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Medicine Lodge, United States

Zeller T.,University of Hamburg | Zeller T.,German Center for Cardiovascular Research e.V. | Zeller T.,Ludwig Maximilians University of Munich | Haase T.,University of Hamburg | And 40 more authors.
Circulation: Cardiovascular Genetics | Year: 2015

Background-Interleukin-18 (IL-18) is a pleiotropic cytokine centrally involved in the cytokine cascade with complex immunomodulatory functions in innate and acquired immunity. Circulating IL-18 concentrations are associated with type 2 diabetes mellitus, cardiovascular events, and diverse inflammatory and autoimmune disorders. Methods and Results-To identify causal variants affecting circulating IL-18 concentrations, we applied various omics and molecular biology approaches. By genome-wide association study, we confirmed association of IL-18 levels with a single nucleotide polymorphism in the untranslated exon 2 of the inflammasome component NLRC4 (NLR family, caspase recruitment domain-containing 4) gene on chromosome 2 (rs385076; P=2.4×10-45). Subsequent molecular analyses by gene expression analysis and reporter gene assays indicated an effect of rs385076 on NLRC4 expression and differential isoform usage by modulating binding of the transcription factor PU.1. Conclusions-Our study provides evidence for the functional causality of single nucleotide polymorphism rs385076 within the NLRC4 gene in relation to IL-18 activation. © 2015 American Heart Association, Inc.

Schnabel R.B.,University of Hamburg | Wilde S.,University of Hamburg | Sinning C.R.,University of Hamburg | Ojeda F.M.,University of Hamburg | And 7 more authors.
Journal of Hypertension | Year: 2013

Objective: The relation of noninvasive vascular function to sex, sex hormones, and reproductive history in the general population is little understood. Methods: We simultaneously assessed flow-mediated dilation (FMD) and peripheral arterial tonometry in 454 women (mean age 40.4+16.1 years, age range 19-78 years) and 100 men (mean age 44.7+15.3 years) in a community-based cohort. Plasma estradiol, progesterone, luteinizing hormone, and follicle stimulating hormones were measured, and menstrual cycle and reproductive history were recorded. Results: Vascular function was blunted in men as compared to women irrespective of menopausal status and adjustment for classical cardiovascular risk factors and hormones. Vascular reactivity changed during the menstrual cycle and correlated with estradiol concentrations for FMD, r=0.13 and inversely with progesterone for pulse amplitude, r=-0.14, and brachial artery diameter, r=-0.10. Multivariable-Adjusted regressions showed a relation of estradiol with FMD, b 0.658, 95% confidence interval (CI) 0.084/1.232, P=0.025 in women. Age at menarche (b 0.070, 95% CI 0.039/0.101, P<0.0001) and breastfeeding duration (β -0.006, 95% CI -0.011/-0.001, P=0.036) were related to brachial artery diameter, age at menarche also to FMD (β -0.455, 95% CI -0.886/-0.023, P=0.039). Conclusion: Sex differences in noninvasive conduit and peripheral arterial function with better vascular reactivity in women were not fully explained by female sex hormones and menopausal status. Age at menarche and duration of breastfeeding were also related to vascular function and need further investigation. © Lippincott Williams and Wilkins.

Ardelt P.U.,University of Basel | Ardelt P.U.,Albert Ludwigs University of Freiburg | Ardelt P.U.,University of Wurzburg | Ebbing J.,University of Basel | And 8 more authors.
PLoS ONE | Year: 2015

Background To use combinatorial epitope mapping ("fingerprinting") of the antibody response to identify targets of the humoral immune response in patients with transitional cell carcinoma (TCC) of the bladder. Methods A combinatorial random peptide library was screened on the circulating pool of immunoglobulins purified from an index patient with a high risk TCC (pTa high grade plus carcinoma in situ) to identify corresponding target antigens. A patient cohort was investigated for antibody titers against ubiquitin. Results We selected, isolated, and validated an immunogenic peptide motif from ubiquitin as a dominant epitope of the humoral response. Patients with TCC had significantly higher antibody titers against ubiquitin than healthy donors (p<0.007), prostate cancer patients (p<0.0007), and all patients without TCC taken together (p<0.0001). Titers from superficial tumors were not significantly different from muscle invasive tumors (p = 0.0929). For antibody response against ubiquitin, sensitivity for detection of TCC was 0.44, specificity 0.96, positive predictive value 0.96 and negative predictive value 0.41. No significant titer changes were observed during the standard BCG induction immunotherapy. Conclusions This is the first report to demonstrate an anti-ubiquitin antibody response in patients with TCC. Although sensitivity of antibody production was low, a high specificity and positive predictive value make ubiquitin an interesting candidate for further diagnostic and possibly immune modulating studies. © 2015 Ardelt et al.

