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ABSTRACT: BACKGROUND: Endoscopic ultrasound (EUS) is considered a gold standard in the initial staging of esophageal cancer. There is an ongoing debate whether EUS is useful for tumor staging after neoadjuvant chemotherapy (NAC). METHODS: Ninety-five patients with esophageal cancer were retrospectively analyzed. In 45 patients, EUS was performed prior to and after NAC, while 50 patients had no induction therapy. Histological correlation through surgery was available. uT/uN classifications were compared to pT/pN stages. Statistical analysis included calculation of sensitivity, specificity, and accuracy rates. Agreement between endosonography and T staging was assessed with Cohen's kappa statistics. RESULTS: For those patients with prior NAC, overall accuracy of yuT and yuN classification was 29 and 62%, respectively. Sensitivity, specificity, and accuracy rates for local tumor extension after NAC were as follows (%): T1: -/97/84, T2: 13/76/53, T3:86/29/46, T4:20/100/91, T1/2: 27/83/56, T3/4: 89/31/56. Cohen's kappa indicated poor agreement (kappa = 0.129) between yuT classification and ypT stage. Relative to positive lymph node detection, sensitivity and specificity were 100 and 6%, respectively (kappa = 0.06). T stage was overstaged in 23 (51%) and understaged in seven (16%) patients. CONCLUSION: EUS is an unreliable tool for staging esophageal cancer after NAC. Overstaging of the T stage is common after NAC.
Journal of Gastrointestinal Surgery 04/2013; · 2.83 Impact Factor
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ABSTRACT: To report the largest patient cohort study investigating the diagnostic yield of intraductal ultrasound (IDUS) in indeterminate strictures of the common bile duct.
A patient cohort with bile duct strictures of unknown etiology was examined by IDUS. Sensitivity, specificity and accuracy rates of IDUS were calculated relating to the definite diagnoses proved by histopathology or long-term follow-up in those patients who did not undergo surgery. Analysis of the endosonographic report allowed drawing conclusions with respect to the T and N staging in 147 patients. IDUS staging was compared to the postoperative histopathological staging data allowing calculation of sensitivity, specificity and accuracy rates for T and N stages. The endoscopic retrograde cholangio-pancreatography and IDUS procedures were performed under fluoroscopic guidance using a side-viewing duodenoscope (Olympus TJF 160, Olympus, Ltd., Tokyo, Japan). All procedures were performed under conscious sedation (propofol combined with pethidine) according to the German guidelines. For IDUS, a 6 F or 8 F ultrasound miniprobe was employed with a radial scanner of 15-20 MHz at the tip of the probe (Aloka Co., Tokyo, Japan).
A total of 397 patients (210 males, 187 females, mean age 61.43 ± 13 years) with indeterminate bile duct strictures were included. Two hundred and sixty-four patients were referred to the department of surgery for operative exploration, thus surgical histopathological correlation was available for those patients. Out of 264 patients, 174 had malignant disease proven by surgery, in 90 patients benign disease was found. In these patients decision for surgical exploration was made due to suspicion for malignant disease in multimodal diagnostics (computed tomography scan, endoscopic ultrasound or magnetic resonance imaging). Twenty benign bile duct strictures were misclassified by IDUS as malignant while 14 patients with malignant strictures were initially misdiagnosed by IDUS as benign resulting in sensitivity, specificity and accuracy rates of 93.2%, 89.5% and 91.4%, respectively. In the subgroup analysis of malignancy prediction, IDUS showed best performance in cholangiocellular carcinoma as underlying disease (sensitivity rate, 97.6%) followed by pancreatic carcinoma (93.8%), gallbladder cancer (88.9%) and ampullary cancer (80.8%). A total of 133 patients were not surgically explored. 32 patients had palliative therapy due to extended tumor disease in IDUS and other imaging modalities. Ninety-five patients had benign diagnosis by IDUS, forceps biopsy and radiographic imaging and were followed by a surveillance protocol with a follow-up of at least 12 mo; the mean follow-up was 39.7 mo. Tumor localization within the common bile duct did not have a significant influence on prediction of malignancy by IDUS. The accuracy rate for discriminating early T stage tumors (T1) was 84% while for T2 and T3 malignancies the accuracy rates were 73% and 71%, respectively. Relating to N0 and N1 staging, IDUS procedure achieved accuracy rates of 69% for N0 and N1, respectively.
Pre-test likelihood of 52% may not rule out bias and over-interpretation due to the clinical scenario or other prior performed imaging tests.
