der Zunahme an ambulanten Interventionen sowie verl{\"a}ngerten bzw. zus{\"a}tzlichen station{\"a}ren Aufenthalten. In unserer Studie hatte die Gruppe mit der schlechtesten Nierenfunktion die meisten Komplikationen und verursachte so die h{\"o}chsten Kosten. Wir errechneten einen Gesamtkostenbetrag von 43.000€ im ersten Jahr nach Nierentransplantation pro Patient. 48 \% der Gesamtkosten entfielen dabei auf die DRG-Pauschale der Transplantation selbst, 28\% auf die immunsuppressive Therapie sowie 10 \% auf die Therapie und Prophylaxe von Infektionen. Somit lagen unsere Kosten f{\"u}r eine Nierentransplantation im ersten Jahr verglichen mit den Kosten f{\"u}r die H{\"a}modialyse in anderen, aktuellen Studien gleich oder h{\"o}her. Im Vergleich zu den Kosten der Peritonealdialyse anderer Studien waren sie durchgehend h{\"o}her. Die Kosten f{\"u}r einen transplantierten Patienten reduzierten sich laut Studien jedoch deutlich ab dem zweiten Jahr auf durchschnittlich 12.000€. Die Kosten einer H{\"a}modialyse beliefen sich je nach Studie auf 28.000-43.000 € pro Jahr. Eine Peritonealdialyse kostete ca. 25.000€. Damit ist die Transplantation mittel- und langfristig die g{\"u}nstigste Therapieform. Aus finanzieller Sicht sollten mehr dialysepflichtige Patienten mittels Peritonealdialyse behandelt und die Transplantationszahlen m{\"o}glichst gesteigert werden. Da die Anzahl an Nierentransplantationen von Risikopatienten weiter steigen wird, ist mit einer Zunahme von behandlungsbed{\"u}rftigen Komplikationen und nachfolgend mit einer Kostensteigerung zu rechnen. Zuk{\"u}nftig sollte versucht werden, Wartezeiten zu reduzieren, die Anzahl der Lebendspenden zu steigern und m{\"o}glichst Normalgewicht vor Transplantation zu erreichen. Um dem Kostenanstieg entgegenzuwirken, sollten Kosteneinsparungen durch Optimierung der immunsuppressiven Schemata und verst{\"a}rkten Einsatz von Generika realisiert werden. Auch eine bessere Infektionsprophylaxe sowie ein fr{\"u}hzeitiges Erkennen und Behandeln von manifesten Infektionen k{\"o}nnten die Kosten weiter reduzieren und die Transplantation {\"o}konomisch noch attraktiver werden lassen.}, subject = {Nierentransplantation}, language = {de} } @phdthesis{Wick2013, author = {Wick, Matthias Christian}, title = {Einfluss des Multidrug Resistance Protein-1 auf die vaskul{\"a}re Funktion im Modell des Streptozotocin-induzierten Diabetes der Maus}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97473}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Vaskul{\"a}re Komplikationen wie Atherosklerose sind bei Diabetikern weit verbreitet. Eine erh{\"o}hte Produktion reaktiver Sauerstoffspezies tr{\"a}gt zu einer Dysfunktion des Endothels bei Diabetes und hohen Glukosespiegeln bei. Glutathion (GSH) ist das h{\"a}ufigste zellul{\"a}re Thiol und stellt ein bedeutendens Antioxidans des menschlichen Organismus dar. Das Multidrug Resistance Protein 1 (MRP 1) ist im Endothel der Haupttransporter von oxidiertem GSH. Blockiert man MRP 1, so wird unter oxidativem Stress der intrazellul{\"a}re GSH-Spiegel erhalten. In dieser Arbeit wird der Einfluss von MRP 1 auf die endotheliale Funktion und Produktion reaktiver Sauerstoffspezies bei Diabetes und erh{\"o}hten Glukosespiegeln anhand von MRP 1-/- -M{\"a}usen und Wildtyp-FVB-Tieren untersucht. Acht Wochen nach Injektion von STZ wurde die endothelabh{\"a}ngige Vasorelaxation an den isolierten thorakalen Aorten bestimmt. Diabetische Wildtyp-Tiere wiesen eine signifikant verminderte endothelabh{\"a}ngige Vasorelaxation auf. In MRP 1-/- -Tieren hingegen kam es zu keiner Beeintr{\"a}chtigung der Endothelfunktion. Die endothelunabh{\"a}ngige Vasorelaxation war nicht signifikant unterschiedlich. STZ-induzierter Diabetes f{\"u}hrte zu einer signifikant erh{\"o}hten Produktion von Superoxidanionen sowie Wasserstoffperoxid in Wildtyp-Tieren. Diabetische MRP 1-/- -M{\"a}use hingegen zeigten keinen Anstieg der Produktion reaktiver Sauerstoffspezies. Erh{\"o}hte Glukosekonzentrationen f{\"u}hrten in vitro in humanen aortalen Endothelzellen ebenso zur erh{\"o}hten Superoxidanion-Produktion. In Zellen, in denen MRP 1 mittels siRNA herunterreguliert war, zeigte sich keine Erh{\"o}hung von Superoxidanionen. In Wildtyp-M{\"a}usen f{\"u}hrte Diabetes zu einer Verminderung des vaskul{\"a}ren GSH-Spiegels, wohingegen bei MRP 1-/- -Tieren keine Ver{\"a}nderung auftrat. Diese Daten weisen auf die wichtige Rolle von MRP 1 bei der unter hohen Glukosekonzentrationen auftretenden endothelialen Dysfunktion hin. MRP 1 stellt somit einen neuen Ansatzpunkt in der Behandlung der durch Diabetes ausgel{\"o}sten vaskul{\"a}ren Dysfunktion dar.}, subject = {Endothelial dysfunction}, language = {de} } @article{HaringLengRobinsonetal.2013, author = {Haring, Bernhard and Leng, Xiaoyan and Robinson, Jennifer and Johnson, Karen C. and Jackson, Rebecca D. and Beyth, Rebecca and Wactawski-Wende, Jean and Wyler von Ballmoos, Moritz and Goveas, Joseph S. and Kuller, Lewis H. and Wassertheil-Smoller, Sylvia}, title = {Cardiovascular Disease and Cognitive Decline in Postmenopausal Women: Results From the Women's Health Initiative Memory Study}, doi = {10.1161/JAHA.113.000369)}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111376}, year = {2013}, abstract = {Background Data on cardiovascular diseases (CVD) and cognitive decline are conflicting. Our objective was to investigate if CVD is associated with an increased risk for cognitive decline and to examine whether hypertension, diabetes, or adiposity modify the effect of CVD on cognitive functioning. Methods and Results: Prospective follow-up of 6455 cognitively intact, postmenopausal women aged 65 to 79 years old enrolled in the Women's Health Initiative Memory Study (WHIMS). CVD was determined by self-report. For cognitive decline, we assessed the incidence of mild cognitive impairment (MCI) or probable dementia (PD) via modified mini-mental state examination (3 MS) score, neurocognitive, and neuropsychiatric examinations. The median follow-up was 8.4 years. Women with CVD tended to be at increased risk for cognitive decline compared with those free of CVD (hazard ratio [HR], 1.29; 95\% CI: 1.00, 1.67). Women with myocardial infarction or other vascular disease were at highest risk (HR, 2.10; 95\% CI: 1.40, 3.15 or HR, 1.97; 95\% CI: 1.34, 2.87). Angina pectoris was moderately associated with cognitive decline (HR 1.45; 95\% CI: 1.05, 2.01) whereas no significant relationships were found for atrial fibrillation or heart failure. Hypertension and diabetes increased the risk for cognitive decline in women without CVD. Diabetes tended to elevate the risk for MCI/PD in women with CVD. No significant trend was seen for adiposity. Conclusions: CVD is associated with cognitive decline in elderly postmenopausal women. Hypertension and diabetes, but not adiposity, are associated with a higher risk for cognitive decline. More research is warranted on the potential of CVD prevention for preserving cognitive functioning.}, language = {en} } @phdthesis{Lang2013, author = {Lang, Katharina}, title = {Selektive Aldosteronsynthaseinhibitoren in der funktionellen Bildgebung zur Differenzialdiagnose des Prim{\"a}ren Hyperaldosteronismus - Entwicklung eines Testsystems und Evaluation geeigneter Substanzen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-108693}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {5 - 13\% aller Hypertoniker leiden an einem Prim{\"a}ren Hyperaldosteronismus (PA), was diese Erkrankung zu der h{\"a}ufigsten Form sekund{\"a}rer Hypertonie macht. Die Subtypdifferenzierung dient der Unterscheidung zwischen unilateraler, operativ zu therapierender und bilateraler, medikament{\"o}s zu therapierender Form. Der diagnostische Goldstandard in der Subtypdifferenzierung, der selektive Nebennierenvenenkatheter, ist aufgrund seiner Limitationen immer wieder Gegenstand kontroverser Diskussionen. W{\"a}hrend CT- und MRT- Bildgebung einen fester Bestandteil der Stufendiagnostik des PA darstellen, hat die funktionelle Bildgebung, PET und SPECT, hierbei noch keinen festen Platz. In der bildgebenden Darstellung der Nebennieren allgemein gewinnen diese Verfahren, vor allem auf der Basis von Etomidat und seinen Derivaten, zunehmend an Bedeutung. Beipiele hierf{\"u}r sind 11C- Meto- bzw. 18F- FETO- PET und 123I- IMTO- SPECT. Relativ neu in der Entwicklung sind selektive Aldosteronsynthaseinhibitoren. Problematisch hierbei ist die 93\% Homologie in der Aminos{\"a}uresequenz von CYP11B1 und CYP11B2, der Aldosteronsynthase. Die dieser Arbeit zugrunde liegende Idee ist die Entwicklung eines funktionellen Bildgebungsverfahrens zur Differenzialdiagnose des PA auf der Basis fluorierter und iodierter Aldosteronsynthasenhibitoren. Mittels Realtime- PCR konnte gezeigt werden, dass die {\"U}berexpression von CYP11B2 