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Open label trial of granulocyte apheresis suggests therapeutic efficacy in chronically active steroid refractory ulcerative colitis

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World Journal of Gastroenterology 2005年第44期11卷 7001-7006页

作者： Wolfgang Kruis Axel Dignass Elisabeth Steinhagen-Thiessen Julia Morgenstern Joachim M(o|¨)ssner Stephan Schreiber Maurizio Vecchi Alberto Malesci Max Reinshagen Robert L(o|¨)fberg Evangelisches Krankenhaus Kalk medizinische klinik für Hepatologie und Gastroenterologie medizinische klinik und poliklinik Ⅱ medizinische klinik Dep of Int Medicine IRCCS Ospedale Policlinico Istituto Clinico Humanitas Innere Medizin Karolinska Institute at the IBD unit

AIM： To study the efficacy, safety, and feasibility of a granulocyte adsorptive type apheresis system for the treatment of patients with chronically active ulcerative colitis despite standard therapy. METHODS： An open label multicenter study was carried out in 39 patients with active ulcerative colitis （CAI 6-8） despite continuous use of steroids （a minimum total dose of 400 mg prednisone within the last 4 wk）. Patients received a total of five aphereses using a granulocyte adsorptive technique （Adacolumn, Otsuka Pharmaceutical Europe, UK）. Assessments at wk 6 and during follow-up until 4 mo comprised clinical （CAI） and endoscopic （EI） activity index, histology, quality of life （IBDQ）, and laboratory tests. RESULTS： Thirty-five out of thirty-nine patients were qualified for intent-to-treat analysis. After the apheresis treatment at wk 6, 13/35 （37.1%） patients achieved clinical remission and 10/35 （28.6%） patients had endoscopic remission （CAI〈4, EI〈4）. Quality of life （IBDQ） increased significantly （24 points, P〈0.01） at wk 6. Apheresis could be performed in all but one patient. Aphereses were well tolerated, only one patient experienced anemia. CONCLUSION： In patients with steroid refractory ulcerative colitis, five aphereses with a granulocyte/ monocyte depleting filter show potential short-term efficacy. Tolerability and technical feasibility of the procedure are excellent.

关键词： Steroid Refractory colitis Ulcerative colitis Granulocyte Apheresis

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Positive predictors for gastroesophageal reflux disease and the therapeutic response to proton-pump inhibitors

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World Journal of Gastroenterology 2014年第14期20卷 4017-4024页

作者： Valentin Becker Stefan Grotz Christoph Schlag Simon Nennstiel Analena Beitz Bernhard Haller Roland M Schmid Alexander Meining Monther Bajbouj Ⅱ. medizinische klinik und poliklinik Technische Universit?t München Institut für medizinische Statistik und Epidemiologie Technische Universit?t München

AIM: To identify objective and subjective predictors for the reliable diagnosis of gastroesophageal reflux disease (GERD) and the response to proton pump inhibitor (PPI) therapy.

关键词： Gastroesophageal reflux Gastroesophageal reflux disease Non-erosive reflux disease Impedance pH measurement Follow-up Therapy Proton pump inhibitor

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速激肽对大鼠小肠上行及下行反射通路的作用(英文)

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Acta Pharmacologica Sinica 2002年第4期23卷 3-9页

作者： Andreas HAHN, Martin STORR, Hans-Dieter ALLESCHER(// medizinische klinik und poliklinik der Technischen Universitat Munchen, 81675 Munchen, Germany) ll medizinische klinik und poliklinik der Technischen Universitat München 81675 Mtnchen 德国 ll medizinische klinik und poliklinik der Technischen Universitat München 81675 Mtnchen1 德国