IDUS shows good results for accurate diagnostics of bile duct strictures of uncertain etiology thus allowing for adequate further clinical management.
World Journal of Gastroenterology 02/2013; 19(6):874-81. · 2.47 Impact Factor
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ABSTRACT: BACKGROUND: Despite recent advances in imaging techniques, adequate classification of esophageal lesions is still challenging. Accurate staging of tumors of the esophagus is a precondition for targeted therapy. In this retrospective, multicenter study, we report the role of high-frequency endoscopic ultrasound (EUS) catheter probes in pretherapeutic staging of esophageal neoplasms and thus guiding treatment decisions. METHODS: A total of 143 patients (mean age of 63.8 ± 10.7 years) with esophageal carcinoma were recruited from five German centers (Münster, Oldenburg, Hannover, Wiesbaden, and Lüneburg). Tumor type was adenocarcinoma in 112 (78 %) cases and squamous cell carcinoma in 31 (22 %). Tumor localization was as follows: proximal 3, mid esophagus 7, and distal third 133. Histological correlation either through EMR or surgery was available. In all patients, pretherapeutic uT and uN classifications were compared to pT/pN classification obtained from surgically (esophagectomy, n = 93) or endoscopically (EMR, n = 50) resected tissue. RESULTS: Overall, accuracy of uT classification was 60 % and of uN classification was 74 %. Sensitivity, specificity, and accuracy rates for local tumor extension were as follows (%): T1: 68/97/83; T2: 39/84/75; T3: 72/81/79; T4: 13/97/93; T1/2: 73/81/75; T3/4: 78/82/81. Relating to positive lymph node detection, sensitivity and specificity were 76 and 71 %, respectively. CONCLUSIONS: Miniprobe EUS is an established method for the staging of esophageal tumors. Our large multicenter cohort shows a solid accuracy of miniprobe EUS with respect to differentiating locally advanced from limited cancer and assisting to determine the treatment regimen in the era of neoadjuvant therapy; consequently, 78 % of patients would have been assigned to the adequate therapeutic regimen, whereas 11 % of patients would have been overtreated and 11 % undertreated.
Surgical Endoscopy 02/2013; · 4.01 Impact Factor
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ABSTRACT: Abstract Background. Although endoscopic ultrasound (EUS) has improved the diagnostic of potential malignancies, gastric lesions with suspicion of gastrointestinal stromal tumors (GIST) or benign lesions like lipoma or leiomyoma can often not be accurately differentiated by EUS, therefore, requiring tissue sampling with the risk of bleeding complications especially in GIST. As with the newest generation of EUS machines, contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) has become a new option to determine perfusion characteristics. The aim of this analysis was to evaluate whether CEH-EUS may help to discriminate various submucosal lesions. Methods. Data sets of 17 patients with suspicious gastric or esophageal lesions, who were investigated with CEH-EUS were analyzed. Perfusion characteristics were classified by the investigator immediately and statistically analyzed after investigation. Samples from EUS-fine needle aspirates, biopsy samples after needle cut or surgical specimen served as gold standard. Results. CEH-EUS showed nine lesions with reduced contrast enhancement (maximum intensity 6.2 ± 1.9 db) and eight lesions with hyperenhancement (47.3 ± 11.6 db). The latter eight lesions were all histologically identified as GIST, while the nine hypoenhanced lesions emerged to be four lipoma and five leiomyoma. Statistical analysis corresponded with initial perfusion classification in all cases. Conclusion. This is the first study showing that CEH-EUS can discriminate GIST from benign lesions with good accuracy. In the future, CEH-EUS-guided discrimination may lead to individualized diagnostic and therapeutic strategies in handling submucosal lesions.
Scandinavian journal of gastroenterology 11/2012; · 2.08 Impact Factor
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ABSTRACT: Leukocyte infiltration, up-regulation of proinflammatory cytokines and severe oxidative stress caused by increased amounts of reactive oxygen species are characteristics of inflammatory bowel disease. The catechin (2R,3R)-2-(3,4,5-Trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol-3-(3,4,5-trihydroxybenzoate), named epigallocatechin-3-gallate, EGCG, has been demonstrated to exert anti-inflammatory and antioxidative properties, reducing reactive oxygen species in the inflamed tissues. The aim of this study was to evaluate the therapeutic effects of EGCG in a murine model of colitis induced by oral administration of dextran sodium sulfate.