in aldosteronproduzierenden Tumoren dieses Enzym zu einem geeigneten Ansatzpunkt f{\"u}r radioaktiv markierte Tracer macht. Zur Evaluation geeigneter Substanzen wurde daher eine, humanes CYP11B1 bzw. CYP11B2 stabil exprimierende Zelllinie auf Basis der murinen Y1- Nebennierenrindenkarzinom- Zellen, entwickelt. Dies gelang durch Klonierung der humanen Enzyme in den pcDNA3.1zeo(+)- Vektor und anschließende Transfektion mit Lipofectamine. Zur weiteren Substanztestung wurde jeweils der Klon mit hoher Expression der CYP11B Enzyme auf mRNA- und Proteinebene bei gleichzeitig h{\"o}chster Hormonkonzentration im Zellkultur{\"u}berstand ausgew{\"a}hlt. Inkubation dieser Zelllinien mit den CYP11B- Inhibitoren Etomidat und Metomidat erbrachte IC50- Werte im nanomolekularen Bereich. In dem Testsystem stellte sich das fluorierte Naphthenylpyridin- Derivat 5.1 als potentester und zugleich sehr selektiver Inhibitor von CYP11B2 heraus, der erst ab einer Zehnerpotenz {\"u}ber der ermittelten IC50 einen signifikanten antiproliferativen Effekt auf NCI- H295 Zellen aus{\"u}bte. Die stabil transfizierten Y1-CYP11B Zellen stellten sich als geeignetes Testsystem zur Evaluation von Potenz und Selektivit{\"a}t der Aldosteronsynthase- Inhibitoren heraus. Mit der Substanz 5.1 konnte bereits ein potenter und selektiver Inhibitor von CYP11B2 entwickelt werden. Der IC50- Wert f{\"u}r die Inhibition von CYP11B2 lag f{\"u}r diese Substanz aber noch etwa um den Faktor 100 h{\"o}her als f{\"u}r die Referenzsubstanz Etomidat, so dass die Entwicklung und Testung weiterer Inhibitoren folgen muss, bis eine geeignete Substanz f{\"u}r die funktionale Bildgebung zur Differenzialdiagnose des PA gefunden ist.}, subject = {Diagnostik / Bildgebendes Verfahren}, language = {de} } @phdthesis{Guentner2013, author = {G{\"u}ntner, Stephan Matthias}, title = {Effekte von Komorbidit{\"a}t und Pharmakotherapie auf die Langzeitprognose chronisch herzinsuffizienter Patienten - eine prospektive Kohortenstudie}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-90515}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Die chronische Herzinsuffizienz ist eine der f{\"u}hrenden Ursachen f{\"u}r Morbidit{\"a}t und Mortalit{\"a}t in den industrialisierten Nationen. Herzinsuffizienz ist eine Erkrankung des h{\"o}heren Lebensalters, ist h{\"a}ufig assoziiert mit komorbiden Faktoren und stellt in Deutschland mittlerweile die h{\"a}ufigste Hauptdiagnose krankheitsbedingter station{\"a}rer Krankenhausaufenthalte dar. Herzinsuffizienz ist damit einer der wesentlichen kostentreibenden Faktoren unseres Gesundheitssystems. Neben allgemeinen nicht-medikament{\"o}sen Behandlungsempfehlungen und chirurgischen Therapien f{\"u}r Patienten im Endstadium der Erkrankung gibt es pharmakotherapeutische Leitlinien, die sich auf eine solide Evidenzbasis st{\"u}tzen. Die aktuellen Behandlungsleitlinien basieren jedoch gr{\"o}ßtenteils auf großen randomisierten kontrollierten Studien, in denen h{\"a}ufig wichtige Patientengruppen aufgrund von Alter, Geschlecht, Komorbidit{\"a}ten oder erhaltener linksventrikul{\"a}rer Ejektionsfraktion ausgeschlossen waren. Dies wird jedoch der ausgepr{\"a}gten Heterogenit{\"a}t chronisch herzinsuffizienter Patienten im klinischen Alltag nur bedingt gerecht. Zudem ist die medikament{\"o}se Therapie oft komplex und erfordert eine h{\"a}ufige Anpassung an die individuellen Begleiterkrankungen des Patienten sowie wiederholte Anpassungen der Dosis (Auftitration). Die Umsetzung dieser Therapieleitlinien und die damit zu erzielenden prognostischen Effekte in der deutschen Bev{\"o}lkerung sind bislang schlecht beschrieben. Insbesondere ist unklar, inwieweit die Ergebnisse der großen, randomisierten kontrollierten Studien auf die Allgemeinbev{\"o}lkerung {\"u}bertragbar sind. In der vorliegenden Arbeit wurde eine dem Praxisalltag vergleichbare Kohorte konsekutiver chronisch herzinsuffizienter Patienten (n=1054) mit eingeschr{\"a}nkter bzw. erhaltener linksventrikul{\"a}rer Pumpfunktion rekrutiert und {\"u}ber im Mittel f{\"u}nf Jahre nachverfolgt. Im Mittelpunkt stand die Frage, welche Faktoren ausschlaggebend daf{\"u}r sind, dass ein chronisch herzinsuffizienter Patient eine leitliniengerechte Pharmakotherapie (Korrelate einer besseren Leitlinientreue) bzw. eine h{\"o}here Dosierung der Medikation (Korrelate einer optimierten Pharmakotherapie) erh{\"a}lt. Zudem sollten diejenigen Faktoren herausgearbeitet werden, die das Langzeit{\"u}berleben chronisch herzinsuffizienter Patienten beeinflussen. Hier sollte insbesondere auch die Frage untersucht werden, in welchem Ausmaß eine h{\"o}herqualitative Pharmakotherapie die Prognose beeinflussen kann. Als Arbeitshypothese wurde definiert, dass eine bessere Leitlinientreue bzw. eine optimierte Pharmakotherapie die Langzeitprognose chronisch herzinsuffizienter Patienten positiv beeinflusst. Dabei wurde zus{\"a}tzlich angenommen, dass die zu Studienbeginn erfassten Risikofaktoren sowohl die Auswahl der Arzneimittel als auch die H{\"o}he der Dosierungen beeinflussen. Anhand des INH-Register Kollektivs konnte gezeigt werden, dass die Leitlinien der Europ{\"a}ischen Gesellschaft f{\"u}r Kardiologie zur Therapie der chronischen Herzinsuffizienz auch auf das Alltagskollektiv des INH-Registers {\"u}bertragbar sind und sich dabei positiv auf die Prognose dieser Patienten auswirken. Dies ist insbesondere deshalb wichtig, da sich die Leitlinien gr{\"o}ßtenteils auf randomisiert-kontrollierte Studien st{\"u}tzen, in denen bestimmte Patientengruppen - u.a. alte Patienten, Frauen und Patienten mit erhaltener linksventrikul{\"a}rer Funktion - ausgeschlossen wurden. Die vorliegende Arbeit zeigt, dass eben diese Patientengruppen bei der Therapie „benachteiligt" werden. Einen h{\"o}heren Grad an leitliniengerechter Pharmakotherapie und/oder h{\"o}here Dosierungen der Herzinsuffizienzmedikamente erhalten demnach j{\"u}ngere Patienten, M{\"a}nner und Patienten im niedrigeren NYHA-Stadium. Diese Erkenntnisse k{\"o}nnen in Zukunft als m{\"o}glicher Ansatzpunkt zur Verbesserung der Versorgungssituation chronisch herzinsuffizienter Patienten dienen, wodurch sich perspektivisch die Morbidit{\"a}t und Mortalit{\"a}t dieser Patienten weiter senken ließe. Die Daten des INH-Registers untermauerten den {\"U}berlebensvorteil von chronisch herzinsuffizienten Patienten, die mit einem Betablocker, ACE-Hemmer/ARB und/oder Aldosteronantagonisten behandelt wurden bzw. denen ein h{\"o}herer Grad an leitliniengerechter Pharmakotherapie zuteilwurde. Im Gegensatz dazu konnte der Zusammenhang zwischen der Dosierung der Herzinsuffizienzmedikamente und der Prognose der Patienten am Beispiel einer Therapie mit Betablockern bzw. ACE-Hemmern/ARBs nur eingeschr{\"a}nkt aufgezeigt werden. Einen prognostischen Vorteil hatten hierbei lediglich Patienten mit einer hohen Dosis an ACE-Hemmer und einer LVEF <45\%, wobei nach Gewichtsadaptation kein signifikanter Unterschied mehr nachweisbar war. Hinsichtlich der Gabe eines Betablockers weisen die Analysen auf einen prognostischen Vorteil einer solchen Therapie hin, w{\"a}hrend die Dosierung bzw. das Erreichen der Zieldosis von nachrangiger Bedeutung zu sein scheint. Vielmehr scheint es sinnvoll zu sein, sich bei der Betablockertherapie an der Herzfrequenz der Patienten zu orientieren, die einen guten Pr{\"a}diktor f{\"u}r die Prognose darstellt. Prim{\"a}res Ziel muss es demnach in jedem Fall sein, dass der chronisch herzinsuffiziente Patient die jeweilige Substanzklasse erh{\"a}lt, wenn sie nach Leitlinien indiziert ist. Die Dosissteigerung sollte dann nicht forciert nach festen Schemata erfolgen, sondern angepasst an das individuelle Patientenprofil. Ver{\"a}nderungen von Herzfrequenz, Blutdruck und Laborparametern m{\"u}ssen hierzu repetitiv erfasst und in die Behandlungsstrategie eingebunden werden. Nach 5 Jahren waren im Register 57\% der Patienten verstorben, wobei v.a. kardiovaskul{\"a}re Ereignisse aber auch der pl{\"o}tzliche Herztod als Todesursachen dominierten. Wenngleich sich hier ein deutlicher Zusammenhang mit der Schwere der Erkrankung (NYHA-Stadium) best{\"a}tigte, verdeutlichen diese Daten den nach wie vor schwerwiegenden („malignen") Verlauf der chronischen Herzinsuffizienz. Gleichzeitig sind die Daten auch Ansporn, die Pharmakotherapie unter Alltagsbedingungen so zu optimieren, wie es sonst nur unter den Bedingungen klinisch-kontrollierter Studien m{\"o}glich ist. Die Daten der vorliegenden Arbeit legen nahe, dass allein durch die bestm{\"o}gliche Anpassung der „konventionellen medikament{\"o}sen Therapie" sich bereits ein erheblicher prognostischer Nutzen f{\"u}r den einzelnen Patienten aber auch f{\"u}r die Bev{\"o}lkerung und das Gesundheitssystem materialisieren ließe. K{\"u}nftig m{\"u}ssen demnach verst{\"a}rkte Anstrengungen darauf gerichtet werden, diese Therapie-Optimierung fl{\"a}chendeckend und nachhaltig umzusetzen. Studienkollektive wie das INH-Register sind dabei geeignete Instrumente der Versorgungsforschung, die langfristig auch direkt zur Verbesserung der Versorgungssituation der Patienten beitragen.