University Hospital of Schleswig Holstein

of Schleswig Holstein, Germany

University Hospital of Schleswig Holstein

of Schleswig Holstein, Germany
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Carmona F.D.,Institute Parasitologia y Biomedicina Lopez Neyra | Mackie S.L.,University of Leeds | Martin J.-E.,Institute Parasitologia y Biomedicina Lopez Neyra | Taylor J.C.,University of Leeds | And 70 more authors.
American Journal of Human Genetics | Year: 2015

We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10-40, OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1∗04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10-43) and HLA-DQα1 47 (p = 4.02 × 10-46), 56, and 76 (both p = 1.84 × 10-45) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10-6, OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10-6, OR = 1.20), and REL (rs115674477, p = 1.10 × 10-5, OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function. © 2015 The American Society of Human Genetics.


Calderon C.,Janssen Research and Development LLC | Zucht H.-D.,Formerly of Digilab BioVisioN GmbH | Kuhn A.,The Interdisciplinary Center | Wozniacka A.,Medical University of Lódz | And 6 more authors.
Lupus | Year: 2015

Cutaneous lupus erythematosus (CLE) is an inflammatory autoimmune skin disease in which abnormal photosensitivity is an important pathogenetic factor but is difficult to predict, creating a challenge in determining treatment efficacy. Although photosensitivity in CLE patients may change over time, photoprovocation testing with ultraviolet (UV) A and UVB irradiation can be a helpful tool to explore differences between responders and nonresponders during photoprovocation. To identify biomarkers that could substitute for the clinical endpoint lesion development, we performed a global peptidomics profiling analysis of CLE subjects in a controlled photoprovocation study. Plasma and skin biopsy samples were collected before and after UV-irradiation from 13 healthy volunteers and 47 CLE subjects. Twenty-two of the 47 CLE subjects developed skin lesions. The samples were analyzed using a label-free quantitative peptidomics workflow combined with univariate and multivariate statistical analyses. The primary finding was identification of a specific plasma peptide signature separating responders versus nonresponders at baseline. The peptide signature consisted of beta 2-microglobulin (B2MG), human beta-defensin-1, and peptides derived from CD99, polymeric immunoglobulin receptor, and immunoglobulin kappa light chains. In skin, elevated B2MG levels correlated with lesion formation. Our results show that the peptidome is a rich source of potential biomarkers for predicting photosensitivity in CLE. © 2015 The Author(s).


PubMed | University Hospital of Schleswig Holstein, University of Lübeck and University Hospital Of Schleswig Holstein Electronic Address
Type: | Journal: Journal of cardiothoracic and vascular anesthesia | Year: 2017

To clarify whether reactivated cytomegalovirus (CMV) infections in critically ill patients lead to worse outcome or just identify more severely ill patients. If CMV has a pathogenic role, latently infected (CMV-seropositive) patients should have worse outcome than seronegative patients because only seropositive patients can experience a CMV reactivation.Post-hoc analysis of a prospective observational study.Single university hospital.The study comprised 983 consecutive patients scheduled for on-pump surgery.None.CMV antibodies were analyzed in preoperative plasma samples. Postoperative adverse events (reintubation, low cardiac output or reinfarction, dialysis, stroke) and 30-day and 1-year mortality were evaluated prospectively. The plasma of reintubated patients and matched control patients was tested for CMV deoxyribonucleic acid, and 618 patients were found to be seropositive for CMV (63%). Among these, the risk for reintubation was increased (10% v 4%, p = 0.001). This increase remained significant after correction for confounding factors (odds ratio 2.70, p = 0.003) and was detectable from the third postoperative day throughout the whole postoperative period. Other outcome parameters were not different. Reintubated seropositive patients were more frequently CMV deoxyribonucleic acid-positive than were matched control patients (40% v 8%, p<0.001).CMV-seropositive patients had an increased risk of reintubation after cardiac surgery, which was associated with reactivations of their CMV infections. Additional studies should determine whether this complication may be prevented by monitoring of latently infected patients and administering antiviral treatment for reactivated CMV infections.


Thill M.,University Hospital of Schleswig Holstein | Thill M.,Agaplesion Markus Hospital | Baumann K.,University Hospital of Schleswig Holstein
Breast Care | Year: 2012

Since breast-conserving surgery has become the gold standard for early breast cancer, the development of less radical or less burdensome technologies has been pressed for in order to preserve the patient from unnecessary harm through the operative procedure. Different technical approaches are under evaluation, and some of them are already being used in the clinical setting. The aim of this article is to present a perspective on future breast cancer surgery by shedding light on the current innovative and new techniques. © 2012 S. Karger GmbH, Freiburg.