Mice received a daily oral administration of 6.9 mg/kg body weight EGCG or Piper nigrum (L.) alkaloid (2E,4E)-5-(1,3-benzodioxol-5-yl)-1-piperidin-1-ylpenta-2,4-dien-1-one, named piperine (2.9 mg/kg body weight) or the combination of the both - piperine was used in this combination to enhance the bioavailability of EGCG.
In vivo data revealed the combination of EGCG and piperine to significantly reduce the loss of body weight, improve the clinical course and increase overall survival in comparison to untreated groups. The attenuated colitis was associated with less histological damages to the colon and reduction of tissue concentrations of malondialdehyde, the final product of lipid peroxidation. Neutrophils accumulation indicator myeloperoxidase was found to be reduced in colon tissue, while antioxidant enzymes like superoxide dismutase and glutathione peroxidase showed an increased activity. In vitro, the treatment with EGCG plus piperine enhanced the expression of SOD as well as GPO and also reduced the production of proinflammatory cytokines.
These data support the concept of anti-inflammatory properties of EGCG being generally beneficial in the DSS-model of colitis, an effect that may be mediated by its strong antioxidative potential.
Journal of Crohn s and Colitis 03/2012; 6(2):226-35. · 2.57 Impact Factor
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Frank Lenze,
Johannes Wessling,
Janbernd Bremer,
Hansjoerg Ullerich,
Tillmann Spieker,
Matthias Weckesser,
Sarid Gonschorrek,
Klaus Kannengieβer,
Emile Rijcken,
Jan Heidemann,
Andreas Luegering,
Otmar Schober,
Wolfram Domschke, Torsten Kucharzik,
Christian Maaser
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ABSTRACT: BACKGROUND: Differentiation between inflammatory and fibromatous strictures in Crohn's disease (CD) is difficult but crucial for therapeutic decisions. The aim of this study was to assess the best noninvasive imaging method for the detection and differentiation of inflammatory and fibromatous stenoses in CD in comparison to endoscopic and histologic evaluation. METHODS: Patients with suspected CD strictures were included. According to a formalized endoscopic and histologic protocol, strictures were classified as inflammatory, mixed, and fibrostenotic. Strictures were further analyzed using fluorine 18-labeled fluoro-2-deoxy-D-glucose ((18) FDG) / positron emission tomography (PET) low-dose computed tomography (CT), magnetic resonance (MR) enteroclysis and transabdominal ultrasound using standardized scoring systems. RESULTS: Thirty patients with 37 strictures were evaluated (inflamed n = 22; mixed n = 12, fibromatous n = 3). (18) FDG-PET/CT detected 81%, MR-enteroclysis 81%, and ultrasound 68% of the strictures. Correct differentiation rates of strictures were 57% for MRE, 53% for (18) FDG-PET/CT, and 40% for ultrasound. Differences of detection rates and differentiation rates were not statistically significant. When combining transabdominal ultrasound with (18) FDG-PET/CT or MR-enteroclysis all strictures that required invasive treatment were detected. CONCLUSIONS: Detection rates of the strictures were not significantly different between (18) FDG-PET/CT, MR-enteroclysis, and ultrasound. Despite good stricture detection rates relating to our gold standard, (18) FDG-PET/CT nor MR-enteroclysis nor ultrasound can accurately differentiate inflamed from fibrotic strictures. A combination of MR-enteroclysis and ultrasound as well as a combination of (18) FDG-PET/CT and ultrasound resulted in a 100% detection rate of strictures requiring surgery or endoscopic dilation therapy, suggesting the combination of these methods as an alternative to endoscopy at least in the group of patients not able to perform an adequate bowel preparation. (Inflamm Bowel Dis 2012;).