}, subject = {Chronische Herzinsuffizienz}, language = {de} } @phdthesis{Hittler2013, author = {Hittler, Friederike Hel{\´e}ne}, title = {Chemokinrezeptorexpression auf humanen Monozyten vor und nach perkutaner Koronarangiographie mit Stentimplantation}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-107731}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Die Koronare Herzkrankheit (KHK) z{\"a}hlt zu den h{\"a}ufigsten Todesursachen in Deutschland und weltweit. Die Atherosklerose der Herzkranzgef{\"a}ße gilt als pathophysiologisches Korrelat der KHK. Die manifeste KHK geht mit Myokardhypoxie einher, persistierende Myokardhypoxie resultiert im Myokardinfarkt. Atherosklerose ist ein multifaktorieller, sich selbst verst{\"a}rkender Inflammationsprozess, an dem multiple Zellen und Molek{\"u}le beteiligt sind. Hierzu z{\"a}hlen zum Beispiel das monozyt{\"a}r-phagozyt{\"a}re System (MPS) und Chemokine sowie Chemokinrezeptoren. Auch im Regenerationsprozess nach Myokardinfarkt spielt die MPS-Chemokinrezeptor-Interaktion eine bedeutsame Rolle. Die perkutane Koronarintervention mit Stentimplantation (PCI) hat sich als geeignete Behandlungsm{\"o}glichkeit der manifesten KHK etabliert. H{\"a}ufigste Komplikationsfolge der Implantation von Bare-Metal-Stents stellt die In-Stent-Restenose aufgrund einer {\"u}berschießenden Inflammationsreaktion dar. Konsekutiv entwickelte Drug-Eluting-Stents sondern Immunmodulatoren zu Eind{\"a}mmung der Inflammationsreaktion ab. Dadurch kommt es auch zu Eind{\"a}mmung der gewollten Reendothelialisierung des Stents mit Zunahme gef{\"u}rchteter Stent-Thrombosen. Ideal w{\"a}re demnach eine selektivere Hemmung der Inflammationsreaktion, die die gew{\"u}nschte Reendothelialisierung nicht beeintr{\"a}chtigt. Hierzu m{\"u}ssen die molekularbiologischen Zusammenh{\"a}nge am Gef{\"a}ßbett nach Stenting beleuchtet werden. In der vorliegenden Arbeit wurde das Expressionsverhalten der Chemokinrezeptoren CXCR4, CX3CR1 und CCR2 auf Monozyten vor und nach PCI im humanen Modell untersucht, alle untersuchten Probanden litten an Atherosklerose, circa die H{\"a}lfte hatte bereits vormalig einen Myokardinfarkt erlitten. 24 Stunden nach Stenting zeigte sich eine signifikant geringere CXCR4-Expression und Positivit{\"a}t auf Monozyten der Gesamtpopulation. Dies ist vermutlich Korrelat einer Achsenaktivierung mittels CXCR4-typischer Rezeptorinternalisierung und mittels Abwanderung CXCR4-positiver Monozyten ins Gef{\"a}ßbett und spricht f{\"u}r eine grundlegende Rolle der CXCR4-MPS-Interaktion nach PCI. Patienten, die bereits einen Myokardinfarkt erlitten hatten, konnten eine signifikant niedrigere CXCR4-Expression auf Monozyten aufweisen als die Vergleichsgruppe. Weiterhin zeigten Patienten mit pectangin{\"o}sen Beschwerden einen signifikant h{\"o}heren Rezeptorverlust an der Oberfl{\"a}che der Monozyten nach Stenting. Dies deutet auf eine grundlegende Rolle der CXCR4-MPS-Interaktion bei Myokardhypoxie hin und liefert einen Einblick in das komplexe Geschehen der Infarktheilung und Hypoxiekompensation. Hypothetisch denkbar w{\"a}re eine protektive Rolle der CXCR4-Achse nach Isch{\"a}mie, mit Hypoxie-vermittelter Pr{\"a}konditionierung humaner Monozyten nach stattgehabtem Myokardinfarkt und konsekutiv basal gesteigerter CXCR4-Expression, die nach erneutem Hypoxie-Ereignis einen schnelleren Zugriff auf CXCR4-vermittelte, protektive Signalwege erlauben k{\"o}nnte. Patienten, die sich bereits vormals einem Stenting unterzogen hatten, konnten eine signifikant niedrigere CX3CR1-Expression auf Monozyten aufweisen. Dies steht in Kongruenz mit Ergebnissen von Tierstudien, die eine grundlegende Rolle von CX3CR1 im chronischen Monozytenrecruitment nach Gef{\"a}ßverletzung beschrieben hatten. F{\"u}r CCR2 ergaben sich keine relevanten Ergebnisse. Die Rolle der Interaktion der Chemokinrezeptoren CXCR4, CX3CR1 und CCR2 mit humanen Monozyten in Neointimagenese, Atherosklerose und Myokardheilung nach Infarkt ist nicht eindeutig beschrieben und wird zum Teil kontrovers diskutiert. Unsere Studie liefert interessante neue Erkenntnisse bez{\"u}glich der Beteiligung der untersuchten Rezeptoren und dem MPS bei den beschriebenen pathogenetischen Prozessen. Die erstmalig beschriebene CXCR4-MPS-Interaktion nach Stenting sowie die Hinweise auf eine Beteiligung von CX3CR1 im chronischen Monozytenrecruitment der humanen Neointimagenese liefern einen interessanten Anhaltspunkt f{\"u}r die Entwicklung neuer, selektiver Antagonisten im Kampf gegen die In-Stent-Restenose.}, subject = {Monozyten}, language = {de} } @phdthesis{Fey2013, author = {Fey, Holger}, title = {Effekte von Paricalcitol auf Inflammation und Kalzifikationsregulation bei H{\"a}modialysepatienten}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-98930}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Die Mortalit{\"a}t bei Dialysepatienten ist bedeutend h{\"o}her als in der Allgemeinbev{\"o}lkerung. Hauptgrund ist eine deutlich erh{\"o}hte kardiovaskul{\"a}re Morbidit{\"a}t und Mortalit{\"a}t. Als wichtige Ursachen hierf{\"u}r gelten bei Dialysepatienten unter anderem das vermehrte Auftreten systemischer Inflammation und die St{\"o}rung des Kalzium-Phosphathaushaltes, welche mit vermehrter vaskul{\"a}rer Kalzifikation einhergeht. Da große Beobachtungsstudien darauf hinweisen, dass aktive Vitamin D-Therapie mit einem {\"U}berlebensvorteil f{\"u}r Dialysepatienten assoziiert ist, besteht die Hypothese, dass Paricalcitol antiinflammatorische und verkalkungsinhibitorische Effekte haben k{\"o}nnte. In dieser vorliegenden multizentrischen, doppelverblindeten, prospektiven und Placebo-kontrollierten Crossover-Studie wurden 43 H{\"a}modialysepatienten eingeschlossen, randomisiert und zwei Behandlungssequenzen zugeordnet. In der einen Behandlungssequenz erfolgte zun{\"a}chst eine 12-w{\"o}chige Behandlung mit Paricalcitol (Startdosis 2 μg/Tag) und nach einer 4-w{\"o}chigen Washout- Phase eine 12-w{\"o}chige Behandlung mit Placebo. In der anderen Behandlungssequenz erfolgte nach gleichem Modus zun{\"a}chst eine Behandlung mit Placebo und dann eine Behandlung mit Paricalcitol. Die Adjustierung der Dosis der Studienmedikation erfolgte entsprechend der Werte f{\"u}r Kalzium, Phosphat und PTH intakt. Zur Untersuchung der Hypothese wurden Zielparameter f{\"u}r Inflammation (hsCRP, Hepcidin) und Kalzifikation (Fetuin A , t-ucMGP, FGF-23) in regelm{\"a}ßigen Intervallen gemessen. Als prim{\"a}rer Endpunkt wurden die 30\%-ige Senkung des hsCRP-Levels und 20\%-ige Steigerung der Fetuin A-Serumwerte definiert. Sekund{\"a}re Endpunkte waren Ver{\"a}nderungen der Serumkonzentrationen von Hepcidin, FGF-23 und t- ucMGP. Insgesamt wurde die Studie von 25 Patienten protokollgem{\"a}ß beendet. Bez{\"u}glich der prim{\"a}ren Zielparameter zeigten sich keine signifikanten Unterschiede zwischen der Behandlung mit Paricalcitol und Placebo. Es konnte lediglich bei hsCRP ein leichter Trend zu niedrigeren Werten unter Paricalcitolbehandlung registriert werden. Bei den sekund{\"a}ren Zielparametern zeigte sich eine Borderline-Signifikanz (p = 0,051) hinsichtlich h{\"o}herer FGF-23- Werte unter Paricalcitol. Bei Hepcidin und t-ucMGP konnten keine signifikanten Unterschiede zwischen der Behandlung mit Paricalcitol und Placebo verzeichnet werden. In der vorliegenden Studie konnten die prim{\"a}ren Endpunkte unter Paricalcitoltherapie somit nicht erreicht werden. Die Expression von Fetuin A wird von Paricalcitol wahrscheinlich nicht beeinflusst. M{\"o}glicherweise existiert aber ein leichter antiinflammatorischer Effekt, der eine Senkung der hsCRP- Serumwerte bedingen k{\"o}nnte. Des Weiteren steigert Paricalcitol die Expression von FGF-23, w{\"a}hrend die von Hepcidin und t-ucMGP unbeeinflusst zu sein scheint.