[Position paper on reporting of intestinal ultrasound findings in patients with inflammatory bowel disease]. / Positionspapier zur Befunderhebung von Darmultraschallbefunden bei chronisch entzündlichen Darmerkrankungen.

BACKGROUND: Intestinal ultrasound is increasingly used for primary diagnosis, detection of complications and monitoring of patients with Crohn's disease and ulcerative colitis. Standardization of reporting is relevant to ensure quality of the methodology and to improve communication between different specialties. The current manuscript describes the features required for optimized reporting of intestinal ultrasound findings in inflammatory bowel disease (IBD). METHODS: An expert consensus panel of gastroenterologists, radiologists, pathologists, paediatric gastroenterologists and surgeons conducted a systematic literature search. In a Delphi- process members of the Kompetenznetz Darmerkrankungen in collaboration with members of the German Society for Radiology (DRG) voted on relevant criteria for reporting of findings in intestinal ultrasound. Based on the voting results statements were agreed by expert consensus. RESULTS: Clinically relevant aspects of intestinal ultrasound (IUS) findings have been defined to optimize reporting and to standardize terminology. Minimal requirements for standardized reporting are suggested. The statements focus on description of disease activity as well as on complications of IBD. Attributes of intestinal inflammation are described and illustrated by exemplary images. CONCLUSION: The current manuscript provides practical recommendations on how to standardize documentation and reporting from intestinal ultrasound findings in patients with IBD.

[Position paper on endoscopic reporting in IBD]. / Positionspapier zur Befunderstellung endoskopischer Untersuchungen bei Patienten mit chronisch-entzündlichen Darmerkrankungen.

The complete and reliable documentation of endoscopic findings make up the crucial foundation for the treatment of patients with inflammatory bowel diseases such as Crohn´s disease and ulcerative colitis. These findings are, on the one hand, a prerequisite for therapeutic decisions and, on the other hand, important as a tool for assessing the response to ongoing treatments. Endoscopic reports should, therefore, be recorded according to standardized criteria to ensure that the findings of different endoscopists can be adequately compared and that changes in the course of the disease can be traced back. In consideration of these necessities, fifteen members of the Imaging Working Group of the German Kompetenznetz Darmerkrankungen have created a position paper proposing a structure and specifications for the documentation of endoscopic exams. In addition to the formal report structure, the recommendations address a large number of attributes of acute and chronic inflammatory alterations as well as endoscopically detectable complications, which are explained in detail and illustrated using exemplary images. In addition, more frequently used endoscopic activity indices are presented and their use in everyday clinical practice is discussed.

Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn's disease.

OBJECTIVE: Anti-tumour necrosis factor (TNF) antibodies are successfully used for treatment of Crohn's disease. Nevertheless, approximately 40% of patients display failure to anti-TNF therapy. Here, we characterised molecular mechanisms that are associated with endoscopic resistance to anti-TNF therapy. DESIGN: Mucosal and blood cells were isolated from patients with Crohn's disease prior and during anti-TNF therapy. Cytokine profiles, cell surface markers, signalling proteins and cell apoptosis were assessed by microarray, immunohistochemistry, qPCR, ELISA, whole organ cultures and FACS. RESULTS: Responders to anti-TNF therapy displayed a significantly higher expression of TNF receptor 2 (TNFR2) but not IL23R on T cells than non-responders prior to anti-TNF therapy. During anti-TNF therapy, there was a significant upregulation of mucosal IL-23p19, IL23R and IL-17A in anti-TNF non-responders but not in responders. Apoptosis-resistant TNFR2+IL23R+ T cells were significantly expanded in anti-TNF non-responders compared with responders, expressed the gut tropic integrins α4ß7, and exhibited increased expression of IFN-γ, T-bet, IL-17A and RORγt compared with TNFR2+IL23R- cells, indicating a mixed Th1/Th17-like phenotype. Intestinal TNFR2+IL23R+ T cells were activated by IL-23 derived from CD14+ macrophages, which were significantly more present in non-responders prior to anti-TNF treatment. Administration of IL-23 to anti-TNF-treated mucosal organ cultures led to the expansion of CD4+IL23R+TNFR2+ lymphocytes. Functional studies demonstrated that anti-TNF-induced apoptosis in mucosal T cells is abrogated by IL-23. CONCLUSIONS: Expansion of apoptosis-resistant intestinal TNFR2+IL23R+ T cells is associated with resistance to anti-TNF therapy in Crohn's disease. These findings identify IL-23 as a suitable molecular target in patients with Crohn's disease refractory to anti-TNF therapy.