Inflammatory Bowel Diseases 02/2012; · 4.86 Impact Factor
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Dominik Bettenworth,
Marion Buyse,
Markus Böhm,
Rudolf Mennigen,
Isabel Czorniak,
Klaus Kannengiesser,
Thomas Brzoska,
Thomas A Luger, Torsten Kucharzik,
Wolfram Domschke,
Christian Maaser,
Andreas Lügering
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ABSTRACT: Treatment options for inflammatory bowel disease (IBD) are incompletely helpful, and surgery is often needed. One promising class of future therapeutic agents for IBD is melanocortin-related peptides, which exhibit potent immunomodulatory effects. We investigated KdPT, a tripeptide derivative of the C-terminus of α-melanocyte-stimulating hormone, as an anti-inflammatory small molecule in vivo and in vitro. Intestinal inflammation was studied after oral administration of dextran sodium sulfate and in IL-10 gene-deficient mice. The effects of KdPT on key colonic epithelial cell functions were studied in vitro and in vivo by evaluating proliferation, wound healing, transepithelial resistance, and expression of tight junction proteins. Melanin assays were performed to determine the melanotropic effects of KdPT. KdPT-treated animals showed markedly reduced severity of inflammation in both colitis models. In colonic epithelial cells, KdPT increased proliferation, accelerated closure of wounds, and improved transepithelial electrical resistance after stimulation with interferon-γ/tumor necrosis factor-α. Moreover, treatment with KdPT also prevented the loss of tight junction protein expression and improved barrier function in vivo. KdPT acted independently of IL-1 receptor type I in vivo and did not affect melanogenesis in vitro. KdPT is capable of attenuating the course of experimental colitis in different models and maintains epithelial cell function. Furthermore, KdPT does not induce pigmentation, emphasizing the potential of this small molecule for the future treatment of IBD.
American Journal Of Pathology 09/2011; 179(3):1230-42. · 4.89 Impact Factor
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Journal of Digestive Diseases 08/2011; 12(4):308-11. · 1.59 Impact Factor
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ABSTRACT: With immunosuppressive therapy of inflammatory bowel diseases (IBDs) becoming more aggressive, the risk of serious infections is increasing. Guidelines are currently being modified in respect to advisable immunizations. The aim of this study was to evaluate the immunization habits of IBD patients in daily practice before the implementation of specific guidelines.
Hundred and two consecutive patients attending the outpatients IBD clinic at our hospital were interviewed regarding their immunization record. In addition, hepatitis B and C, HIV, and cytomegalovirus (CMV) serostatus were measured following a European Crohn's and Colitis Organization (ECCO) consensus.
Hundred and two patients with IBD have been included; of these 72% were taking steroids, 46% azathioprine, and 23% anti-TNF medication. Nineteen percent of the study population had been vaccinated against influenza, 3% against pneumoccous pneumonia, 22% against hepatitis B, 5% against varizella, 55% against rubella/mumps/measles, and 63% against tetanus. Of those who had traveled, 9% had been vaccinated for hepatitis A and 1% for yellow fever. Reasons given for not being vaccinated were not being aware of the necessity in 45% of those questioned and being afraid in 17%. While no patient was tested positive for hepatitis B, HIV, and CMV-IgM, one female patient was tested positive for hepatitis C (antibody and PCR positive, genotype I), which was unknown at that point.
Considering the high number of our patients receiving immunosuppressive therapy, the immunization record is alarmingly poor supporting the need for optimized IBD guidelines, better awareness, and patient education. In addition, the screening for chronic infections appears to be useful as suggested by the positive finding of a previously unknown hepatitis C.
Scandinavian journal of gastroenterology 04/2011; 46(7-8):855-61. · 2.08 Impact Factor
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Jan Däbritz,
Frauke Friedrichs,
Toni Weinhage,
Jochen Hampe, Torsten Kucharzik,
Andreas Lügering,
Ulrich Broeckel,
Stefan Schreiber,
Tilmann Spieker,
Monika Stoll,
Dirk Foell
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ABSTRACT: The receptor for advanced glycation end products (RAGE) is involved in innate immune mechanisms. Polymorphisms of the RAGE gene have been described as a factor amplifying inflammation in susceptible patients, but the association with Crohn's disease (CD) is not known. The coding RAGE polymorphism G82S (rs2070600) and two promoter polymorphisms, -374T/A (rs1800624) and -429T/C (rs1800625), were studied in two samples from Germany and the United States consisting of 421 and 317 CD patients and 549 and 218 controls, respectively. To test the functional relevance, additional data on serum soluble RAGE (sRAGE), tissue RNA, and protein levels were collected and immunohistochemical stainings of bowel tissue of CD patients and healthy controls as well as models of experimental (dextran sodium sulfate-induced) colitis in RAGE knockout and wild-type mice were performed. The -374T/A RAGE promotor single nucleotide polymorphism (SNP) was negatively associated with CD (odds ratio = 0.708, 95% confidence interval = 0.535-0.938, P = 0.016) and with stenosis (OR = 0.627, P = 0.04) in the German sample. Transmission disequilibrium testing confirmed an undertransmission of the -374A allele. Serum sRAGE levels were higher in patients in complete remission of the -374AA/TA group (1,975 ± 299 pg/ml; -374TT group: 1,310 ± 153 pg/ml SE, P < 0.05) and showed a trend toward decreased levels in CD patients with active disease compared with CD patients in remission. Further in vitro and in vivo studies indicated that an increase of sRAGE ameliorates inflammation. The -429T/C and the G82S polymorphism were not associated with CD. The -374T/A RAGE polymorphism leading to facilitated RAGE gene transcription may to some degree protect from developing a stricturing subphenotype of CD, most likely by increasing levels of sRAGE, which neutralizes proinflammatory mediators.
