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Frankfurt am Main, Germany

Neugebauer E.A.M.,Witten/Herdecke University | Becker M.,Witten/Herdecke University | Buess G.F.,University Hospital of Tuebingen | Cuschieri A.,University of Dundee | And 10 more authors.
Surgical Endoscopy and Other Interventional Techniques

Background Under the mandate of the European Association for Endoscopic Surgery (EAES) a guideline on methodology of innovation management in endoscopic surgery has been developed. The primary focus of this guideline is patient safety, efficacy, and effectiveness. Methods An international expert panel was invited to develop recommendations for the assessment and introduction of surgical innovations. A consensus development conference (CDC) took place in May2009 using the method of a nominal group process (NGP). The recommendations were presented at the annual EAES congress in Prague, Czech Republic, on June 18th, 2009 for discussion and further input. After further Delphi processes between the experts, the final recommendations were agreed upon. Results The development and implementation of innovations in surgery are addressed in five sections: (1) definition of an innovation, (2) preclinical and (3) clinical scientific development, (4) scientific approval, and (5) implementation along with monitoring. Within the present guideline each of the sections and several steps are defined, and several recommendations based on available evidence have been agreed within each category. A comprehensive workflow of the different steps is given in an algorithm. In addition, issues of health technology assessment (HTA) serving to estimate efficiency followed by ethical directives are given. Conclusions Innovations into clinical practice should be introduced with the highest possible grade of safety for the patient (nil nocere: do no harm). The recommendations cancontribute to the attainment of this objective without preventing future promising diagnostic and therapeutic innovations in the field of surgery and allied techniques. © Springer Science+Business Media, LLC 2010. Source

Meier F.M.P.,Justus Liebig University | Frommer K.W.,Justus Liebig University | Peters M.A.,Justus Liebig University | Brentano F.,University of Zurich | And 8 more authors.
Journal of Biological Chemistry

Adipokines such as adiponectin and visfatin/pre-B-cell colony- enhancing factor (PBEF) have been recently shown to contribute to synovial inflammation in rheumatoid arthritis (RA). In this study, we evaluated the pathophysiological implication of visfatin/PBEF in the molecular patterns of RA synovial tissue, focusing on RA synovial fibroblasts (RASFs), key players in RA synovium. Expression of visfatin/PBEF in synovial fluid and tissue of RA patients was detected by immunoassays and immunohistochemistry. RASFs were stimulated with different concentrations of visfatin/PBEF over varying time intervals, and changes in gene expression were evaluated at the RNA and protein levels using Affymetrix array, real-time PCR, and immunoassays. The signaling pathways involved were identified. The influence of visfatin/PBEF on fibroblast motility and migration was analyzed. In RA synovium, visfatin/PBEF was predominantly expressed in the lining layer, lymphoid aggregates, and interstitial vessels. In RASFs, visfatin/PBEF induced high amounts of chemokines such as IL-8 and MCP-1, proinflammatory cytokines such as IL-6, and matrix metalloproteinases such as MMP-3. Phosphorylation of p38 MAPK was observed after visfatin/PBEF stimulation, and inhibition of p38MAPKshowed strong reduction of visfatin-induced effects. Directed as well as general fibroblast motility was increased by visfatin/PBEF-induced factors. The results of this study indicate that visfatin/ PBEF is involved in synovial fibroblast activation by triggering fibroblast motility and promoting cytokine synthesis at central sites in RA synovium. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Published. Source

Reuter K.C.,Goethe University Frankfurt | Loitsch S.M.,Goethe University Frankfurt | Dignass A.U.,Markus Hospital | Steinhilber D.,Goethe University Frankfurt | Stein J.,Goethe University Frankfurt