Mueller L.,University Hospital of Schleswig Holstein | von Seggern L.,University of Hamburg | Schumacher J.,University Hospital of Schleswig Holstein | Goumas F.,University Hospital of Schleswig Holstein | And 3 more authors.
Biochemical and Biophysical Research Communications | Year: 2010

Cancer-associated fibroblasts (CAFs) represent the predominant cell type of the neoplastic stroma of solid tumors, yet their biology and functional specificity for cancer pathogenesis remain unclear. We show here that primary CAFs from colorectal liver metastases express several inflammatory, tumor-enhancing factors, including interleukin (IL)-6 and monocyte-chemoattractant protein (MCP)-1. Both molecules were intensely induced by TNF-α on the transcript and protein level, whereas PDGF-BB, TGF-β1 and EGF showed no significant effects. To verify their potential specialization for metastasis progression, CAFs were compared to fibroblasts from non-tumor liver tissue. Interestingly, these liver fibroblasts (LFs) displayed similar functions. Further analyses revealed a comparable up-regulation of intercellular adhesion molecule-1 (ICAM-1) by TNF-α, and of alpha-smooth muscle actin, by TGF-β1. Moreover, the proliferation of both cell types was induced by PDGF-BB, and CAFs and LFs displayed an equivalent migration towards HT29 colon cancer cells in Boyden chamber assays. In conclusion, colorectal liver metastasis may be supported by CAFs and resident fibroblastic cells competent to generate a prometastatic microenvironment through inflammatory activation of IL-6 and MCP-1. © 2010 Elsevier Inc.


Krieger D.,Justus Liebig University | Moericke A.,University of Kiel | Oschlies I.,University Hospital of Schleswig Holstein | Zimmermann M.,Justus Liebig University | And 4 more authors.
Haematologica | Year: 2010

Although deletions of cell cycle regulatory gene loci have long been reported in various malignancies, little is known regarding their relevance in pediatric T-cell lymphoblastic lymphoma (T-LBL) and T-cell lymphoblastic leukemia (TALL). The current study focused on loss of heterozygosity (LOH) analyses of the CDKN2A/B (chromosome 9p), ATM (chromosome 11q) and p53 (chromosome 17p) gene loci. Frequencies of LOH were compared in 113 pediatric T-LBL and 125 T-ALL who were treated uniformly according to ALL-BFM strategies. Furthermore, LOH findings were correlated with clinical characteristics and tested for their prognostic relevance. LOH at 9p was detected in 47% of T-LBL and 51% of T-ALL, and was associated with male gender in both. In T-ALL, LOH at 9p was associated with favorable initial treatment response. A tendency for favorable eventfree-survival was observed in LOH 9p positive T-LBL. The frequency of LOH at chromosomes 11q and 17p was 5% or less for both diseases. ©2010 Ferrata Storti Foundation.


Csernok E.,University Hospital of Schleswig Holstein | Moosig F.,University Hospital of Schleswig Holstein
Nature Reviews Rheumatology | Year: 2014

Detection of antineutrophil cytoplasmic antibodies (ANCAs) is a well-established diagnostic test used to evaluate suspected necrotizing vasculitis of small blood vessels. Conditions associated with these antibodies, collectively referred to as ANCA-associated vasculitides, include granulomatosis with polyangiitis (formerly known as Wegener granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome). The diagnostic utility of ANCA testing depends on the type of assay performed and on the clinical setting. Most laboratories worldwide use standard indirect immunofluorescence tests (IFT) to screen for ANCA and then confirm positive IFT results with antigen-specific tests for proteinase 3 (PR3) and myeloperoxidase (MPO). Developments such as automated image analysis of immunofluorescence patterns, so-called third-generation PR3-ANCA and MPO-ANCA ELISA, and multiplex technology have improved the detection of ANCAs. However, challenges in routine clinical practice remain, including methodological aspects of IFT performance, the diverse antigen-specific assays available, the diagnostic value of testing in clinical settings and the prognostic value of serial ANCA monitoring in the prediction of disease relapse. This Review summarizes the available data on ANCA testing, discusses the usefulness of the various ANCA assays and advises on the clinical indications for the use of ANCA testing. © 2014 Macmillan Publishers Limited.