AJP Gastrointestinal and Liver Physiology 02/2011; 300(5):G823-32. · 3.43 Impact Factor
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ABSTRACT: Double balloon enteroscopy (DBE) has evolved as one of the most innovative and fast spreading endoscopic procedures in the last decade. With increasing experience of performing endoscopic procedures in the mid gut outside the operating room it is necessary to investigate the effectiveness of DBE regarding therapeutic consequences, long-term efficacy as well as safety.
To address this we retrospectively analyzed all DBE performed over a period of 2 years at our department. Furthermore, in order to evaluate long-term effectiveness of DBE procedures we performed a follow-up analysis on all patients, whose DBE procedure was at least 6 months ago. In addition, 100 consecutive patients who underwent DBE were questioned regarding procedure associated complaints using a standardized questionnaire.
Retrospective analysis of all DBE procedures performed in our department before November 2006 (n = 545) revealed an overall diagnostic yield of 39.7% and a therapeutic yield of 31.1%. The overall number of major complications accounted to 0.9%. Follow-up analysis revealed a long-term effect of endoscopic interventions in more than 50%, while in those patients with an initially negative DBE long-term follow-up only revealed symptom explaining findings in 17% with the majority of the other patients being asymptomatic during follow-up. Regarding patient related complaints the prospective analysis showed that DBE procedures in general are well tolerated with the most common complaint being meteorism.
DBE showed to be a relatively safe and well tolerated procedure. However, more sensitive algorithms are needed to enhance the therapeutic results.
Scandinavian journal of gastroenterology 03/2010; 45(7-8):992-9. · 2.08 Impact Factor
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ABSTRACT: Syndecan-1 (Sdc1) plays a major role in wound healing and modulates inflammatory responses. Sdc1 expression is reduced in lesions of patients with ulcerative colitis. The aim of this study was to investigate the role of Sdc1 in murine dextran sodium sulfate (DSS)-induced colitis. DSS colitis was induced in Sdc1-deficient (knockout (KO)) and wild-type mice by oral administration of 3% DSS. KO mice exhibited a significantly increased lethality as compared with wild-type controls (61 versus 5%, P < 0.05). Impaired mucosal healing and prolonged recruitment of inflammatory cells in KO mice were accompanied by significant up-regulation of tumor necrosis factor-alpha, CC chemokine ligand 3/macrophage inflammatory protein-1alpha, and vascular cell adhesion molecule-1, as determined by histological correlation between 0 and 15 days after colitis induction, TaqMan low-density array analysis, and quantitative real-time PCR. Treatment from days 7 through 14 with enoxaparin, a functional analogue of the Sdc1 heparan sulfate chains, significantly reduced lethality of KO mice due to DSS-induced colitis, which was correlated with improved mucosal healing. In vitro, Sdc1-deficient polymorphonuclear cells displayed increased adhesion to endothelial cells and intercellular adhesion molecule-1, and enoxaparin reverted adhesion to wild-type levels. Small interfering RNA-mediated knockdown of Sdc1 expression resulted in reduced basic fibroblast growth factor-mediated mitogen-activated protein kinase signaling and reduced Caco-2 cell proliferation. We conclude that Sdc1 has a protective effect during experimental colitis. The modification of missing Sdc1 function by heparin analogues may emerge as a promising anti-inflammatory approach.
American Journal Of Pathology 12/2009; 176(1):146-57. · 4.89 Impact Factor
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ABSTRACT: Biliary obstruction and cholangitis are common problems in gastroenterology. Infections of the biliary tract with Candida and other fungal species have increasingly been seen in the last few years.
To investigate the prevalence, associations, and trends of biliary-tract candidiasis.
A prospective, observational, diagnostic study.
University Hospital, Muenster, Germany.
Consecutive patients undergoing ERCP for various indications.
