University Hospital Dsseldorf

Germany

University Hospital Dsseldorf

Germany
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Westenfeld R.,University Hospital Dsseldorf | Krueger T.,RWTH Aachen | Schlieper G.,RWTH Aachen | Cranenburg E.C.M.,Maastricht University | And 8 more authors.
American Journal of Kidney Diseases | Year: 2012

Background: Vascular calcification is a predictor of cardiovascular morbidity and mortality. Hemodialysis patients experience severe vascular calcifications. Matrix Gla protein (MGP) is a central calcification inhibitor of the arterial wall; its activity depends on vitamin Kdependent γ-glutamate carboxylation. Uncarboxylated MGP, formed as a result of vitamin K deficiency, is associated with cardiovascular disease. Recent studies suggest poor vitamin K status in hemodialysis patients. We therefore aimed to investigate whether daily vitamin K supplementation improves the bioactivity of vitamin Kdependent proteins in hemodialysis patients, assessed by circulating dephosphorylated- uncarboxylated MGP, uncarboxylated osteocalcin, and uncarboxylated prothrombin (PIVKA-II [protein induced by vitamin K absence II]). Study Design: Interventional randomized nonplacebo-controlled trial with 3 parallel groups. Setting & Participants: 53 long-term hemodialysis patients in stable conditions, 18 years or older. 50 healthy age-matched individuals served as controls. Interventions: Menaquinone-7 (vitamin K 2) treatment at 45, 135, or 360 μg/d for 6 weeks. Outcomes: Plasma levels of dephosphorylated- uncarboxylated MGP, uncarboxylated osteocalcin, and PIVKA-II. Measurements: Plasma levels were assessed using enzyme-linked immunosorbent assays. Results: At baseline, hemodialysis patients had 4.5-fold higher dephosphorylated- uncarboxylated MGP and 8.4-fold higher uncarboxylated osteocalcin levels compared with controls. PIVKA-II levels were elevated in 49 hemodialysis patients. Vitamin K 2 supplementation induced a dose- and time-dependent decrease in circulating dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and PIVKA-II levels. Response rates in the reduction in dephosphorylated-uncarboxylated MGP levels were 77% and 93% in the groups receiving 135 μg and 360 μg of menaquinone-7, respectively. Limitations: Small sample size. Conclusions: This study confirms that most hemodialysis patients have a functional vitamin K deficiency. More importantly, it is the first study showing that inactive MGP levels can be decreased markedly by daily vitamin K 2 supplementation. Our study provides the rationale for intervention trials aimed at decreasing vascular calcification in hemodialysis patients by vitamin K supplementation. © 2012 National Kidney Foundation, Inc.


Neizel M.,University of Heidelberg | Neizel M.,University Hospital Dsseldorf | Korosoglou G.,University of Heidelberg | Lossnitzer D.,University of Heidelberg | And 8 more authors.
Journal of the American College of Cardiology | Year: 2010

Objectives This study evaluated the value of systolic and diastolic deformation indexes determined by strain-encoded imaging to predict persistent severe dysfunction at follow-up in patients after reperfused acute myocardial infarction (AMI) in comparison with late gadolinium enhancement (LGE). Background Animal studies suggest that regional diastolic function provides information about myocardial viability after AMI. However, data in humans are sparse. Methods Twenty-six patients underwent magnetic resonance imaging 3 ± 1 days after successfully reperfused ST-segment elevation myocardial infarction and at a follow-up of 6 months. Cine, strain-encoded, and LGE images were acquired. Peak systolic circumferential strain (Ecc) and early diastolic strain rate (Ecc/s) were calculated for each segment at baseline and at follow-up. A cutoff Ecc value of-9% was used to define severe dysfunction at follow-up. Results A total of 312 segments were analyzed; 119 segments showed abnormal baseline function. Thirty-five segments showed severe dysfunction at follow-up, which was defined as Ecc at follow-up <9%. The area under the curve for Ecc/s was 0.82 (95% confidence interval [CI]: 0.72 to 0.89), for Ecc 0.74 (95% CI: 0.64 to 0.83), and for LGE 0.85 (95% CI: 0.77 to 0.92). A comparison of receiver-operating characteristic curves demonstrates that LGE is not significantly different than Ecc/s but is significantly different than Ecc (p = 0.32 vs. p < 0.05) for prediction of severe dysfunction at follow-up. Conclusions Regional diastolic function provides similar accuracy to predict persistent severe dysfunction at follow-up to LGE and is superior to regional systolic function in patients after AMI. Diastolic deformation indexes may serve as a new parameter for assessment of viability in patients after AMI. (SENC in AMI Study; NCT00752713). © 2010 American College of Cardiology Foundation.