Perceived distress, personality characteristics, coping strategies and psychosocial impairments in a national German multicenter cohort of patients with Crohn's disease and ulcerative colitis.

BACKGROUND AND AIMS: This study examined differences in personality, psychological distress, and stress coping in inflammatory bowel disease (IBD) depending on type of disease and disease activity. We compared patients suffering from Crohn's disease (CD) and ulcerative colitis (UC) with controls. While the literature is replete with distinctive features of the pathogenesis of IBD, the specific differences in psychological impairments are not well studied. METHODS: In this German national multicenter study, participants were recruited from 32 centers. Two hundred ninety-seven questionnaires were included, delivering vast information on disease status and psychological well-being based on validated instruments with a total of 285 variables. RESULTS: CD patients were more affected by psychological impairments than patients suffering from UC or controls. Importantly, patients with active CD scored higher in neuroticism (p < 0.01), psychological distress (p < 0.001) and maladaptive stress coping (escape, p = 0.03; rumination, p < 0.03), but less need for social support (p = 0.001) than controls. In contrast, patients suffering from active UC showed psychological distress (p < 0.04) and maladaptive coping (avoidance, p < 0.03; escape, p = 0.01). Patients in remission seemed to be less affected. In particular, patients with UC in remission were not inflicted by psychological impairments. The group of CD patients in remission however, showed insecurity (p < 0.01) and paranoid ideation (p = 0.04). CONCLUSIONS: We identified specific aspects of psychological impairment in IBD depending on disease and disease activity. Our results underscore the need for psychological support and treatment particularly in active CD.

Prediction of clinical outcomes in Crohn's disease by using confocal laser endomicroscopy: results from a prospective multicenter study.

BACKGROUND AND AIMS: Assessment of prognostic factors in patients with Crohn's disease (CD) is of pivotal importance for early intervention and "treat-to-target" strategies. Confocal laser endomicroscopy (CLE) enables on-demand in vivo characterization of mucosal inflammatory and architectural changes during endoscopy. We prospectively assessed the value of CLE for prediction of clinical outcome parameters in CD. METHODS: Consecutive patients with CD undergoing colonoscopy were included in a multicenter study. Confocal imaging focused on 2 highly reproducible histologic hallmarks of active colonic inflammation: focal cryptitis and crypt architectural abnormality. We evaluated whether CLE, CD endoscopic index of severity (CDEIS), serum C-reactive protein (CRP), and CD activity index (CDAI) were associated with the risk of medical treatment escalation, transmural adverse events, and CD-related hospitalization or surgery during a 4-year follow-up. RESULTS: Among 49 patients (53% men, median age, 39 years), baseline CRP was ≥5 mg/L in 47%, CDEIS ≥3 in 75%, and CDAI >150 in 51%. Focal cryptitis and crypt architectural abnormality were observed in 63% (CLE+ group). CLE+ patients showed an increased incidence of medical treatment escalation (P < .001; relative risk [RR] = 3.27) and transmural lesions (P = .025; RR = 1.70), whereas patients with CRP ≥5 mg/L had increased CD-related hospitalization and surgery (P = .020, RR = 2.71) at 1-year follow-up. No further association with prognostic clinical outcomes was found over the 1-year follow-up as well as for CDEIS and CDAI at any time. CONCLUSIONS: CLE reveals CD-related features of mucosal inflammation and allows for early prediction of relevant clinical outcomes. Further studies should now address whether this promising prognostic tool could refine the timing of treatment strategies in patients with CD.

Batf-dependent Th17 cells critically regulate IL-23 driven colitis-associated colon cancer.