In 54 of 123 patients, we found Candida species in bile samples (44%). In only 7 patients, candidiasis was suspected on endoscopy before mycologic proof. Only 4 of these 7 patients were correctly diagnosed with biliary candidiasis by simple morphologic aspects. The fungus was mainly differentiated as Candida albicans or Candida glabrata and rarely as Candida parapsilosis, Candida tropicalis, or other subspecies. Immunosuppression for various reasons was significantly associated with bile-duct candidiasis (P < .02). No significant association was found between positive fungal cultures and prior endoscopic sphincterotomy (P = .0824) or prior ERCP (P = .1152). Biliary candidiasis was neither associated with positive fungal cultures of buccal smears (P = .0722) nor with positive findings in stool samples (P = .0860).
Highly selected patient population. Buccal smears and stool samples were not obtained from all patients. Contamination artifacts cannot totally be excluded with the ERCP procedure.
Candida species very frequently can be detected in the bile. Positive fungal cultures of bile samples are not just contamination artifacts. This has to be taken into account when designing an anti-infectious treatment for recurrent cholangitis or even more cholangiosepsis. Especially in immunosuppressed patients or recipients of long-term antibiotic therapy, physicians should screen for biliary-tract candidiasis during endoscopic examination.
Gastrointestinal endoscopy 06/2009; 70(3):480-7. · 6.71 Impact Factor
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Martin Floer,
David G Binion,
Victoria M Nelson,
Sharon Manley,
Michael Wellner,
Saba Sadeghi,
Behnaz Behmaram,
Chloe Sewell,
Mary F Otterson, Torsten Kucharzik,
Parvaneh Rafiee
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ABSTRACT: Tissue remodeling and mesenchymal cell accumulation accompanies chronic inflammatory disorders involving joints, lung, vasculature, and bowel. Chronic inflammation may alter DNA-mismatch repair (MMR) systems in mesenchymal cells, but is not defined in Crohn's disease (CD) and its associated intestinal remodeling and stricture formation. We determined whether DNA-MMR alteration plays a role in the pathogenesis of CD tissue remodeling. Control and CD bowel tissues were used to generate primary cultures of muscularis mucosa myofibroblasts, which were assessed directly or following stimulation with TNF-alpha/LPS or H2O2. MutS homolog (MSH)2, MSH3, and MSH6 expression in tissues and myofibroblasts was determined. Immunohistochemical staining revealed an increased expression of MSH2 in CD muscularis mucosa and submucosal tissues compared with controls or uninvolved CD tissue, and MSH2 expression was increased in CD myofibroblasts compared with control cells. TNF-alpha/LPS and H2O2 further enhanced MSH2 expression in both control and CD cells, which were decreased by simvastatin. There were no significant changes in MSH3 and MSH6 expression. Proliferating cell nuclear antigen and Ki67 staining of CD tissue revealed increased proliferation in the muscularis mucosa and submucosa of chronically inflamed tissues, and enhanced proliferation was seen in CD myofibroblasts compared with controls. Simvastatin reversed the effects of inflammatory stress on the DNA-MMR and inhibited proliferation of control and CD myofibroblasts. Gene silencing with MSH2 siRNA selectively decreased CD myofibroblast proliferation. These data demonstrate a potential role for MSH2 in the pathogenesis of nonneoplastic mesenchymal cell accumulation and intestinal remodeling in CD chronic inflammation.
AJP Gastrointestinal and Liver Physiology 09/2008; 295(3):G581-90. · 3.43 Impact Factor
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Jan M Ehrchen,
Johannes Roth,
Kirsten Roebrock,
Georg Varga,
Wolfram Domschke,
Rodney Newberry,
Clemens Sorg,
Carsten Müller-Tidow,
Cord Sunderkötter, Torsten Kucharzik,
Thomas W Spahn
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ABSTRACT: Lymph nodes (LNs) are important sentinel organs where antigen-presenting cells interact with T cells to induce adaptive immune responses. In cutaneous infection of mice with Leishmania major, resistance depends on the induction of a T-helper-cell-1 (Th1)-mediated cellular immune response in draining, peripheral LNs. We investigated whether draining, peripheral LNs are absolutely required for resistance against L. major infection. We investigated the course of experimental leishmaniasis in wild-type (wt) mice lacking peripheral LNs (pLNs), which we generated by in utero blockade of membrane-bound lymphotoxin, and in mice lacking pLNs or all LNs due to genetic deletion of lymphotoxin ligands or receptors. wt mice of the resistant C57BL/6 strain without local skin-draining LNs were still able to generate specific T-cell responses, but this yielded Th2 cells. This switch to a Th2 response resulted in severe systemic infection. We also confirmed these results with mice lacking pLNs due to genetic depletion of lymphotoxin-beta. The complete absence of LNs due to a genetic depletion of the lymphotoxin-beta receptor also resulted in a marked deterioration of disease and a Th2 response. Thus, in the absence of pLNs, an L. major-specific Th2 response is induced in the remaining secondary lymphoid organs, such as the spleen and non-skin-draining LNs. This indicates a critical requirement for pLNs to induce protective Th1 immunity and suggests that whether Th1 or Th2 priming to the same antigen occurs depends on the site of the primary antigen recognition.