PubMed | Karolinska Institutet, Protagen, Janssen Research & Development LLC, Medical University of Lódz and 3 more.
Type: Clinical Trial | Journal: Lupus | Year: 2015

Cutaneous lupus erythematosus (CLE) is an inflammatory autoimmune skin disease in which abnormal photosensitivity is an important pathogenetic factor but is difficult to predict, creating a challenge in determining treatment efficacy. Although photosensitivity in CLE patients may change over time, photoprovocation testing with ultraviolet (UV) A and UVB irradiation can be a helpful tool to explore differences between responders and nonresponders during photoprovocation. To identify biomarkers that could substitute for the clinical endpoint lesion development, we performed a global peptidomics profiling analysis of CLE subjects in a controlled photoprovocation study. Plasma and skin biopsy samples were collected before and after UV-irradiation from 13 healthy volunteers and 47 CLE subjects. Twenty-two of the 47 CLE subjects developed skin lesions. The samples were analyzed using a label-free quantitative peptidomics workflow combined with univariate and multivariate statistical analyses. The primary finding was identification of a specific plasma peptide signature separating responders versus nonresponders at baseline. The peptide signature consisted of beta 2-microglobulin (B2MG), human beta-defensin-1, and peptides derived from CD99, polymeric immunoglobulin receptor, and immunoglobulin kappa light chains. In skin, elevated B2MG levels correlated with lesion formation. Our results show that the peptidome is a rich source of potential biomarkers for predicting photosensitivity in CLE.


PubMed | University Hospital of Schleswig Holstein
Type: Journal Article | Journal: Biochemical and biophysical research communications | Year: 2010

Cancer-associated fibroblasts (CAFs) represent the predominant cell type of the neoplastic stroma of solid tumors, yet their biology and functional specificity for cancer pathogenesis remain unclear. We show here that primary CAFs from colorectal liver metastases express several inflammatory, tumor-enhancing factors, including interleukin (IL)-6 and monocyte-chemoattractant protein (MCP)-1. Both molecules were intensely induced by TNF-alpha on the transcript and protein level, whereas PDGF-BB, TGF-beta1 and EGF showed no significant effects. To verify their potential specialization for metastasis progression, CAFs were compared to fibroblasts from non-tumor liver tissue. Interestingly, these liver fibroblasts (LFs) displayed similar functions. Further analyses revealed a comparable up-regulation of intercellular adhesion molecule-1 (ICAM-1) by TNF-alpha, and of alpha-smooth muscle actin, by TGF-beta1. Moreover, the proliferation of both cell types was induced by PDGF-BB, and CAFs and LFs displayed an equivalent migration towards HT29 colon cancer cells in Boyden chamber assays. In conclusion, colorectal liver metastasis may be supported by CAFs and resident fibroblastic cells competent to generate a prometastatic microenvironment through inflammatory activation of IL-6 and MCP-1.


PubMed | University Hospital of Schleswig Holstein
Type: Clinical Trial | Journal: British journal of anaesthesia | Year: 2012

Arterial pressure (AP) monitoring should be accurate, easy to use, free of risks, and ideally continuous. The continuous non-invasive arterial pressure (CNAP) device is non-invasive and provides continuous pressure readings. This study was performed to compare the agreement of CNAP and invasive AP monitoring.Ninety patients undergoing surgery under general anaesthesia were enrolled. Invasive pressure monitoring was established at the radial artery. CNAP monitoring using a finger sensor recording was begun before induction of anaesthesia. Statistical analysis was conducted with the Bland-Altman method for comparisons of repeated measures.We obtained 16 843 valid pressure readings from 85 patients. Mean (sd) bias during maintenance of anaesthesia was: systolic AP: 4.2 (16.5) mm Hg; mean AP (MAP): -4.3 (10.4) mm Hg; and diastolic AP: -5.8 (6) mm Hg. The results of a subgroup analysis of patients who had a mean intra-arterial pressure of <70 mm Hg were as follows: systolic pressure: -0.3 (9.7) mm Hg; mean pressure: -6.8 (7.6) mm Hg; and diastolic pressure: -7.9 (7.2) mm Hg. Bias and percentage error during the induction period were greater in both the main and subgroup analyses, probably due to recalibration being omitted after induction.The CNAP monitor showed an acceptable agreement and was interchangeable with invasive pressure monitoring for MAP during normotensive conditions. During induction of anaesthesia and when the AP was low, the agreement was less good and interchangeability was not achieved. These results suggest that CNAP is not statistically equivalent to invasive monitoring during all periods of anaesthesia but may be a useful additional AP monitor.

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