AIM: To examine the effect of tachykinins on the ascending reflex pathway in rat small intestine, we used different selective neurokinin (NK) receptor antagonists (RA); a) NK1-RA; GR-82334 and CP-96.345, b) NK2-RA: MEN-10.376 and L-659.877. The aim was further to investigate the effect of substance P (SP) on the ascending excitatory and descending inhibitory reflex pathway. METHODS: The whole segments of rat ileum (10 cm in length) were studied in an organ bath. Ascending contraction of circle muscle was elicited by anal electrical stimulation (3 Hz, 1ms, 20 V) and measured as change of intraluminal pressure by a perfused manometric system 2 cm and 4 cm orad of the stimulation site. RESULTS: GR-82334 and CP-96.345 (NK1-RA) caused a significant dose-related inhibition of the oral contraction at a distance of 4 cm: GR-82334 [area: -10 % ± 8 % (10 nmol/L); - 29 %±10 % (1000 nmol/L). P 10 ], CP-96.345 [area: -2 %±6 %(0.1 nmol/L);-14 %±10 %(10nmol/ L). P 1, n = 8], whereas the contractil

关键词：速激肽类神经激肽-1受体神经激肽-2受体 P物质

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Arterial thrombosis in the context of HCV-associated vascular disease can be prevented by protein C

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Cellular & Molecular Immunology 2017年第12期14卷 986-996页

作者： Philipp Blüm Joachim Pircher Monika Merkle Thomas Czermak Andrea Ribeiro Hanna Mannell Florian Krötz Alexander Hennrich Michael Spannagl Simone Köppel Erik Gaitzsch Markus Wörnle medizinische klinik und poliklinik IV InnenstadtKlinikum der Universität München80336 MünchenGermany Walter Brendel Centre of Experimental Medicine and Munich Heart Alliance Ludwig Maximilians University München80336 MünchenGermany medizinische klinik und poliklinik I Klinikum der Universität München80336 MünchenGermany abteilung für Transfusionsmedizin Zelltherapeutika und HämostaseologieKlinikum der Universität München80336 MünchenGermany

Hepatitis C virus(HCV)infection is a major problem *** is not limited to liver disease but is frequently complicated by immune-mediated extrahepatic manifestations such as glomerulonephritis or vasculitis.A fatal complication of HCV-associated vascular disease is ***:polyribocytidylic acid(poly(I:C)),a synthetic analog of viral RNA,induces a Toll-like receptor 3(TLR3)-dependent arteriolar thrombosis without significant thrombus formation in venules in *** procoagulant effects are caused by increased endothelial synthesis of tissue factor and PAI-1 without platelet *** addition to human umbilical endothelial cells(HUVEC),human mesangial cells(HMC)produce procoagulatory factors,cytokines and adhesion molecules after stimulation with poly(I:C)or HCV-containing cryoprecipitates from a patient with a HCV infection as *** protein C(APC)is able to prevent the induction of procoagulatory factors in HUVEC and HMC in vitro and blocks the effects of poly(I:C)and HCV-RNA on the expression of cytokines and adhesion molecules in HMC but not in *** vivo,protein C inhibits poly(I:C)-induced arteriolar ***,endothelial cells are de facto able to actively participate in immune-mediated vascular thrombosis caused by viral ***,we provide evidence for the ability of protein C to inhibit TLR3-mediated arteriolar thrombosis caused by HCV infection.

关键词： hepatitis C thrombosis toll-like receptor 3

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Treatment of metastatic colorectal carcinomas by systemic inhibition of vascular endothelial growth factor signaling in mice

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World Journal of Gastroenterology 2005年第28期11卷 4332-4336页

作者： Volker Schmitz Miroslaw Kornek Tobias Hilbert Christian Dzienisowicz Esbher Raskopf Christian Rabe Tilman Sauerbruch Cheng Qian Wolfgang H Caselmann medizinische klinik und poliklinik I Universitatsklinikum BonnGermany Universidad de Navarra Clinica Universitaria Pamplona Spain Bavarian State Ministry of the Environment Public Health and Consumer Protection Munich 81901 Germany