Infection and immunity 08/2008; 76(9):4241-50. · 4.21 Impact Factor
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ABSTRACT: Diagnostic and therapeutic interventions in the biliary and pancreatic system in the previously operated patient by conventional endoscopic retrograde cholangiopancreaticography (ERCP) are difficult and, depending on the surgical procedure, in many cases unsuccessful. We describe our experience of ERCP performed with a double balloon enteroscope (DBE) as an alternative examination technique for these patients.
In a retrospective analysis of all DBE procedures at our department between November 2004 and June 2007, 11 patients were identified with various anatomic variations in whom ERCP was performed using a DBE.
In 72% of the patients, previous conventional ERCP examinations failed (8/11). In these patients, DBE-ERCP was successful in 63%. The overall success rate of DBE-ERCP in all patients was 64% (7/11 patients). In those patients, interventions such as papillotomy, calculus extractions, as well as stent placement could be performed even though tools for DBE-ERCP are still very limited. Despite most of the DBE-ERCPs having included therapeutic interventions, no major complications occurred in our case series and minor side effects were restricted to meteorism and mild to moderate abdominal pain.
DBE-ERCP is an alternative method for diagnostic as well as therapeutic interventions in the biliary as well pancreatic system in the operated patient. However, it should be limited to selected patients, e.g., with contraindications for PTC, as it is a time-consuming as well as a cost-intensive procedure.
The American Journal of Gastroenterology 05/2008; 103(4):894-900. · 7.28 Impact Factor
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ABSTRACT: Discs large homolog 5 (DLG5), a member of the membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins, has been associated with Crohn's disease (CD), but its role in the pathogenesis of this inflammatory bowel disease is disputed. Here, we used sequence comparisons and phylogenies to analyse the DLG5 gene and its protein product. We identified a 5' exon, which codes for an N-terminal caspase recruitment domain (CARD) and experimentally confirmed its expression in colonic tissue. DLG5 shares this new domain with nucleotide-binding oligomerisation domain containing 2 (NOD2); the first CD susceptibility factor identified in genetic studies. An extensive phylogenetic analysis redefines the family organisation of the MAGUK proteins: DLG5 is closely related to CARD10, CARD11 and CARD14, CARD-containing proteins which initiate pro-inflammatory NFkappaB signalling, but not to DLG1-4, previously considered the closest related proteins. Therefore, we suggest renaming DLG5 to correctly annotate the gene in its phylogenetic and functional context. Our study provides evidence that the scaffolding protein DLG5 belongs to the CARD protein family. Thus, DLG5 likely acts in the regulation of NFkB activation or caspase activation as part of host defence mechanisms. As there is substantial crosstalk between CARD-mediated pathways, both CD susceptibility genes, NOD2 and DLG5, may interact functionally to contribute to CD risk.
Journal of Molecular Medicine 05/2008; 86(4):423-32. · 4.67 Impact Factor
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Matthias Stelljes,
Sven Hermann,
Jörn Albring,
Gabriele Köhler,
Markus Löffler,
Christiane Franzius,
Christopher Poremba,
Verena Schlösser,
Sarah Volkmann,
Corinna Opitz,
Christoph Bremer, Torsten Kucharzik,
Gerda Silling,
Otmar Schober,
Wolfgang E Berdel,
Michael Schäfers,
Joachim Kienast
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ABSTRACT: Gastrointestinal graft-versus-host disease (GVHD) is a common and potentially life-threatening complication after allogeneic hematopoietic stem-cell transplantation (HSCT). Noninvasive tests for assessment of GVHD activity are desirable but lacking. In the present study, we were able to visualize intestinal GVHD-associated inflammation in an allogeneic murine transplantation model by (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in vivo. A predominant localization of intestinal GVHD to the colon was verified by histology and fluorescence reflectance imaging of enhanced green fluorescent protein (EGFP)-expressing donor cells. Colonic infiltration by EGFP(+) donor lymphocytes matched increased FDG uptake in PET examinations. These preclinical data were prospectively translated into 30 patients with suspected intestinal GVHD beyond 20 days after transplantation. A total of 14 of 17 patients with a diagnostic histology showed significant FDG uptake of the gut, again predominantly in the colon. No increased FDG uptake was detected in 13 patients without histologic evidence of intestinal GVHD. Our findings indicate that FDG-PET is a sensitive and specific noninvasive imaging technique to assess intestinal GVHD, map its localization, and predict and monitor treatment responsiveness. Novel targeted tracers for PET may provide new insights into the pathophysiology of GVHD and bear the potential to further improve GVHD diagnosis.