}, subject = {Inflammation}, language = {de} } @phdthesis{Witz2013, author = {Witz, Eva-Katharina}, title = {Verbesserung des linksventrikul{\"a}ren Remodelings durch Inhibition des Transkriptionsfaktors Nuclear Factor kappa B (NF-κB) in Makrophagen und Granulozyten}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-103828}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Nach einem Myokardinfarkt werden ventrikul{\"a}res Remodeling und myokardiale Funktion unter anderem durch die ablaufenden Reaktionen des angeborenen Immunsystems beeinflusst. Von zentraler Bedeutung f{\"u}r die Regulation dieser Immunreaktion ist der Transkriptionsfaktor Nuclear Factor kappa B. Tiere, bei denen NF-κB durch das Fehlen seiner Untereinheit p50 global inaktiv ist, wei- sen einen Schutz vor linksventrikul{\"a}rem Remodeling auf. Bisher ist jedoch un- klar, welche Zellen f{\"u}r diesen protektiven Effekt verantwortlich sind. Vorange- gangene Studien konnten zeigen, dass die Protektion nicht auf die fehlende NF- κB Aktivierung in Kardiomyozyten zur{\"u}ckzuf{\"u}hren ist. Aus Isch{\"a}mie- Reperfusions-Experimenten an NF-κB-defizienten Tieren ergaben sich Hinwei- se, dass v.a. die Hemmung von NF-κB in Entz{\"u}ndungszellen die protektiven Effekte vermittelt. Durch Kreuzung von LysMCre- mit lox-IKKβ-Tieren erzeugten wir Tiere, denen makrophagenspezifisch IκB-Kinase β (IKKβ) fehlt. IKK deaktiviert den Inhibitor von NF-κB und ist somit essentiell f{\"u}r eine NF-κB-Aktivierung. Als Modell der Herzinsuffizienz diente der chronische Myokardinfarkt. Die Nachbeobachtung erfolgte {\"u}ber 56 Tage. Die Knockout-Tiere (KO) hatten im Vergleich zu den Wildtyp-Tiere (WT) eine signifikant bessere {\"U}berlebensrate (KO vs. WT, 100\% vs. 49\%, p < 0,01). Pr{\"a}operativ sowie postoperativ an den Tagen 1, 21 und 56 wurden transthora- kale Echokardiographien durchgef{\"u}hrt. Bei gleicher Infarktgr{\"o}ße zeigten die KO-Tiere eine deutlich geringere linksventrikul{\"a}re Dilatation. Es konnte moleku- larbiologisch keine Reduktion der humoralen Entz{\"u}ndungsreaktion nachgewie- sen werden, ebenso blieb das Entz{\"u}ndungszellinfiltrat immunhistochemisch unver{\"a}ndert. Auch bez{\"u}glich Apoptoserate und Neovaskularisation zeigte sich kein Unterschied zwischen den Gruppen. Allerdings zeigten die LysM-IKKβ-KO-Tiere 56 Tage nach Myokardinfarkt einen deutlich erh{\"o}hten septalen Kollagen- gehalt als Hinweis auf ein ver{\"a}ndertes extrazellul{\"a}res Remodeling. Aus diesen Ergebnissen kann geschlossen werden, dass die protektiven Effek- te der globalen NF-κB-Hemmung durch die fehlende NF-κB-Aktivierung in Ma- krophagen und Granulozyten, nicht aber in Kardiomyozyten vermittelt wurden. Die durch die makrophagenspezifische NF-κB-Hemmung vermittelten Ver{\"a}nde- rungen im Remodeling der extrazellul{\"a}ren Matrix f{\"u}hren zu einer Verbesserung der {\"U}berlebensrate, besseren funktionellen Ergebnissen und einem insgesamt verminderten linksventrikul{\"a}ren Remodeling nach Myokardinfarkt.}, subject = {Remodeling}, language = {de} } @phdthesis{Hundertmark2013, author = {Hundertmark, Moritz Jens}, title = {Die Bedeutung des Eya4-Signalweges f{\"u}r die Entstehung und Entwicklung von Herzkrankheiten}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-102257}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Diese Arbeit untersucht die Relevanz des Transkriptionskofaktors Eya4 in der Entstehung und Entwicklung von Herzkrankheiten. Hierzu wurde, neben adenoviralen Transfektionsarbeiten in neonatalen Rattenkardiomyozyten, ein transgenes Mausmodell etabliert, wodurch die Identifikation von Downstreamtargets des Transkriptionskofaktors Eya4 im Sinne eines Signalweges erm{\"o}glicht wurde. Der Transkriptionskofaktor Eya4 wirkt als Suppressor des cyclinabh{\"a}ngigen Kinaseinhibitors p27, w{\"a}hrend die trunkierende Mutante des wildtypischen Proteins (E193) die Suppression auf p27 aufhebt.Ph{\"a}notypisch entwickeln E193-{\"u}berexprimierende M{\"a}use eine altersabh{\"a}ngig einsetzende DCM w{\"a}hrend die Eya4-{\"u}berexprimierenden Tiere eine konzentrische Myokardhypertrophie entwickeln.}, subject = {Eya4}, language = {de} } @phdthesis{Loebbert2013, author = {L{\"o}bbert, Anne-Katrin}, title = {F{\"u}hrt VIRTUAL-REALITY-Simulationstraining zur Stressreduktion bei angehenden interventionellen Kardiologen? : eine stratifiziert randomisierte Studie}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-99978}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Die Simulationstechnologie in der Medizin hat in den letzten Jahren große Fortschritte gemacht. In der Zwischenzeit gibt es auch f{\"u}r Herzkatheteruntersuchungen und -interventionen „Virtual reality" Simulatoren, die ein realistisches Training von Kathetereingriffen erlauben. Nicht gekl{\"a}rt ist bislang, ob Simulationstraining das Stressniveau des Untersuchers reduzieren kann. Im Rahmen dieser Studie wurde zur Beantwortung der genannten Fragestellung der Effekt von Virtual-Reality-Training auf das Stressniveau von Anf{\"a}ngern in der interventionellen Kardiologie untersucht. Hierzu wurde eine randomisiert-stratifizierte Studie bei 33 Anf{\"a}ngern in der interventionellen Kardiologie durchgef{\"u}hrt. Die Probanden wurden in eine Kontroll- und Simulationsgruppe aufgeteilt. Die Simulationsgruppe erhielt ein achtst{\"u}ndiges intensives Training an verschiedenen Simulatoren, w{\"a}hrend die Kontrollgruppe kein Simulationstraining, sondern lediglich eine theoretische Wissensvermittlung erhielt. Alle Teilnehmer mussten unter realit{\"a}tsnahen Umst{\"a}nden im Herzkatheterlabor der Universit{\"a}tsklinik W{\"u}rzburg innerhalb von 30 Minuten eine PCI an einem pulsatilen Herzkreislaufmodell durchf{\"u}hren. Die Probanden dokumentierten vor und nach der Pr{\"a}- und Postevaluation ihr aktuelles „Befinden" anhand eines psychologi-schen Fragebogens PANAS. Ebenso wurden die Probanden hinsichtlich ihrer manuellen F{\"a}higkeiten nach einem strukturierten Evaluationsbogen von einem interventionell t{\"a}tigen Kardiologen bewertet Die Ergebnisse zeigten initial f{\"u}r die Parameter „aktiv, interessiert, freudig erregt, stark, angeregt, stolz, begeistert, wach, entschlossen und aufmerksam" des Fragebogens PANAS keinen gruppenspezifischen Unterschied. Nach einem achtst{\"u}ndigen Simulationstraining gab die Simulationsgruppe eine signifikante Reduktion des Stressniveaus im Vergleich zur Kontrollgruppe an. Die aktuelle Studie zeigte, dass das Training an den Virtual Reality Simulatoren die herk{\"o}mmliche Ausbildung in effektiver Weise erg{\"a}nzen kann. Weitere Studien mit einer gr{\"o}ßeren und zugleich homogeneren Stichprobengr{\"o}ße sind n{\"o}tig, um die genannten Hypothesen zu best{\"a}tigen.}, subject = {Simulator}, language = {de} } @phdthesis{Schlereth2013, author = {Schlereth, Florian}, title = {Expression of the DHEA/DHEAS-Shuttle in cell lines and foetal tissue of human liver, adrenal and cartilage}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-102068}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {DHEA is a precursor for the male and female sex hormones testosterone and estradiol, which are mainly secreted from the testes and the ovary, respectively. In addition, epidemiological studies showed that low serum levels of DHEA and DHEAS correlate with the incidence of autoimmune disease, cancer and cardiovascular disease. In vitro, DHEA and DHEAS influenced glucose metabolism in a favourable manner. However, positive effects of DHEA substitution were only significant adrenal insufficiency in women. Steroid sulphotransferase 2A1 (SULT2A1) is the responsible enzyme for sulphonation of DHEA to DHEAS which is thought to be the inactive form of DHEA. In this role, SULT2A1 acts as a central regulator of steroid synthesis because sulphonation of DHEA withdraws the substrate for further downstream conversion. Another essential cofactor for sulphonation is PAPS, which is produced by the enzyme PAPS synthase (PAPSS) from ATP and anorganic sulphate. PAPSS exists in the different isoforms PAPSS1 and PAPSS2 and splice variants PAPSS2a and PAPSS2b. Changes in PAPSS activity are thought to influence sulphonation of DHEA significantly. However, neither regulation of PAPSS nor its influence on SULT2A1 have been investigated in human cell lines or humans. The main goal of this thesis was to analyze the enzyme expression of the DHEA/DHEA shuttle, i.e. mRNA and protein of SULT2A1, PAPSS1 and PAPSS2, in various human cell lines. Furthermore, I investigated which cell line could serve as a suitable model for further research regarding regulation of SULT2A1, PAPSS1 and PAPSS2. Here, I could show that the enzymes of the DHEA/DHEAS shuttle were expressed in the human adrenal cell line NCI-h295R as both mRNA and protein. In enzyme assays, I was able to prove conversion of DHEA to DHEAS as well as to different other steroids. However, applying Trilostane, a potent inhibitor of CYP3B, effectively directed conversion of DHEA to DHEAS. Using these findings, future experiments can investigate for example the influence of certain cytokines or endocrine disruptors on expression and activity of PAPSS1/2 and on sulphonation of DHEA. In particular, the relatively equal expression of PAPSS1 and PAPSS2 will enable us to do knock down experiments with siRNA to elucidate how the activity of one enzyme changes when the other one fails. Sulphonation of DHEA by SULT2A1 is thought to happen in the cytoplasm or more precisely in the Golgi apparatus. However, experiments in transfected cells have shown both a cytoplasmatic and a nuclear localisation when both enzymes were expressed