Sandrock-Lang K.,Albert Ludwigs University of Freiburg | Oldenburg J.,University of Bonn | Wiegering V.,University of Wurzburg | Halimeh S.,Coagulation Center Rhine Ruhr | And 13 more authors.
Thrombosis and Haemostasis | Year: 2015

Glanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder characterised by quantitative and/or qualitative defects of the platelet glycoprotein (GP) IIb/IIIa complex, also called integrin αIIbβ3. αIIbβ3 is well known as a platelet fibrinogen receptor and mediates platelet aggregation, firm adhesion, and spreading. This study describes the molecular genetic analyses of 19 patients with GT who were diagnosed on the basis of clinical parameters and platelet analyses. The patients’ bleeding signs include epistaxis, mucocutaneous bleeding, haematomas, petechiae, gastrointestinal bleeding, and menorrhagia. Homozygous or compound heterozygous mutations in ITGA2B or ITGB3 were identified as causing GT by sequencing of genomic DNA. All exons including exon/intron boundaries of both genes were analysed. In a patient with an intronic mutation, splicing of mRNA was analysed using reverse transcriptase (RT)-PCR of platelet-derived RNA. In short, 16 of 19 patients revealed 27 different mutations (ITGA2B: n=17, ITGB3: n=10). Seventeen of these mutations have not been published to date. Mutations in ITGA2B or ITGB3 were identified as causing GT in 16 patients. We detected a total of 27 mutations in ITGA2B and ITGB3 including 17 novel missense, nonsense, frameshift and splice site mutations. In addition, three patients revealed no molecular genetic anomalies in ITGA2B or ITGB3 that could explain the suspected diagnosis of GT. We assume that these patients may harbour defects in a regulatory element affecting the transcription of these genes, or other proteins may exist that are important for activating the αIIbβ3 complex that may be affected. © 2015 Schattauer.

Liang H.P.H.,Blood Research Institute | Liang H.P.H.,Sutton Arthritis Research Laboratory | Kerschen E.J.,Blood Research Institute | Basu S.,Blood Research Institute | And 11 more authors.
Blood | Year: 2015

The key effectormolecule of the natural proteinCpathway, activatedproteinC(aPC), exerts pleiotropic effects on coagulation, fibrinolysis, and inflammation. Coagulation-independent cell signaling by aPC appears to be the predominant mechanism underlying its highly reproducible therapeutic efficacy in most animal models of injury and infection. In this study, using a mousemodel of Staphylococcus aureus sepsis,we demonstratemarked disease stage-specific effects of the anticoagulant and cell signaling functions of aPC. aPC resistance of factor (f)V due to the R506Q Leiden mutation protected against detrimental anticoagulant effects of aPCtherapy but also abrogated the anti-inflammatory andmortalityreducing effects of the signaling-selective 5A-aPC variant that has minimal anticoagulant function.We foundthatprocofactorV(cleaved byaPCatR506)andproteinSwerenecessary cofactors for the aPC-mediated inhibition of inflammatory tissue-factor signaling. The antiinflammatory cofactor function of fV involved the same structural features that govern its cofactor function for the anticoagulant effects of aPC, yet its anti-inflammatory activities did not involve proteolysis of activated coagulation factors Va and VIIIa. These findings reveal a novel biological function and mechanism of the protein C pathway in which protein S and the aPC-cleaved form of fV are cofactors for anti-inflammatory cell signaling by aPC in the context of endotoxemia and infection. © 2015 by The American Society of Hematology.

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