OBJECTIVES: IBDs have an increased risk for development of colorectal cancer (CRC). Here, we aimed at the characterisation of the functional role of Th17-associated transcription factors in sporadic and colitis-associated colon cancer in vivo. DESIGN: We used mice deficient or transgenic for the activating protein 1 family member basic leucine zipper transcription factor ATF-like (Batf) to evaluate the role of Th17 cells during sporadic and inflammation-induced colon carcinogenesis. We also studied the expression of Batf and RORγt in patients with IBD and CRC. RESULTS: Batf but not retinoic acid-related orphan receptor γt(RORγt) expression was significantly increased together with interleukin (IL) 23 expression in UC but not in Crohn's disease (CD) tissue samples. In CRC also Batf but not RORγt expression was increased and its expression correlated with the IL-23 and IL-23 receptor (IL-23R) expression. Finally, Batf but not RORγt was coexpressed with IL-17a, IL-23R and IL-6 within CRC-infiltrating CD4(+) T cells. Functional studies in mice revealed that Batf-dependent T cells are crucial regulators of sporadic and inflammation-induced CRC. Colitis-associated Batf(-/-) tumours lacked IL-17a(+)IL-23R(+)IL-6(+)CD4(+) T cells, hence displaying characteristics reminiscent of human CRC-infiltrating CD4(+) T cells. Strikingly, Batf(-/-) tumours contained low IL-23 but high IL-17a expression levels. Tumour formation and intratumoral IL-23 expression could be restored by administration of Hyper-IL-6 consisting of IL-6 and soluble IL-6 receptor. CONCLUSIONS: Batf-dependent IL-23R(+)IL-6(+)CD4(+) Th17 cells critically control IL-23 driven colitis-associated tumour formation and the progression of sporadic colon tumours. Batf-dependent IL-23R(+) T cells represent a potential future therapeutic target limiting CRC progression.

Dysphagia in Patients with Acute Ischemic Stroke: Early Dysphagia Screening May Reduce Stroke-Related Pneumonia and Improve Stroke Outcomes.

BACKGROUND: Dysphagia is associated with poor outcome in stroke patients. Studies investigating the association of dysphagia and early dysphagia screening (EDS) with outcomes in patients with acute ischemic stroke (AIS) are rare. The aims of our study are to investigate the association of dysphagia and EDS within 24 h with stroke-related pneumonia and outcomes. METHODS: Over a 4.5-year period (starting November 2007), all consecutive AIS patients from 15 hospitals in Schleswig-Holstein, Germany, were prospectively evaluated. The primary outcomes were stroke-related pneumonia during hospitalization, mortality, and disability measured on the modified Rankin Scale ≥2-5, in which 2 indicates an independence/slight disability to 5 severe disability. RESULTS: Of 12,276 patients (mean age 73 ± 13; 49% women), 9,164 patients (74%) underwent dysphagia screening; of these patients, 55, 39, 4.7, and 1.5% of patients had been screened for dysphagia within 3, 3 to <24, 24 to ≤72, and >72 h following admission. Patients who underwent dysphagia screening were likely to be older, more affected on the National Institutes of Health Stroke Scale score, and to have higher rates of neurological symptoms and risk factors than patients who were not screened. A total of 3,083 patients (25.1%; 95% CI 24.4-25.8) had dysphagia. The frequency of dysphagia was higher in patients who had undergone dysphagia screening than in those who had not (30 vs. 11.1%; p < 0.001). During hospitalization (mean 9 days), 1,271 patients (10.2%; 95% CI 9.7-10.8) suffered from stroke-related pneumonia. Patients with dysphagia had a higher rate of pneumonia than those without dysphagia (29.7 vs. 3.7%; p < 0.001). Logistic regression revealed that dysphagia was associated with increased risk of stroke-related pneumonia (OR 3.4; 95% CI 2.8-4.2; p < 0.001), case fatality during hospitalization (OR 2.8; 95% CI 2.1-3.7; p < 0.001) and disability at discharge (OR 2.0; 95% CI 1.6-2.3; p < 0.001). EDS within 24 h of admission appeared to be associated with decreased risk of stroke-related pneumonia (OR 0.68; 95% CI 0.52-0.89; p = 0.006) and disability at discharge (OR 0.60; 95% CI 0.46-0.77; p < 0.001). Furthermore, dysphagia was independently correlated with an increase in mortality (OR 3.2; 95% CI 2.4-4.2; p < 0.001) and disability (OR 2.3; 95% CI 1.8-3.0; p < 0.001) at 3 months after stroke. The rate of 3-month disability was lower in patients who had received EDS (52 vs. 40.7%; p = 0.003), albeit an association in the logistic regression was not found (OR 0.78; 95% CI 0.51-1.2; p = 0.2). CONCLUSIONS: Dysphagia exposes stroke patients to a higher risk of pneumonia, disability, and death, whereas an EDS seems to be associated with reduced risk of stroke-related pneumonia and disability.