at the same time. Immunocytochemistry revealed the same results in the adrenal cell line NCI-h295R, where both enzymes were expressed strongly in the nucleus. The physiological role is not clear and requires further research. Presumably, sulphate is activated in the nucleus. However, one could also speculate that a shift of PAPSS to the nucleus could generate a reservoir, which can be activated by re-localisation to the cytoplasm when more PAPS is needed. Expression of SULT2A1 in some foetal tissues has been investigated earlier. Whilst in adult human cartilage PAPSS1 is predominant, in newly born hamsters PAPSS2 is more abundantly expressed. The expression of PAPSS isoforms in highly sulphonating tissue has not been investigated in humans, so far. This work demonstrated a differential expression of SULT2A1, PAPSS1 and PAPSS2 in adult and foetal liver, adrenal and foetal cartilage tissue. In adult and foetal adrenal expression was similar. However, foetal and adult liver differed in the expression of SULT2A1, which was expressed much more in adult tissue. Most importantly, in foetal cartilage there was only a low expression of SULT2A1 and PAPS seems to mostly provided by PAPSS1, which was considerably higher expressed in cartilage than in other tissues. In contrast, PAPSS2 was mainly expressed in adult and foetal adrenal. Additionally, we reported a case of a female patient who had been investigated for hyperandrogenism. Two mutations in the PAPSS2 gene had led to massively reduced serum levels of DHEAS. One heterozygous mutation in the domain of the APS kinase of the PAPSS2 protein leads to substitution of one amino acid at position 48 (T48R). In vitro experiments showed a residual activity of 6\% for this mutation. A second mutation in the ATP sulphurylase domain of PAPSS2 was found. The introduction of thymidine instead of cytidine leads to a stop codon, which is presumed to truncate the protein at position 329 (R329X). In vitro, no residual activity was seen for this mutation. The lack of PAPS reduces sulphonation of DHEA but also sulphonation of proteoglycanes, which leads to skeletal abnormalities. The abundance of DHEA enables massive downstream conversion to androgens leading to clinical features of hyperandrogenism. Regarding the bone abnormalities, it is interesting and surprising that activity of PAPSS1 compensated to a great extent in cartilage but was not able to keep up a more considerable sulphonation of DHEA. Possibly, the subcellular localisation might play a role in this scenario.}, subject = {Dehydroepiandrosteron}, language = {en} } @phdthesis{Michalska2013, author = {Michalska, Marta}, title = {Molecular Imaging of atherosclerosis}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-73243}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Atherosklerose ist eine aktive und progressive Erkrankung, bei der vaskul{\"a}re Adh{\"a}sionsmolek{\"u}le wie VCAM-1 eine entscheidende Rolle durch Steuerung der Rekrutierung von Immunzellen in den fr{\"u}hen und fortgeschrittenen Plaques spielen. Ein zielgerichteter Einsatz von VCAM-1-Molek{\"u}len mit spezifischen Kontrastmitteln ist daher eine M{\"o}glichkeit, die VCAM-1-Expression zu kontrollieren, Plaquewachstum ab einem fr{\"u}hen Zeitpunkt zu visualisieren und eine fr{\"u}he Pr{\"a}vention von Atherosklerose vor Beginn der Thrombusbildung zu etablieren. Des Weiteren bietet die nichtinvasive Magnetresonanz (MR)-Bildgebung den Vorteil der Kombination molekularer und morphologischer Daten. Sie erm{\"o}glicht, mithilfe von entwickelten VCAM-1-markierten Eisenoxidpartikeln, den spezifischen Nachweis entz{\"u}ndlicher Prozesse w{\"a}hrend der Atherosklerose. Diese Arbeit belegt, dass mit dem VCAM-1-Konzept eine vielversprechende Herangehensweise gefunden wurde und dass das, mit spezifischen superparamagnetischen Eisenoxid (USPIO) konjugierte VCAM-1-Peptid, gegen{\"u}ber unspezifischer USPIOs ein erh{\"o}htes Potenzial bei der Untersuchung der Atherosklerose in sich tr{\"a}gt. Im ersten Teil der Arbeit konnte im Mausmodell gezeigt werden, dass gerade das VCAM-1-Molek{\"u}l ein sinnvoller Ansatzpunkt zur Darstellung und Bildgebung von Atherosklerose ist, da in der fr{\"u}hen Phase der Entz{\"u}ndung die vaskul{\"a}ren Zelladh{\"a}sionsmolek{\"u}le {\"u}berexprimiert und auch kontinuierlich, w{\"a}hrend der fortschreitenden Plaquebildung, hochreguliert werden. Weiterhin beschreibt diese Arbeit die Funktionst{\"u}chtigkeit und das Verm{\"o}gen des neu gestalteten USPIO Kontrastmittels mit dem zyklischen Peptid, in seiner Spezialisierung auf die VCAM-1 Erkennung. Experimentelle Studien mit ultra-Hochfeld-MRT erm{\"o}glichten weitere ex vivo und in vivo Nachweise der eingesetzten USPIO-VCAM-1-Partikel innerhalb der Region um die Aortenwurzel in fr{\"u}hen und fortgeschrittenen atherosklerotischen Plaques von 12 und 30 Wochen alten Apolipoprotein E-defizienten (ApoE-/-) M{\"a}usen. Mit ihrer Kombination aus Histologie und Elektronenmikroskopie zeigt diese Studie zum ersten Mal die Verteilung von VCAM-1-markierten USPIO Partikeln nicht nur in luminalem Bereich der Plaques, sondern auch in tieferen Bereichen der medialen Muskelzellen. Dieser spezifische und sensitive Nachweis der fr{\"u}hen und fortgeschrittenen Stadien der Plaquebildung bringt auf molekularer Ebene neue M{\"o}glichkeiten zur Fr{\"u}herkennung von atherosklerotischen Plaques vor dem Entstehen von 8 Rupturen. Im Gegensatz zum USPIO-VCAM-1-Kontrastmittel scheiterten unspezifische USPIO Partikel an der Identifikation fr{\"u}her Plaqueformen und begrenzten die Visualisierung von Atherosklerose auf fortgeschrittene Stadien in ApoE-/- M{\"a}usen.}, subject = {VCAM}, language = {en} } @phdthesis{Wiemer2013, author = {Wiemer, Laura Elisa}, title = {In-vitro-Untersuchungen zur molekularen Wirkung von Mitotane beim Nebennierenrindenkarzinom}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-94526}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Das Nebennierenrindenkarzinom ist eine hochmaligne Erkrankung und hat eine schlechte Prognose. Mitotane ist bis heute die einzige hierf{\"u}r zugelassene Therapie. Um die molekularen Mechanismen der Mitotanetherapie besser zu verstehen, wurde die Nebennierenkarzinom-Zelllinie NCI-H295 mit unterschiedlichen Konzentrationen von Mitotane inkubiert und die Wirkung auf mehreren Ebenen untersucht. Dabei kam der Untersuchung der Steroidogenese und apoptotischer Vorg{\"a}nge ein besonderer Fokus zu. In den Hormonanalysen via Immunoassay zeigte sich eine zeit- und konzentrationsabh{\"a}ngige Hemmung der adrenalen Steroidsekretion. So kam es unter 24-st{\"u}ndiger Inkubation mit 100µM Mitotane zu einer Reduktion der Cortisolsekretion um 89\%. Diese Hormonsuppression geht einher mit einer Herabregulation von steroidogenen Enzymen in den durchgef{\"u}hrten Microarray-basierten Genexpressionsanalysen. So konnte gezeigt werden, dass vor allem Steroidbiosynthese-Enzyme der Zona fasciculata und reticularis betroffen sind. Als weitere wichtige Gene im Zusammenhang mit der Beeinflussung des Steroidhaushalts unter Mitotanetherapie konnten SQLE, LDLR, SCD, SREBF1 und ABCG1 identifiziert werden. Gleichzeitig konnte durch Durchflusszytometrie und Zelltod-ELISA die proapoptotische Wirkung von Mitotane gezeigt werden (FACS: 100µM Mitotane, 24 Stunden; Zunahme der Apoptose um den Faktor 2,13). Dies best{\"a}tigte sich beispielsweise auch in der {\"U}berexpression des Apoptosegens BAX in der Real-Time-PCR. Weiterhin zeigte der RNA-Microarray eine starke Expressionszunahme bei Genen, die mit dem programmierten Zelltod zusammenh{\"a}ngen wie GDF15, DUSP4, TRIB3 und CHOP. Ausgehend von den klinischen Effekten und best{\"a}tigt durch die oben genannten in vitro Ergebnisse bewirkt Mitotane auch molekular folgende {\"A}nderungen in Nebennierenrindenzellen: Hemmung der Steroidogenese und Induktion von Apotose. Es stellt sich damit die Frage, ob diese Mechanismen parallel und separat voneinander ablaufen oder ob es einen gemeinsamen Nenner gibt. Interessanterweise ergab die Analyse der Genexpressionsdaten, dass viele der proapoptotischen Gene mit dem sogenannten ER-Stress zusammenh{\"a}ngen. Einerseits k{\"o}nnte Mitotane durch direkte Inhibition der Hormonsekretion wirken, andererseits k{\"o}nnte ER-Stress durch Mitotane-induzierte-Bildung toxischer Lipide, wie Cholesterol, ausgel{\"o}st werden. Um den genauen Wirkmechanismus endg{\"u}ltig zu kl{\"a}ren, werden weitere Experimente ben{\"o}tigt. Mitotane-induzierter ER-Stress liefert einen vollst{\"a}ndig neuen Blickwinkel auf die molekulare Wirkweise von Mitotane auf Nebennierenrindenkarzinomzellen. Gerade da die Mediatoren des ER-Stresses gut definiert und ER-Stress spezifisch sind, k{\"o}nnten sie sinnvolle Ziele in der Therapie darstellen. Die Beobachtung, dass Mitotane ER-Stress hervorruft, k{\"o}nnte in Zukunft somit zur Entwicklung wirksamerer und spezifischerer Therapien des Nebennierenrindenkarzinoms f{\"u}hren und so die infauste Prognose dieser malignen Krankheit verbessern.