AIM： Tumor angiogenesis has been shown to be promoted by vascular endothelial growth factor （VEGF） via stimulating endothelial cell proliferation, migration, and survival. Blockade of VEGF signaling by different means has been demonstrated to result in reduced tumor growth and suppression of tumor angiogenesis in distinct tumor entities. Here, we tested a recombinant adenovirus, AdsFItl-3, that encodes an antagonistically acting fragment of the VEGF receptor 1 （Fit-l）, for systemic antitumor effects in pre-established subcutaneous CRC tumors in mice.METHODS： Murine colorectal carcinoma cells （CT26） were inoculated subcutaneously into Balb/c mice for in vivo studies. Tumor size and survival were determined. 293 cell line was used for propagation of the adenoviral vectors. Human lung cancer line A549 and human umbilical vein endothelial cells were transfected for in vitro experiments.RESULTS： Infection of tumor cells with AdsFlt1-3 resulted in protein secretion into cell supernatant, demonstrating correct vector function. As expected, the secreted sFlt1-3 protein had no direct effect on CT26 tumor cell proliferation in vitro, but endothelial cell function was inhibited by about 46% as compared to the AdLacZ control in a tube formation assay. When AdsFlt1-3 （5×10^9 PFU/animal） was applied to tumor bearing mice, we found a tumor inhibition by 72% at d 12 after treatment initiation, in spite of these antitumoral effects, the survival time was not improved. According to reduced intratumoral microvessel density in AdsFlt1-3-treated mice, the antitumor mechanism can be attributed to angiostatic vector effects. We did not detect increased systemic VEGF levels after AdsFlt1-3 treatment and liver toxicity was low as judged by serum alanine aminotransferase determination.CONCLUSION： In this study we confirmed the value of a systemic administration of AdsFItl-3 to block VEGF signaling as antitumor therapy in an experimental metastatic colorectal carcinoma model in mice.

关键词： Colorectal carcinomas Vascular endothelial growth factor Systemic inhibition

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Mandatory criteria for the application of variability-based parameters of fluid responsiveness: a prospective study in different groups of ICU patients

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2018年第7期19卷 515-524页

作者： Wolfgang HUBER Uli MAYR ANDreas UMGELTER Michael FRANZEN Wolfgang REINDL RolAND M.SCHMID Florian ECKEL Ⅱ. medizinische klinik und poliklinik Klinikum rechts der Isar der Technischen Universitat Munchen Ismaninger Straβe 22 D-81675 Miinchen Germany Universitatsklinik fur Innere Medizin I Salzburger Landeskliniken Universitatsklinikum Salzburg Mullner Hauptstraβe 48A-5020 Salzburg Austria Ⅱ. medizinische klinik Universitatsklinikum Mannheim Theodor-Kutzer-Ufer 1-3 D-68167 Mannheim Germany klinik fur Innere Medizin RoMed Klinik Bad Aibling Harthauser Straβe 16 D-83043 Bad Aibling Germany

Background and objective： Stroke volume variation（SVV） has high sensitivity and specificity in predicting fluid responsiveness. However, sinus rhythm（SR） and controlled mechanical ventilation（CV） are mandatory for their application. Several studies suggest a limited applicability of SVV in intensive care unit（ICU） patients. We hypothesized that the applicability of SVV might be different over time and within certain subgroups of ICU patients. Therefore, we analysed the prevalence of SR and CV in ICU patients during the first 24 h of Pi CCO-monitoring（primary endpoint） and during the total ICU stay. We also investigated the applicability of SVV in the subgroups of patients with sepsis, cirrhosis, and acute pancreatitis. Methods： The prevalence of SR and CV was documented immediately before 1241 thermodilution measurements in 88 patients. Results： In all measurements, SVV was applicable in about 24%. However, the applicability of SVV was time-dependent： the prevalence of both SR and CV was higher during the first 24 h compared to measurements thereafter（36.1% vs. 21.9%; P0.001）. Within different subgroups, the applicability during the first 24 h of monitoring ranged between 0% in acute pancreatitis, 25.5% in liver failure, and 48.9% in patients without pancreatitis, liver failure, pneumonia or sepsis. Conclusions： The applicability of SVV in a predominantly medical ICU is only about 25%–35%. The prevalence of both mandatory criteria decreases over time during the ICU stay. Furthermore, the applicability is particularly low in patients with acute pancreatitis and liver failure.