[Inflammatory Bowel Disease Competence Network]. / Kompetenznetz Darmerkrankungen.

The Inflammatory Bowel Disease Competence Network is a network of more than 500 physicians and scientists from university clinics, hospitals and gastroenterology practices. The focus extends from the two major forms of inflammatory bowel diseases, Crohn's disease and ulcerative colitis, into other chronic inflammatory conditions affecting the intestine, including coeliac disease and microscopic colitis. The network translates basic science discoveries (in particular in the molecular epidemiology research) into innovative diagnostics and therapy. Through its strong networking structures it supports a continuous process to improve quality and standardisation in patient care that is implemented in close interaction with European networks addressing this disease group.Optimisation of patient care based on scientifically proven evidence is a main focus of the network. Therefore, it supports and coordinates translational research and infrastructure projects that investigate aetiology, improvement of diagnostic methods, and development of new or improved use of established therapies. Members participate in various training projects, thus ensuring the rapid transfer of research results into clinical practice.The competence network cooperates with the main patient organisations to engage patients in all levels of activities. The network and the patient organisations have interest in promoting public awareness about the disease entities, because their importance and burden is underestimated in non-specialised medical fields and among the general public.

IL-9 and its receptor are predominantly involved in the pathogenesis of UC.

OBJECTIVE: Several pathogenic roles attributed over the past two decades to either T helper (Th)1 or Th2 cells are increasingly becoming associated with interleukin (IL)-17 and most recently IL-9 signalling. However, the implication of IL-9 in IBD has not been addressed so far. DESIGN: We investigated the expression of IL-9 and IL-9R by using peripheral blood, biopsies and surgical samples. We addressed the functional role of IL-9 signalling by analysis of downstream effector proteins. Using Caco-2 cell monolayers we followed the effect of IL-9 on wound healing. RESULTS: IL-9 mRNA expression was significantly increased in inflamed samples from patients with UC as compared with controls. CD3(+) T cells were major IL-9-expressing cells and some polymorphonuclear leucocytes (PMN) also expressed IL-9. IL-9 was co-localised with the key Th9 transcription factors interferon regulatory factor 4 and PU.1. Systemically, IL-9 was abundantly produced by activated peripheral blood lymphocytes, whereas its receptor was overexpressed on gut resident and circulating PMN. IL-9 stimulation of the latter induced IL-8 production in a dose-dependent manner and rendered PMN resistant to apoptosis suggesting a functional role for IL-9R signalling in the propagation of gut inflammation. Furthermore, IL-9R was overexpressed on gut epithelial cells and IL-9 induced STAT5 activation in these cells. Moreover, IL-9 inhibited the growth of Caco-2 epithelial cell monolayers in wound healing experiments. CONCLUSIONS: Our results provide evidence that IL-9 is predominantly involved in the pathogenesis of UC suggesting that targeting IL-9 might become a therapeutic option for patients with UC.

Confocal laser endomicroscopy for the differential diagnosis of ulcerative colitis and Crohn's disease: a pilot study.