}, subject = {Nebenniere}, language = {de} } @article{ChopraLangSalzmannetal.2013, author = {Chopra, Martin and Lang, Isabell and Salzmann, Steffen and Pachel, Christina and Kraus, Sabrina and B{\"a}uerlein, Carina A. and Brede, Christian and Jord{\´a}n Garrote, Ana-Laura and Mattenheimer, Katharina and Ritz, Miriam and Schwinn, Stefanie and Graf, Carolin and Sch{\"a}fer, Viktoria and Frantz, Stefan and Einsele, Hermann and Wajant, Harald and Beilhack, Andreas}, title = {Tumor Necrosis Factor Induces Tumor Promoting and Anti-Tumoral Effects on Pancreatic Cancer via TNFR1}, series = {PLoS ONE}, journal = {PLoS ONE}, doi = {10.1371/journal.pone.0075737}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97246}, year = {2013}, abstract = {Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF) in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5\%), TNF deficient (12.5\%), and TNFR2 deficient mice (22.2\%) were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4+ T cells and CD4+ forkhead box P3 (FoxP3)+ regulatory T cells (Treg) but reduced numbers of CD8+ T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8+ T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome.}, language = {en} } @article{SbieraRonchiLeichetal.2013, author = {Sbiera, Silviu and Ronchi, Cristina L. and Leich, Ellen and Henzel, Katharina and Rosenwald, Andreas and Allolio, Bruno and Fassnacht, Martin}, title = {Single Nucleotide Polymorphism Array Profiling of Adrenocortical Tumors - Evidence for an Adenoma Carcinoma Sequence?}, series = {PLoS ONE}, journal = {PLoS ONE}, doi = {10.1371/journal.pone.0073959}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97218}, year = {2013}, abstract = {Adrenocortical tumors consist of benign adenomas and highly malignant carcinomas with a still incompletely understood pathogenesis. A total of 46 adrenocortical tumors (24 adenomas and 22 carcinomas) were investigated aiming to identify novel genes involved in adrenocortical tumorigenesis. High-resolution single nucleotide polymorphism arrays (Affymetrix) were used to detect copy number alterations (CNAs) and copy neutral losses of heterozygosity (cnLOH). Genomic clustering showed good separation between adenomas and carcinomas, with best partition including only chromosome 5, which was highly amplified in 17/22 malignant tumors. The malignant tumors had more relevant genomic aberrations than benign tumors, such as a higher median number of recurrent CNA (2631 vs 94), CNAs >100 Kb (62.5 vs 7) and CN losses (72.5 vs 5.5), and a higher percentage of samples with cnLOH (91\% vs 29\%). Within the carcinoma cohort, a precise genetic pattern (i.e. large gains at chr 5, 7, 12, and 19, and losses at chr 1, 2, 13, 17, and 22) was associated with a better prognosis (overall survival: 72.2 vs 35.4 months, P=0.063). Interestingly, >70\% of gains frequent in beningn were also present in malignant tumors. Notch signaling was the most frequently involved pathway in both tumor entities. Finally, a CN gain at imprinted "IGF2" locus chr 11p15.5 appeared to be an early alteration in a multi-step tumor progression, followed by the loss of one or two alleles, associated with increased IGF2 expression, only in carcinomas. Our study serves as database for the identification of genes and pathways, such as Notch signaling, which could be involved in the pathogenesis of adrenocortical tumors. Using these data, we postulate an adenoma-carcinoma sequence for these tumors.}, language = {en} } @phdthesis{Schoenfeld2013, author = {Sch{\"o}nfeld, Stephan}, title = {Aldosteron und Cortisol bei Dialysepatienten - Effekt auf kardiale und vaskul{\"a}re Ereignisse}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96156}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Dialysepatienten weisen eine hohe Anzahl kardiovaskul{\"a}rer Ereignisse auf. Betrachtet man die h{\"a}ufigsten Todesursachen von Dialysepatienten, so f{\"a}llt ein großer Teil in den kardiovaskul{\"a}ren Bereich. In dieser Arbeit wurde der Einfluss von Aldosteron und Cortisol auf kardiale und vaskul{\"a}re Ereignisse bei Dialysepatienten mit Diabetes mellitus untersucht. Dazu wurden Daten von 1255 Dialysepatienten mit Diabetes mellitus aus der Deutschen Diabetes Dialyse Studie analysiert. In der vorliegenden Arbeit konnte gezeigt werden, dass mit erh{\"o}hten Aldosteronkonzentrationen ein signifikanter Anstieg des Risikos f{\"u}r pl{\"o}tzlichen Herztod (HR: 1.69; 95\% CI: 1.06-2.69) einhergeht. Das Risiko an pl{\"o}tzlichem Herztod zu versterben war bei hohen Konzentrationen von Aldosteron und gleichzeitig vorliegenden hohen Konzentrationen von Cortisol noch deutlicher erh{\"o}ht (HR: 2.86, 95\% CI: 1.32-6.21). Ebenso war die Gesamtsterblichkeit signifikant erh{\"o}ht bei Patienten, die hohe Aldosteron- und Cortisolkonzentrationen aufwiesen im Vergleich zu Patienten mit niedrigen Spiegeln beider Hormone (HR: 1.62, 95\% CI: 1.01-2.62). In dieser Arbeit konnte somit ein deutlicher Zusammenhang hoher Aldosteron- und Cortisolkonzentrationen mit pl{\"o}tzlichem Herztod und Gesamtsterblichkeit gezeigt werden.}, subject = {Aldosteron}, language = {de} } @article{WinterKampfHelluyetal.2013, author = {Winter, Patrick and Kampf, Thomas and Helluy, Xavier and Gutjahr, Fabian T. and Meyer, Cord B. and Rommel, Eberhard and Bauer, Wolfgang R. and Jakob, Peter M. and Herold, Volker}, title = {Fast retrospectively triggered local pulse-wave velocity measurements in mice with CMR-microscopy using a radial trajectory}, series = {Journal of Cardiovascular Magnetic Resonance}, journal = {Journal of Cardiovascular Magnetic Resonance}, doi = {10.1186/1532-429X-15-88}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96602}, year = {2013}, abstract = {Background The aortic pulse-wave velocity (PWV) is an important indicator of cardiovascular risk. In recent studies MRI methods have been developed to measure this parameter noninvasively in mice. Present techniques require additional hardware for cardiac and respiratory gating. In this work a robust self-gated measurement of the local PWV in mice without the need of triggering probes is proposed. Methods The local PWV of 6-months-old wild-type C57BL/6J mice (n=6) was measured in the abdominal aorta with a retrospectively triggered radial Phase Contrast (PC) MR sequence using the flow-area (QA) method. A navigator signal was extracted from the CMR data of highly asymmetric radial projections with short repetition time (TR=3 ms) and post-processed with high-pass and low-pass filters for retrospective cardiac and respiratory gating. The self-gating signal was used for a reconstruction of high-resolution Cine frames of the aortic motion. To assess the local PWV the volume flow Q and the cross-sectional area A of the aorta were determined. The results were compared with the values measured with a triggered Cartesian and an undersampled triggered radial PC-Cine sequence. Results In all examined animals a self-gating signal could be extracted and used for retrospective breath-gating and PC-Cine reconstruction. With the non-triggered measurement PWV values of 2.3±0.2 m/s were determined. These values are in agreement with those measured with the triggered Cartesian (2.4±0.2 m/s) and the triggered radial (2.3±0.2 m/s) measurement. Due to the strong robustness of the radial trajectory against undersampling an acceleration of more than two relative to the prospectively triggered Cartesian sampling could be achieved with the retrospective method. Conclusion With the radial flow-encoding sequence the extraction of a self-gating signal is feasible. The retrospective method enables a robust and fast measurement of the local PWV without the need of additional trigger hardware.}, language = {en} } @article{GassenmaierGorskiAleksicetal.2013, author = {Gassenmaier, Tobias and Gorski, Armin and Aleksic, Ivan and Deubner, Nikolas and Weidemann, Frank and Beer, Meinrad}, title = {Impact of cardiac magnet resonance imaging on management of ventricular septal rupture after acute myocardial infarction}, series = {World Journal of Cardiology}, journal = {World Journal of Cardiology}, doi = {10.4330/wjc.v5.i5.151}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96562}, year = {2013}, abstract = {A 74-year-old man was admitted to the cardiac catheterization laboratory with acute myocardial infarction. After successful angioplasty and stent implantation into the right coronary artery, he developed cardiogenic shock the following day. Echocardiography showed ventricular septal rupture. Cardiac magnet resonance imaging (MRI) was performed on the critically ill patient and provided detailed information on size and localization of the ruptured septum by the use of fast MRI sequences. Moreover, the MRI revealed that the ventricular septal rupture was within the myocardial infarction area, which was substantially larger than the rupture. As the patient's condition worsened, he was intubated and had intra-aortic balloon pump implanted, and extracorporeal membrane oxygenation was initiated. During the following days, the patient's situation improved, and surgical correction of the ventricular septal defect could successfully be performed. To the best of our knowledge, this case report is the first description of postinfarction ventricular septal rupture by the use of cardiac MRI in an intensive care patient with cardiogenic shock and subsequent successful surgical repair.