关键词： Hemodynamic monitoring Preload Fluid responsiveness Stroke volume variation Pulse pressure variation

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Management of occluded self-expanding biliary metal stents in malignant biliary disease

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Hepatobiliary & Pancreatic Diseases International 2018年第1期17卷 49-54页

作者： Simon Nennstiel Isolde Tschurtschenthaler Bruno Neu Hana Algül Monther Bajbouj Roland M. Schmid Stefan von Delius Andreas Weber klinik und poliklinik fur Innere Medizin Ⅱ Klinikum rechts der Isar der Technischen Universitar Manchen Ismaninger Straβe 22 Munich 81675 Germany medizinische klinik II Krankenhaus Landshut-Achdorf Academic Teaching Hospital Technische Universitar Munchen Achdorferweg 3 Landshut 84036Germany

Background: Occlusion of self-expanding metal stents(SEMS) in malignant biliary obstruction occurs in up to 40% of patients. This study aimed to compare the different techniques to resolve stent occlusion in our collective of ***: Patients with malignant biliary obstruction and occlusion of biliary metal stent at a tertiary referral endoscopic center were retrospectively identified between April 1, 1994 and May 31, 2014. The clinical records were further analyzed regarding the characteristics of patients, malignant strictures, SEMS,management strategies, stent patency, subsequent interventions, survival time and case ***: A total of 108 patients with biliary metal stent occlusion were identified. Seventy-nine of these patients were eligible for further analysis. Favored management was plastic stent insertion in 73.4% patients. Second SEMS were inserted in 12.7% patients. Percutaneous transhepatic biliary drainage and mechanical cleansing were conducted in a minority of patients. Further analysis showed no statistically significant difference in median overall secondary stent patency(88 vs. 143 days, P = 0.069), median survival time(95 vs. 192 days, P = 0.116), median subsequent intervention rate(53.4% vs. 40.0%, P = 0.501)and median case charge(€5145 vs. €3473, P = 0.803) for the treatment with a second metal stent insertion compared to plastic stent insertion. In patients with survival time of more than three months,significantly more patients treated with plastic stents needed re-interventions than patients treated with second SEMS(93.3% vs. 57.1%, P = 0.037).Conclusions: In malignant biliary strictures, both plastic and metal stent insertions are feasible strategies for the treatment of occluded SEMS. Our data suggest that in palliative biliary stenting, patients especially those with longer expected survival might benefit from second SEMS insertion. Careful patient selection is important to ensure a proper decision for either management

关键词： Self-expanding metal stents Biliary tract neoplasms Endoscopic retrograde cholangiopancreatography Biliary tract diseases Complications

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Targeting metabolic rewiring might decrease spread of tumor cells: Mitochondrial tRNA modifications promote cancer metastasis

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Signal Transduction and Targeted Therapy 2022年第11期7卷 3987-3988页

作者： Maik Luu Alexander Visekruna Lehrstuhl für Zelluläre Immuntherapie Medizinische Klinik und Poliklinik IIUniversitätsklinikum WürzburgWürzburgGermany Institute for Medical Microbiology and Hygiene Philipps-UniversityMarburgGermany

In a recent study published in Nature,Delaunay and colleagues demonstrate that tRNA modifications in mitochondria have the potential to affect the synthesis of mitochondrial proteins involved in oxidative phosphorylation(OXPHOS),which drives the invasive spread of cancer *** inhibition of one particular RNA-modifying enzyme was sufficient to prevent the cancer cell invasion and dissemination.

关键词： invasion metastasis cancer

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Reduced expression of Ca^(2+)-regulating proteins in the upper gastrointestinal tract of patients with achalasia

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World Journal of Gastroenterology 2006年第37期12卷 6002-6007页

作者： Harald Fischer Judith Fischer Peter Boknik Ulrich Gergs Wilhelm Schmitz Wolfram Domschke Jan W Konturek Joachim Neumann medizinische klinik und poliklinik B Universittsklinikum Mnster 48129 Mnster Germany Institut fr Pharmakologie und Toxikologie Universittsklinikum Mnster 48149 Mnster Germany Institut fr Pharmakologie und Toxikologie Martin-Luther-Universitt Halle-Wittenberg 06112 Halle (Saale) Germany klinik fr Innere Medizin/Gastroenterologie Elbe Klinikum Stade 21682 Stade Germany