Hermsen D.,University Hospital Dsseldorf | Eckstein A.,University of Duisburg - Essen | Schinner S.,Heinrich Heine University Düsseldorf | Willenberg H.S.,Heinrich Heine University Düsseldorf | And 3 more authors.
Hormone and Metabolic Research | Year: 2010

Most recently, a new rapid and fully-automated TSH receptor autoantibody (TRAb) assay has been established. This assay system uses the M22 human monoclonal antibody for competing against the patient's TSH receptor autoantibodies (TRAb) to be detected. The aim of our present study was to compare the reproducibility of TRAb values based on measurements with different TSH receptor preparations in a lot-to-lot comparison. For TRAb values > 2 IU/l the relative differences ranged from 9.0 to +10.0%. The mean difference was 0.28 8%. For TRAb values around the cutoff for positivity (1.75 IU/l) a higher range of relative differences from 20 up to +15% was obtained. The overall mean of differences was 0.814%. The data clearly demonstrate that the automated TRAb assay has a high stability in regard to TSH receptor preparations. © Georg Thieme Verlag KG Stuttgart New York.


Heller C.,University Hospital Dsseldorf | Kuhn M.C.,University Hospital Dsseldorf | Mulders-Opgenoorth B.,University Hospital Dsseldorf | Schott M.,University Hospital Dsseldorf | And 3 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2011

The Wnt-signaling pathway regulates β -cell functions. It is not known how the expression of endogenous Wnt-signaling molecules is regulated in β -cells. Therefore, we investigated the effect of antidiabetic drugs and glucose on the expression of Wnt-signaling molecules in -cells. Primary islets were isolated and cultured. The expression of Wnt-signaling molecules (Wnt-4, Wnt-10b, Frizzled-4, LRP5, TCF7L2) and TNFα was analyzed by semiquantitative PCR and Western blotting. Transient transfections were carried out and proliferation assays of INS-1 β -cells performed using [3H]thymidine uptake and BrdU ELISA. Insulin secretion was quantified. A knockdown (siRNA) of Wnt-4 in β -cells was carried out. Exendin-4 significantly increased the expression of Wnt-4 in β -cells on the mRNA level (2.8-fold) and the protein level (3-fold) (P < 0.001). The effect was dose dependent, with strongest stimulation at 10 nM, and it was maintained after long-term stimulation over 4 wk. Addition of exd- (9 -39), a GLP-1 receptor antagonist, abolished the effect of exendin- 4. Treatment with glucose, insulin, or other antidiabetic drugs had no effect on the expression of any of the examined Wnt-signaling molecules. Functionally, Wnt-4 antagonized the activation of canonical Wnt-signaling in β -cells. Wnt-4 had no effect on glucosestimulated insulin secretion or insulin gene expression. Knocking down Wnt-4 decreased β -cell proliferation to 45% of controls (P < 0.05). In addition, Wnt-4 and exendin-4 treatment decreased the expression of TNFaα mRNA in primary β -cells. These data demonstrate that stimulation with exendin-4 increases the expression of Wnt-4 in β -cells. Wnt-4 modulates canonical Wnt signaling and acts as regulator of β -cell proliferation and inflammatory cytokine release. This suggests a novel mechanism through which GLP-1 can regulate β -cell proliferation. © 2011 the American Physiological Society.

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