BACKGROUND AND STUDY AIM: The differential diagnosis of ulcerative colitis from Crohn's disease is of pivotal importance for the management of inflammatory bowel diseases, as both entities involve specific therapeutic management strategies. Confocal laser endomicroscopy (CLE) allows on-demand, in vivo characterization of architectural and cellular details during endoscopy. The aim of this study was to assess the efficacy of CLE to differentiate between ulcerative colitis and Crohn's disease. PATIENTS AND METHODS: This was a prospective study involving consecutive patients with a well-established diagnosis of ulcerative colitis or Crohn's disease who underwent colonoscopy with fluorescein-aided confocal imaging. RESULTS: Overall, 79 patients were included (40 Crohn's disease, 39 ulcerative colitis). CLE findings in patients with Crohn's disease, showed significantly more discontinuous inflammation (87.5 % vs. 5.1 %), focal cryptitis (75.0 % vs. 12.8 %), and discontinuous crypt architectural abnormality (87.5 % vs. 10.3 %) than in ulcerative colitis (P < 0.0001). Conversely, ulcerative colitis was associated with severe, widespread crypt distortion (87.2 % vs. 17.5 % in Crohn's disease), decreased crypt density (79.5 % vs. 22.5 %), and frankly irregular surface (89.7 % vs. 17.5 %; P < 0.0001 for all comparisons). Statistically significant differences were not seen for heavy, diffuse lamina propria cell increase or mucin preservation. No granulomas were visible. Based on these findings, a CLE scoring system was developed that revealed excellent accuracy (93.7 %) when compared with the historical clinical diagnosis and the histopathological gold standard. CONCLUSIONS: CLE could visualize several disease-specific microscopic features, which are conventionally used in standard histopathology to differentiate between ulcerative colitis and Crohn's disease. However, because of the limited penetration depth of CLE, submucosal details or granulomas were not visible. The new scoring system may allow in vivo diagnosis of ulcerative colitis or Crohn's disease. Trial registered at ClinicalTrials.gov: NCT 02238665.

A variant of Smurf2 protects mice against colitis-associated colon cancer by inducing transforming growth factor ß signaling.

BACKGROUND & AIMS: Transforming growth factor (TGF)-ß signaling, which is down-regulated by the E3 ubiquitin ligase Smad ubiquitin regulating factor 2 (Smurf2), promotes development of cancer. We identified a splice variant of Smurf2 (ΔE2Smurf2) and investigated its role in colon carcinogenesis in mice. METHODS: Colitis-associated colon cancer was induced in mice by administration of azoxymethane, followed by 3 cycles of oral administration of dextran sodium sulfate. Messenger RNA levels of Smurf2 in colon tumors and control tissue were measured by quantitative polymerase chain reaction; lymphocyte and cytokine levels were measured in tumor and tissue samples. RESULTS: Tumor-infiltrating CD4(+) cells expressed higher levels of ΔE2Smurf2 than CD4(+) cells from nontumor tissues of wild-type mice. T cell-specific overexpression of ΔE2Smurf2 increased TGF-ß signaling by suppressing protein levels of Smurf2, accompanied by an increase in levels of TGF-ß receptor type II. Transgenic mice that overexpress ΔE2Smurf2 were protected against development of colitis-associated tumors and down-regulated proinflammatory cytokines such as interleukin-6. Patients with chronic inflammatory bowel disease had a significantly lower ratio of Smurf2/ΔE2Smurf2 than control individuals. CONCLUSIONS: T cell-specific ΔE2Smurf2 degrades wild-type Smurf2 and controls intestinal tumor growth in mice by up-regulating TGF-ß receptor type II, reducing proliferation and production of proinflammatory cytokines.

Prevalence of collagen VII-specific autoantibodies in patients with autoimmune and inflammatory diseases.