Introduction: Despite the excellent anti-inflammatory and immunosuppressive action of glucocorticoids (GCs), their use for the treatment of inflammatory bowel disease (IBD) still carries significant risks in terms of frequently occurring severe side effects, such as the impairment of intestinal tissue repair. The recently-introduced selective glucocorticoid receptor (GR) agonists (SEGRAs) offer anti-inflammatory action comparable to that of common GCs, but with a reduced side effect profile. Methods: The in vitro effects of the non-steroidal SEGRAs Compound A (CpdA) and ZK216348, were investigated in intestinal epithelial cells and compared to those of Dexamethasone (Dex). GR translocation was shown by immunfluorescence and Western blot analysis. Trans-repressive effects were studied by means of NF-κB/p65 activity and IL-8 levels, trans-activation potency by reporter gene assay. Flow cytometry was used to assess apoptosis of cells exposed to SEGRAs. The effects on IEC-6 and HaCaT cell restitution were determined using an in vitro wound healing model, cell proliferation by BrdU assay. In addition, influences on the TGF-β- or EGF/ERK1/2/MAPK-pathway were evaluated by reporter gene assay, Western blot and qPCR analysis. Results: Dex, CpdA and ZK216348 were found to be functional GR agonists. In terms of trans-repression, CpdA and ZK216348 effectively inhibited NF-κB activity and IL-8 secretion, but showed less trans-activation potency. Furthermore, unlike SEGRAs, Dex caused a dose-dependent inhibition of cell restitution with no effect on cell proliferation. These differences in epithelial restitution were TGF-β-independent but Dex inhibited the EGF/ERK1/2/MAPK-pathway important for intestinal epithelial wound healing by induction of MKP-1 and Annexin-1 which was not affected by CpdA or ZK216348. Conclusion: Collectively, our results indicate that, while their anti-inflammatory activity is comparable to Dex, SEGRAs show fewer side effects with respect to wound healing. The fact that SEGRAs did not have a similar effect on cell restitution might be due to a different modulation of EGF/ERK1/2 MAPK signalling. © 2012 Reuter et al. Source

Hoffmann P.,Kliniken Essen Mitte | Sturm A.,Charite Medical School Campus Virchow Clinic | Stein J.,Elisabethen Hospital | Dignass A.U.,Markus Hospital
Regulatory Peptides

Introduction: Interferon γ (IFN γ) has been originally identified by its anti-viral activity and has been demonstrated to act as potent modulator of the immune system with a range of target cells limited largely to immune cell populations. Although IFN γ has been shown to directly affect the barrier function of intestinal epithelial cells, only limited information is available about other functional effects of IFN γ on intestinal epithelial cells. Methods: The effects on intestinal epithelial cell migration were studied using a previously described in-vitro model of epithelial restitution in confluent IEC-6 cell monolayers. Intestinal epithelial cell proliferation rates were assessed in various human and rat intestinal and colon epithelial cell lines using colorimetric MTT assays. Apoptosis of IEC-6 cells exposed to IFN γ was assessed by flow cytometry. In addition, transforming growth factor β mRNA expression after IFN γ treatment of IEC-6 cells was assessed by Northern blot analysis. Results: IFN γ significantly stimulated intestinal epithelial cell migration in an in-vitro wounding model. Furthermore, IFN γ caused a significant dose-dependent inhibition of epithelial cell proliferation in non-transformed small intestinal IEC-6 cells and human colon cancer-derived HT-29 cells and no significant rates of apoptosis were detected in the exposed epithelial cells. The effect of IFN γ on epithelial cell migration and proliferation could be completely blocked by neutralizing antibodies against TGF γ indicating that these effects are mediated through a TGFβ dependent pathway. In addition, increased expression of TGF γ1 mRNA by IEC-6 cells after treatment with IFN γ supports the hypothesis that IFN γ modulates intestinal epithelial cell function through a TGF γ-dependent pathway. Conclusion: These studies suggest that IFN γ produced by constituents of the mucosal immune system modulates epithelial cell functions with relevance for intestinal wound healing and may play a role in preserving the integrity of the intestinal epithelium following various forms of injuries. © 2011 Elsevier B.V. Source

Hatzinger M.,Markus Hospital
AMHA - Acta Medico-Historica Adriatica

The early and unexpected death of Wolfgang Amadeus Mozart (Salzburg, 1756 - Vienna, 1791) was a mystery from the very first day and the subject of wildest speculations and adventurous assertions. Over the last 100 years, medical science has investigated the physical sufferings and the mysterious death of Mozart with increasing intensity. The aim of this article was to recreate Mozart's pathography relying on the his correspondence with father Leopold and sister Nannerl and on reports from his physicians and contemporaries. The rumour that Mozart was poisoned followed shortly after his death on 5 December 1791, at the age of 35, and has survived to this day. The alleged culprits were his physician van Swieten, Mozart's freemasons lodge, and the Imperial Chapel Master Salieri. Mozart however died of chronic kidney disease and ultimately of uraemia. If kidney damage reaches a critical point, even a minimum additional stress can lead to its failure. This usually occurs in the fourth decade of life. Next time we listen to Mozart, we should remember that this apparently happy person was actually a precocious boy, ripped of his childhood, whose short life was an endless chain of complaints, fatigue, misery, concern, and malady. Source

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