}, language = {en} } @article{UeceylerKahnKrameretal.2013, author = {{\"U}{\c{c}}eyler, Nurcan and Kahn, Ann-Kathrin and Kramer, Daniela and Zeller, Daniel and Casanova-Molla, Jordi and Wanner, Christoph and Weidemann, Frank and Katsarava, Zaza and Sommer, Claudia}, title = {Impaired small fiber conduction in patients with Fabry disease: a neurophysiological case-control study}, series = {BMC Neurology}, journal = {BMC Neurology}, doi = {10.1186/1471-2377-13-47}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96527}, year = {2013}, abstract = {Background Fabry disease is an inborn lysosomal storage disorder which is associated with small fiber neuropathy. We set out to investigate small fiber conduction in Fabry patients using pain-related evoked potentials (PREP). Methods In this case-control study we prospectively studied 76 consecutive Fabry patients for electrical small fiber conduction in correlation with small fiber function and morphology. Data were compared with healthy controls using non-parametric statistical tests. All patients underwent neurological examination and were investigated with pain and depression questionnaires. Small fiber function (quantitative sensory testing, QST), morphology (skin punch biopsy), and electrical conduction (PREP) were assessed and correlated. Patients were stratified for gender and disease severity as reflected by renal function. Results All Fabry patients (31 men, 45 women) had small fiber neuropathy. Men with Fabry disease showed impaired cold (p < 0.01) and warm perception (p < 0.05), while women did not differ from controls. Intraepidermal nerve fiber density (IENFD) was reduced at the lower leg (p < 0.001) and the back (p < 0.05) mainly of men with impaired renal function. When investigating A-delta fiber conduction with PREP, men but not women with Fabry disease had lower amplitudes upon stimulation at face (p < 0.01), hands (p < 0.05), and feet (p < 0.01) compared to controls. PREP amplitudes further decreased with advance in disease severity. PREP amplitudes and warm (p < 0.05) and cold detection thresholds (p < 0.01) at the feet correlated positively in male patients. Conclusion Small fiber conduction is impaired in men with Fabry disease and worsens with advanced disease severity. PREP are well-suited to measure A-delta fiber conduction.}, language = {en} } @article{EliasHeuschmannSchmittetal.2013, author = {Elias, Johannes and Heuschmann, Peter U. and Schmitt, Corinna and Eckhardt, Frithjof and Boehm, Hartmut and Maier, Sebastian and Kolb-M{\"a}urer, Annette and Riedmiller, Hubertus and M{\"u}llges, Wolfgang and Weisser, Christoph and Wunder, Christian and Frosch, Matthias and Vogel, Ulrich}, title = {Prevalence dependent calibration of a predictive model for nasal carriage of methicillin-resistant Staphylococcus aureus}, series = {BMC Infectious Diseases}, journal = {BMC Infectious Diseases}, doi = {10.1186/1471-2334-13-111}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96091}, year = {2013}, abstract = {Background Published models predicting nasal colonization with Methicillin-resistant Staphylococcus aureus among hospital admissions predominantly focus on separation of carriers from non-carriers and are frequently evaluated using measures of discrimination. In contrast, accurate estimation of carriage probability, which may inform decisions regarding treatment and infection control, is rarely assessed. Furthermore, no published models adjust for MRSA prevalence. Methods Using logistic regression, a scoring system (values from 0 to 200) predicting nasal carriage of MRSA was created using a derivation cohort of 3091 individuals admitted to a European tertiary referral center between July 2007 and March 2008. The expected positive predictive value of a rapid diagnostic test (GeneOhm, Becton \& Dickinson Co.) was modeled using non-linear regression according to score. Models were validated on a second cohort from the same hospital consisting of 2043 patients admitted between August 2008 and January 2012. Our suggested correction score for prevalence was proportional to the log-transformed odds ratio between cohorts. Calibration before and after correction, i.e. accurate classification into arbitrary strata, was assessed with the Hosmer-Lemeshow-Test. Results Treating culture as reference, the rapid diagnostic test had positive predictive values of 64.8\% and 54.0\% in derivation and internal validation corhorts with prevalences of 2.3\% and 1.7\%, respectively. In addition to low prevalence, low positive predictive values were due to high proportion (> 66\%) of mecA-negative Staphylococcus aureus among false positive results. Age, nursing home residence, admission through the medical emergency department, and ICD-10-GM admission diagnoses starting with "A" or "J" were associated with MRSA carriage and were thus included in the scoring system, which showed good calibration in predicting probability of carriage and the rapid diagnostic test's expected positive predictive value. Calibration for both probability of carriage and expected positive predictive value in the internal validation cohort was improved by applying the correction score. Conclusions Given a set of patient parameters, the presented models accurately predict a) probability of nasal carriage of MRSA and b) a rapid diagnostic test's expected positive predictive value. While the former can inform decisions regarding empiric antibiotic treatment and infection control, the latter can influence choice of screening method.}, language = {en} } @article{HaringPettingerBeaetal.2013, author = {Haring, Bernhard and Pettinger, Mary and Bea, Jennifer W. and Wactawski-Wende, Jean and Carnahan, Ryan M. and Ockene, Judith K. and Wyler von Ballmoos, Moritz and Wallace, Robert B. and Wassertheil-Smoller, Sylvia}, title = {Laxative use and incident falls, fractures and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative}, series = {BMC Geriatrics}, journal = {BMC Geriatrics}, doi = {10.1186/1471-2318-13-38}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-95960}, year = {2013}, abstract = {Background Laxatives are among the most widely used over-the-counter medications in the United States but studies examining their potential hazardous side effects are sparse. Associations between laxative use and risk for fractures and change in bone mineral density [BMD] have not previously been investigated. Methods This prospective analysis included 161,808 postmenopausal women (8907 users and 151,497 nonusers of laxatives) enrolled in the WHI Observational Study and Clinical Trials. Women were recruited from October 1, 1993, to December 31, 1998, at 40 clinical centers in the United States and were eligible if they were 50 to 79 years old and were postmenopausal at the time of enrollment. Medication inventories were obtained during in-person interviews at baseline and at the 3-year follow-up visit on everyone. Data on self-reported falls (≥2), fractures (hip and total fractures) were used. BMD was determined at baseline and year 3 at 3 of the 40 clinical centers of the WHI. Results Age-adjusted rates of hip fractures and total fractures, but not for falls were similar between laxative users and non-users regardless of duration of laxative use. The multivariate-adjusted hazard ratios for any laxative use were 1.06 (95\% confidence interval [CI], 1.03-1.10) for falls, 1.02 (95\% CI, 0.85-1.22) for hip fractures and 1.01 (95\% CI, 0.96-1.07) for total fractures. The BMD levels did not statistically differ between laxative users and nonusers at any skeletal site after 3-years intake. Conclusion These findings support a modest association between laxative use and increase in the risk of falls but not for fractures. Its use did not decrease bone mineral density levels in postmenopausal women. Maintaining physical functioning, and providing adequate treatment of comorbidities that predispose individuals for falls should be considered as first measures to avoid potential negative consequences associated with laxative use.