Blood 04/2008; 111(5):2909-18. · 9.90 Impact Factor
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ABSTRACT: Despite some progress in recent years, the options for treating inflammatory bowel disease (IBD) are still dissatisfying, and surgery rates are still high. The anti-inflammatory effects of melanocortin peptides such as alpha-melanocyte-stimulating hormone (alpha-MSH) have been described recently in, for example, dextran sodium sulfate (DSS) colitis in mice. The aim of this study was to investigate the therapeutic potential of the melanocortin-derived tripeptide alpha-MSH(11-13) (KPV) and its mode of action in 2 models of intestinal inflammation.
The anti-inflammatory activity of KPV was analyzed in 2 well-described models of IBD: DSS colitis, and CD45RB(hi) transfer colitis. Furthermore, animals expressing a nonfunctional melanocortin-1 receptor (MC1Re/e) received DSS for induction of colitis and were treated with KPV. The course of inflammation was monitored by weight loss and histological changes in the colon as well as by myeloperoxidase (MPO) activity.
In the DSS-colitis model, treatment with KPV led to earlier recovery and significantly stronger regain of body weight. Histologically, inflammatory infiltrates were significantly reduced in KPV-treated mice, which was confirmed by the significant reduction of MPO activity in colonic tissue after KPV treatment. Supporting these findings, KPV treatment of transfer colitis led to recovery, regain of body weight, and reduced inflammatory changes histologically. In MC1Re/e mice, KPV treatment rescued all animals in the treatment group from death during DSS colitis.
The melanocortin-derived tripeptide KPV showed significant anti-inflammatory effects in 2 murine models of colitis. These effects seem to be at least partially independent of MC1R signaling. In conclusion, our data suggest KPV as an interesting therapeutic option for the treatment of IBD.
Inflammatory Bowel Diseases 04/2008; 14(3):324-31. · 4.86 Impact Factor
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Sabine Westphal,
Andreas Lügering,
Julia von Wedel,
Christof von Eiff,
Christian Maaser,
Thomas Spahn,
Gerhard Heusipp,
M Alexander Schmidt,
Hermann Herbst,
Ifor R Williams,
Wolfram Domschke, Torsten Kucharzik
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ABSTRACT: M cells, specialized cells within Peyer's patches (PPs), are reduced in number in chemokine receptor 6 (CCR6)-deficient mice. The pathogenic microorganism Yersinia enterocolitica exploits M cells for the purpose of mucosal tissue invasion exclusively through PPs. The aim of this study was to evaluate the course of yersiniosis in CCR6-deficient mice and to investigate whether these mice might be used as an in vivo model to determine M-cell function. After oral challenge with Y. enterocolitica, control mice suffered from lethal septic infection whereas CCR6-deficient mice showed very limited symptoms of infection. Immunohistochemical analysis demonstrated PP invasion by Y. enterocolitica in control mice whereas no bacteria could be found in CCR6-deficient mice. In addition, a significant induction of proinflammatory cytokines could be found in control mice whereas proinflammatory cytokine levels in CCR6-deficient mice remained unchanged. In contrast, intraperitoneal infection resulted in severe systemic yersiniosis in both mouse groups. Abrogated oral Y. enterocolitica infection in CCR6-deficient mice demonstrates the importance of CCR6 expression in the physiological and pathological immune responses generated within PPs by influencing M-cell differentiation, underscoring the important role of M cells in the process of microbial uptake. CCR6-deficient mice may therefore represent a suitable model for the study of M-cell function in vivo.
American Journal Of Pathology 04/2008; 172(3):671-80. · 4.89 Impact Factor