AIM: To compare expression of Ca2+-regulating proteins in upper gastrointestinal (GI) tract of achalasia patients and healthy volunteers and to elucidate their role in achalasia. METHODS: Sarcoplasmic reticulum Ca2+ ATPase (SERCA) isoforms 2a and 2b, phospholamban (PLB), calsequestrin (CSQ), and calreticulin (CRT) were assessed by quantitative Western blotting in esophagus and heart of rats, rabbits, and humans. Furthermore, expression profi les of these proteins in biopsies of lower esophageal sphincter and esophagus from patients with achalasia and healthy volunteers were analyzed. RESULTS: SERCA 2a protein expression was much higher in human heart (cardiac ventricle) compared to esophagus. However, SERCA 2b was expressed predominantly in the esophagus. The highest CRT expression was noted in the human esophagus, while PLB, although highly expressed in the heart, was below our detection limit in upper GI tissue. Compared to healthy controls, CSQ and CRT expression in lower esophageal sphincter and distal esophageal body were signif icantly reduced in patients with achalasia (P < 0.05). CONCLUSION: PLB in the human esophagus mightbe of lesser importance for regulation of SERCA than in heart. Lower expression of Ca2+ storage proteins (CSQ and CRT) might contribute to increased lower esophageal sphincter pressure in achalasia, possibly by increasing free intracellular Ca2+.

关键词： Esophageal and gastric motility Esophagus Calsequestrin Calreticulin

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Dietary copper triggers onset of fulminant hepatitis in the Long-Evans cinnamon rat model

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World Journal of Gastroenterology 2012年第39期18卷 5542-5550页

作者： Ramsi Siaj Vanessa Sauer Sandra Stppeler Hans-Ullrich Spiegel Gabriele Khler Andree Zibert Hartmut HJ Schmidt klinik und poliklinik für Transplantationsmedizin Universittsklinikum MünsterD-48149 MünsterGermany abteilung Chirurgische Forschung Klinik und Poliklinik für Allgemein-und ViszeralchirurgieUniversittsklinikum MünsterD-48149 MünsterGermany Gerhard-Domagk-Institut für Pathologie Universittsklinikum MünsterD-48149 MünsterGermany

AIM： To investigate the impact of dietary copper given at different time points on the onset of fulminant hepatitis. METHODS： The Long-Evans cinnamon （LEC） rat mod- el of Wilson＇s disease （WD） was used to study the im- pact of high dietary copper （hCu） on the induction of fulminant hepatitis at early or late time points of life. High Cu diet was started in rat pups or in adults （month 5） for three months. Animals that received reduced di- etary copper （rCu） throughout their lifetime served as a control. Hepatitis-associated serum markers （alanine aminotransferase, aspartate transaminase, bilirubin） were analyzed in animal groups receiving hCu or rCu. Liver copper content and liver histology were revealed at sacrifice. A set of 5 marker genes previously found to be affected in injured liver and which are related to angiogenesis （Vegfa）, fat metabolism （Srebf1）, ex- tracellular matrix （Timp1）, oxidative stress （Hmox1）, and the cell cycle （Cdknla） were analyzed by real-time polymerase chain reaction. RESULTS： Regardless of the time point when hCu was started, LEC rats （35/36） developed fulminant hepati- tis and died. Animals receiving rCu （36/36） remained healthy, did not develop hepatitis, and survived long term without symptoms of overt disease, although liver copper accumulated in adult animals （477 ± 75 μg/g）. With regard to start of hCu, onset of fulminant hepatitis was significantly （P 〈 0.001） earlier in adults （35±9 d） that showed pre-accumulation of liver copper as com- pared to the pup group （77±15 d）. Hepatitis-associ- ated serum markers, liver copper and liver histology, as well as gene expression, were affected in LEC rats re- ceiving hCu. However, except for early and rapid onset of hepatitis, biochemical and molecular markers were similar at the early and late time points of disease. CONCLUSION： Rapid onset of fulminant hepatitis in asymptomatic LEC rats with elevated liver copper sug- gests that there is a critical threshold of liver copper which is imp

关键词： Wilson's disease Fulminant hepatitis Acuteliver failure Dietary copper Long-Evans cinnamon rat A TP7B

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