}, language = {en} } @phdthesis{Kruempel2013, author = {Kr{\"u}mpel, Christian}, title = {Die Rolle des Multidrug Resistance Associated Protein-1 bei der Tumornekrosefaktor-α vermittelten Apoptose in Endothelzellen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-93681}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Die endotheliale Dysfunktion stellt eine der Hauptursachen f{\"u}r die Entstehung von Atherosklerose an humanen Gef{\"a}ßw{\"a}nden dar und ist somit auch wesentlich an der Entstehung von kardiovaskul{\"a}ren Erkrankungen beteiligt. Das proinflammatorische Zytokin Tumornekrosefaktor-α (TNF-α) gilt als einer der Hauptinduktoren der endothelialen Dysfunktion. Da bei der Endothelzellapoptose unter TNF-α diverse rezeptorvermittelte oxidative Prozesse innerhalb der Zelle ablaufen, sollte im Rahmen dieser Arbeit untersucht werden, inwiefern das Multidrug Resistance Associated Protein-1 (MRP-1) bei diesen oxidativen Prozessen und bei der Modulation der TNF-α-Signalkaskade involviert ist.}, subject = {Tumor-Nekrose-Faktor}, language = {de} } @phdthesis{Thomas2013, author = {Thomas, Nicolai}, title = {Einfluss der EKG-Telemetrie auf die strukturellen Abl{\"a}ufe im Herzinfarktnetz Mainfranken bei der Versorgung von Patienten mit ST-Streckenhebungsmyokardinfarkt (STEMI)}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-83769}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Beim akuten Herzinfarkt betr{\"a}gt die 30-Tages-Mortalit{\"a}t immer noch rund 50\%. Die H{\"a}lfte dieser Todesf{\"a}lle geschieht in den ersten 2 Stunden nach Symptombeginn. Zielf{\"u}hrend in der Therapie ist die schnelle Wiederer{\"o}ffnung der verschlossenen Coronararterie. Die Leitlinien der ESC (European Society of Cardiology) empfehlen die prim{\"a}re perkutane Coronarintervention (PPCI) in einem Zeitfenster von weniger als 120 bzw. 90 Minuten nach first medical contact (FMC) durchzuf{\"u}hren. Eine Optimierung der akuten Infarktversorgung erscheint vor diesem Hintergrund dringend erforderlich. Prim{\"a}re Zielgr{\"o}ße des Projekts ist die Verk{\"u}rzung der Contact-to-ballon-Zeit (C2B), also die Zeit zwischen FMC bis zur Ballondilatation. Voraussetzung f{\"u}r schnelle Reaktionszeiten und damit auch f{\"u}r schnelle C2B-Zeiten ist eine sichere und schnelle EKG-Diagnose bereits am pr{\"a}klinischen Einsatzort. Aber, Unsicherheiten bei der STEMI-Diagnostik sind gegenw{\"a}rtig. Um eine Verbesserung der STEMI-Versorgung zu gew{\"a}hrleisten, wurde im Herzinfarktnetz Mainfranken die telemetrische 12-Kanal-EKG-{\"U}bertragung im Pilotversuch eingef{\"u}hrt. In der vorliegenden Arbeit wurde mit Hilfe eines prospektiv erhobenen Patientenregisters untersucht, welchen Einfluss die Etablierung telemetrischer Verfahren in der Akutversorgung von STEMI-Patienten hat. Sowohl die strukturellen Abl{\"a}ufe im Rahmen des Herzinfarktnetzwerkes als auch der klinische Outcome der Patienten wurden untersucht und dokumentiert. Insgesamt erf{\"u}llten {\"u}ber sechs Studienquartale (vom 01.01.2009 bis 30.09.2010) hinweg 310 Patienten die Einschlusskriterien. Die Ergebnisse zeigen, dass durch eine sichere, pr{\"a}klinische EKG-Diagnose mit Hilfe telemetrischer Verfahren, die C2B-Intervalle im Studienzeitraum signifikant reduziert wurden. Auch die innerklinische Behandlung wurde merklich beschleunigt. Zusammenfassend k{\"o}nnen mit Hilfe der telemetrischen EKG-{\"U}bertragung vier wesentliche Punkte verbessert werden. 1. die sichere Diagnosestellung des STEMI; 2. der gezielte Prim{\"a}rtransport in das n{\"a}chstgelegene, geeignete Interventionszentrum; 3. das organsierte Bypassing der n{\"a}chstgelegenen Nicht-Interventionsklinik und somit die Vermeidung von Sekund{\"a}rtransporten; 4. das Bypassing der Notaufnahme und der Intensivstation der Interventionsklinik und somit die Direkt{\"u}bergabe im HKL.}, subject = {Herzinfarkt}, language = {de} } @phdthesis{Devine2013, author = {Devine, Eric}, title = {Increased removal of protein bound uremic toxins through reversible modification of the ionic strength during hemodiafiltration}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-83583}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {A large number of metabolic waste products accumulate in the blood of patients with renal failure. Since these solutes have deleterious effects on the biological functions, they are called uremic toxins and have been classified in three groups: 1) small water soluble solutes (MW < 500 Da), 2) small solutes with known protein binding (MW < 500 Da), and 3) middle molecules (500 Da < MW < 60 kDa). Protein bound uremic toxins are poorly removed by conventional hemodialysis treatments because of their high protein binding and high distribution volume. The prototypical protein bound uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are associated with the progression of chronic kidney disease, cardiovascular outcomes, and mortality of patients on maintenance hemodialysis. Furthermore, these two compounds are bound to albumin, the main plasma protein, via electrostatic and/or Van-der-Waals forces. The aim of the present thesis was to develop a dialysis strategy, based on the reversible modification of the ionic strength in the blood stream by increasing the sodium chloride (NaCl) concentration, in order to enhance the removal of protein bound substances, such as IS and pCS, with the ultimate goal to improve clinical patient outcomes. Enhancing the NaCl concentration ([NaCl]) in both human normal and uremic plasma was efficient to reduce the protein bound fraction of both IS and pCS by reducing their binding affinity to albumin. Increasing the ionic strength was feasible during modified pre-dilution hemodiafiltration (HDF) by increasing the [NaCl] in the substitution fluid. The NaCl excess was adequately removed within the hemodialyzer. This method was effective to increase the removal rate of both protein bound uremic toxins. Its ex vivo hemocompatibility, however, was limited by the osmotic shock induced by the high [NaCl] in the substituate. Therefore, modified pre-dilution HDF was further iterated by introducing a second serial cartridge, named the serial dialyzers (SDial) setup. This setting was validated for feasibility, hemocompatibility, and toxin removal efficiency. A better hemocompatibility at similar efficacy was obtained with the SDial setup compared with the modified pre-dilution HDF. Both methods were finally tested in an animal sheep model of dialysis to verify biocompatibility. Low hemolysis and no activation of both the complement and the coagulation systems were observed when increasing the [NaCl] in blood up to 0.45 and 0.60 M with the modified pre-dilution HDF and the SDial setup, respectively. In conclusion, the two dialysis methods developed to transitory enhance the ionic strength in blood demonstrated adequate biocompatibility and improved the removal of protein bound uremic toxins by decreasing their protein bound fraction. The concepts require follow-on clinical trials to assess their in vivo efficacy and their impact on long-term clinical outcomes.}, subject = {H{\"a}modiafiltration}, language = {en} } @phdthesis{Kaempf2013, author = {K{\"a}mpf, Tanja}, title = {Definition eines klinisch relevanten Morbus Fabry mit Hilfe des Biomarkers Lyso Gb3 bei Patienten mit einer alpha- Galaktosidase Mutation}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-77819}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Der Morbus Fabry ist eine sehr heterogenetische und heteroph{\"a}notypische Krankheit. Ursache der Erkrankung liegt in der Mutation des alpha- Galaktosidase Gens. Es kommt zur Akkumulation von Glykosphingolipiden. Man kann den klassischen Typ von mehreren Varianten unterscheiden. Es konnte bisher noch keine Genotyp- Ph{\"a}notyp Relation hergestellt werden. In unsere Studie wurden 124 Fabry Patienten eingeschlossen. Vier klinische Dom{\"a}nen wurden beurteilt (Herz, Nieren, Nervensystem, Fabry-Symptome). Daneben wurden genetische Analysen und Labortests (inklusive Lyso Gb3) durchgef{\"u}hrt. Die Studie besitzt einen zweiteiligen Aufbau: in die Evaluationsstudie wurden alle bisher bekannten Mutationen eingeschlossen, w{\"a}hrend die bisher unbekannten Mutationen der Validierungsstudie zugeteilt wurden. Es konnte gezeigt werden, dass mithilfe des Biomarkers Lyso Gb3 die Schwere der Erkrankung vorausgesagt werden kann (insbesondere bei Frauen) und die Diagnostik erleichtert werden kann. Eine bisher unbekannte Mutation kann jetzt viel besser eingeordnet werden, da man mithilfe des Biomarkers Lyso Gb3 zwischen atypischer und klassischer Variante unterscheiden kann und man durch den Biomarker die Krankheitskapazit{\"a}t einer Mutation beurteilen kann.}, subject = {Fabry-Krankheit}, language = {de} }