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Buning C.,Charite - Medical University of Berlin | Geissler N.,Charite - Medical University of Berlin | Prager M.,Charite - Medical University of Berlin | Sturm A.,Charite - Medical University of Berlin | And 5 more authors.
Inflammatory Bowel Diseases | Year: 2012

Background: A disturbed epithelial barrier could play a pivotal role in ulcerative colitis (UC). We performed a family-based study analyzing in vivo gastrointestinal permeability in patients with UC, their healthy relatives, spouses, and controls. Methods: In total, 89 patients with UC in remission, 35 first-degree relatives (UC-R), 24 nonrelated spouses (UC-NR), and 99 healthy controls (HC) were studied. Permeability was assessed by a sugar-drink test using sucrose (gastroduodenal permeability), lactulose/mannitol (intestinal permeability), and sucralose (colonic permeability). Data were correlated with clinical characteristics including medical treatment. Results: Increased intestinal permeability was detected significantly more often in UC patients in remission (25/89, 28.1%) compared with HC (6/99, 6.1%; P < 0.001). Similar results were obtained in UC-R (7/35, 20.0%; P = 0.01 compared with HC) regardless of sharing the same household with the patients or not. No difference was found between UC-NR (3/24, 12.5%) and HC. Notably, in UC patients increased intestinal permeability was found in 12/28 patients (42.9%) with pancolitis, 7/30 (23.3%) patients with left-sided colitis, and in 2/19 (10.5%) patients with proctitis (P = 0.04). Gastroduodenal and colonic permeability were similar in all groups. Among patients on azathioprine, increased intestinal permeability was only seen in 1/18 (5.6%) patients. In contrast, in 24/70 (34.3%) patients without azathioprine, an increased intestinal permeability was found (P = 0.005). Conclusions: An increased intestinal but not colonic permeability was found in UC patients in clinical remission that could mark a new risk factor for extensive disease location. Similar findings in healthy relatives but not spouses suggest that this barrier defect is genetically determined. (Inflamm Bowel Dis 2012) Copyright © 2012 Crohn's & Colitis Foundation of America, Inc. Source

Boschmann M.,Franz Volhard Clinical Research Center | Nussberger J.,University of Lausanne | Engeli S.,Hannover Medical School | Danser A.H.J.,Erasmus University Rotterdam | And 4 more authors.
Journal of Hypertension | Year: 2012

Objective: In animals, the direct renin inhibitor aliskiren showed extensive tissue binding in the kidney and long-lasting renal effects. Aliskiren provides prolonged blood pressure-lowering effects following treatment discontinuation in patients. Therefore, we investigated whether aliskiren attains tissue concentrations sufficient to inhibit local renin-angiotensin system (RAS) activity in patients. Methods: We included 10 hypertensive patients with abdominal adiposity in an open-label study. Following 1-2 weeks washout, patients received 2 weeks placebo, then 4 weeks aliskiren 300 mg once daily, followed by 4 weeks washout, and then 4 weeks amlodipine 5 mg once daily. Drug concentrations and RAS biomarkers were measured in interstitial fluid using microdialysis and in biopsies from abdominal subcutaneous adipose and skeletal muscle. Results: We detected aliskiren in all compartments. After 4 weeks of treatment, microdialysate aliskiren concentrations (ng/ml) were 2.4 ± 2.1 (adipose) and 7.1 ± 4.2 (skeletal muscle), similar to plasma concentrations (8.4 ± 4.4); tissue concentrations (ng/g) were 29.0 ± 16.7 (adipose) and 107.3 ± 68.6 (skeletal muscle). Eight weeks after discontinuation, aliskiren was measurable in tissue biopsies but not in plasma or in interstitial fluid. Pooled microdialysate samples from two sets of four patients suggested reduction in tissue angiotensin II with aliskiren but not with amlodipine. Conclusion: In obese hypertensive patients, aliskiren penetrates adipose and skeletal muscle tissue at levels that are apparently sufficient to reduce tissue RAS activity. Furthermore, tissue binding may contribute to aliskiren's prolonged blood pressure-lowering effect following discontinuation. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Wiesner S.,Franz Volhard Clinical Research Center | Birkenfeld A.L.,Yale University | Engeli S.,Hannover Medical School | Haufe S.,Franz Volhard Clinical Research Center | And 9 more authors.
Hormone and Metabolic Research | Year: 2010

Atrial natriuretic peptide (ANP) stimulates lipid mobilization and lipid oxidation in humans. The mechanism appears to promote lipid mobilization during exercise. We tested the hypothesis that water immersion augments exercise-induced ANP release and that the change in ANP availability is associated with increased lipid mobilization and lipid oxidation. In an open randomized and cross-over fashion we studied 17 men (age 31±3.6 years; body mass index 24±1.7kg/m2; body fat 17±6.7%) on no medication. Subjects underwent two incremental exercise tests on a bicycle ergometer. One test was conducted on land and the other test during immersion in water up to the xiphoid process. In a subset (n=7), we obtained electromyography recordings in the left leg. We monitored gas exchange, blood pressure, and heart rate. In addition, we obtained blood samples towards the end of each exercise step to determine ANP, norepinephrine, epinephrine, lactate, free fatty acids, insulin, and glucose concentrations. Heart rate, systolic blood pressure, and oxygen consumption at the anaerobic threshold and during peak exercise were similar on land and with exercise in water. The respiratory quotient was mildly reduced when subjects exercised in water. Glucose and lactate measurements were decreased whereas free fatty acid concentrations were increased with exercise in water. Water immersion attenuated epinephrine and norepinephrine and augmented ANP release during exercise. Even though water immersion blunts exercise-induced sympathoadrenal activation, lipid mobilization and lipid oxidation rate are maintained or even improved. The response may be explained by augmented ANP release. © Georg Thieme Verlag KG. Source

Tank J.,Hannover Medical School | Heusser K.,Hannover Medical School | Diedrich A.,Vanderbilt University | Hering D.,Medical University of Gdansk | And 6 more authors.
Clinical Autonomic Research | Year: 2011

Objectives Previous association studies suggested that common polymorphisms of the beta-2 adrenoreceptor gene leading to glycine for arginine substitution at position 16 or glutamic acid for glutamine substitution at position 27 affect blood pressure. We reasoned that measurements of resting sympathetic nerve traffic could increase the sensitivity of defining a gene phenotype relationship. Methods We studied 111 Caucasian subjects (70 men, 41 women) with blood pressure <140/90 mmHg. We measured electrocardiogram, beat-by-beat finger blood pressure, brachial blood pressure, and muscle sympathetic nerve activity (MSNA) using microneurography. We genotyped the functionally relevant polymorphisms of the beta-2 adrenoreceptor gene by means of allele-specific polymerase chain reaction. Results Sympathetic nerve traffic was similar regardless of genotypes. We obtained similar results when we quantified sympathetic nerve traffic as bursts/100 heart beats or as normalized burst area or when we adjusted resting sympathetic nerve traffic for gender, age, and blood pressure. The polymorphism at position 27 affects sympathetic regulation in men. Men with a Glu/Glu genotype had a significant positive correlation between blood pressure and MSNA. Interpretations While our study was not sufficiently powered to detect subtle influences of genetic variability in the beta-2 adrenoreceptor gene on resting sympathetic nerve traffic, a large effect is unlikely. However the observation that beta-2 adrenoreceptor genotype may affect coupling between resting sympathetic nerve traffic and systolic blood pressure deserves to be tested in larger populations. © Springer-Verlag 2011. Source

Bergmann M.W.,Franz Volhard Clinic | Bergmann M.W.,Franz Volhard Clinical Research Center | Haufe S.,Franz Volhard Clinical Research Center | Von Knobelsdorff-Brenkenhoff F.,Franz Volhard Clinic | And 9 more authors.
European Journal of Heart Failure | Year: 2011

Aims Low-dose epoetin-β improved neo-angiogenesis and cardiac regeneration in experimental models of ischaemic cardiomyopathy without raising haemoglobin. No clinical study has tested this approach to date. Methods and resultsWe performed a randomized, placebo-controlled, double-blind, single-centre study of 35 IU/kg body weight epoetin-β given subcutaneously once weekly for 6 months started within 3 weeks after successful percutaneous coronary intervention (PCI). Patients were included if they presented with a lesion within the proximal segment of the left anterior descending artery, the right coronary artery, or circumflex and had symptomatic heart failure. Patients with ST-segment elevation due to an acute myocardial infarct were excluded. The outcome variables were measured at baseline and at 6 months. Primary outcome measure was individual change in ejection fraction; secondary outcome was safety, change in N-terminal pro-brain natriuretic peptide, and peak VO2. Twenty-four patients completed the 6-month treatment course. No adverse event related to the treatment occurred. Low-dose epoetin-β following PCI significantly improved global ejection fraction as measured by echocardiography (EPO: ΔEF 5.2 ± 2.0, P 0.013; placebo: ΔEF 0.3 ± 1.6, P 0.851; P 0.019 for the inter-group difference) and cardiac magnetic resonance (EPO: ΔEF 3.1 ± 1.6, P 0.124; placebo: -1.9 ± 1.2, P 0.167; P 0.042 for the inter-group difference). N-terminal pro-brain natriuretic peptide levels decreased in both groups without significant inter-group differences. Peak VO2 levels increased significantly by 3.9 ± 1.1 (P< 0.05) in the EPO group, whereas in the placebo group the increase did not reach statistical significance (Δpeak VO2 3.0 ± 1.6, P ns). No significant difference regarding peak VO2 was observed between the EPO and placebo groups. Conclusions Low-dose epoetin-β treatment following PCI is safe and feasible, and has possible beneficial effects on global ejection fraction and measures of exercise capacity. Extended low-dose epoetin-β treatment warrants further mechanistic studies as well as larger clinical trials. Clinical Trial Registration Information: NCT00568542. © 2011 The Author. Source

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