BACKGROUND: Autoimmunity to collagen VII is typically associated with the skin blistering disease epidermolysis bullosa acquisita (EBA), but also occurs occasionally in patients with systemic lupus erythematosus or inflammatory bowel disease. The aim of our present study was to develop an accurate immunoassay for assessing the presence of autoantibodies against collagen VII in large cohorts of patients and healthy donors. METHODS: Based on in silico antigenic analysis and previous wetlab epitope mapping data, we designed a chimeric collagen VII construct containing all collagen VII epitopes with higher antigenicity. ELISA was performed with sera from patients with EBA (n = 50), Crohn's disease (CD, n = 50), ulcerative colitis (UC, n = 50), bullous pemphigoid (BP, n = 76), and pemphigus vulgaris (PV, n = 42) and healthy donors (n = 245). RESULTS: By ELISA, the receiver operating characteristics analysis yielded an area under the curve of 0.98 (95% CI: 0.9638-1.005), allowing to set the cut-off at 0.32 OD at a calculated specificity of 98% and a sensitivity of 94%. Running the optimized test showed that serum IgG autoantibodies from 47 EBA (94%; 95% CI: 87.41%-100%), 2 CD (4%; 95% CI: 0%-9.43%), 8 UC (16%; 95% CI: 5.8%-26%), 2 BP (2.63%; 95% CI: 0%-6.23%), and 4 PV (9.52%; 95% CI: 0%-18.4%) patients as well as from 4 (1.63%; 95% CI: 0%-3.21%) healthy donors reacted with the chimeric protein. Further analysis revealed that in 34%, 37%, 16% and 100% of sera autoantibodies of IgG1, IgG2, IgG3, and IgG4 isotype, respectively, recognized the recombinant autoantigen. CONCLUSIONS: Using a chimeric protein, we developed a new sensitive and specific ELISA to detect collagen specific antibodies. Our results show a low prevalence of collagen VII-specific autoantibodies in inflammatory bowel disease, pemphigus and bullous pemphigoid. Furthermore, we show that the autoimmune response against collagen VII is dominated by IgG4 autoantibodies. The new immunoassay should prove a useful tool for clinical and translational research and should improve the routine diagnosis and disease monitoring in diseases associated with collagen VII-specific autoimmunity.

18F-Fluorodeoxyglucose positron-emission tomography (PET) can be used to assess inflammation non-invasively in Crohn's disease.

BACKGROUND: Differential therapy requires repeated diagnostic assessment for mapping and monitoring of disease activity in Crohn's disease (CD). PURPOSE: The purpose of this prospective study was to evaluate the accuracy of (18)F-fluorodexyglucose positron-emission tomography (FDG-PET) for non-invasive assessment of disease activity in CD. METHODS: Forty-three patients with CD underwent ileocolonoscopy and hydromagnetic resonance imaging (hydro-MRI) as reference standards. In addition, FDG-PET was performed and correlated with clinical data, hydro-MRI, and endoscopy findings. Diagnostic accuracy was determined for all methods. RESULTS: Two-hundred and forty-one bowel segments could be analyzed by all methods. Of 80 endoscopically inflamed segments in CD, FDG-PET detected 72 and hydro-MRI 53 segments. Overall sensitivity was 90 % (FDG-PET) versus 66 % (hydro-MRI), and specificity was 92.6 % versus 99 %. In the proximal ileum, hydro-MRI revealed inflammation in eight out of 49 patients and FDG-PET, also, detected all of these inflamed segments. Seventeen stenoses could be identified in 43 CD patients. With regard to assessment as inflammatory or fibrotic stenosis, there was good concordance between colonoscopy, hydro-MRI, and FDG-PET. In one case only, the nature of the stenosis was assessed differently. In contrast with leukocyte numbers and CDAI, there was significant correlation of FDG-PET activity with C-reactive protein and CDEIS levels (P = 0.019 and P = 0.007, respectively). CONCLUSION: FDG-PET is able to detect mucosal inflammation in CD with high sensitivity and specificity and to enable proper assessment of inflammatory activity in stenoses. FDG-PET is, thus, a promising non-invasive technique for clinical management of CD.

Insight into Crohn's disease pathomorphology.

Crohn's disease (CD) belongs together with ulcerative colitis to the two major forms of inflammatory bowel diseases (IBD). Although its etiology remains poorly understood, several genetic and immune factors and cells (especially T cells) have been shown to be involved in the pathogenesis of IBD. Among these factors, proinflammatory T cells and their secreted cytokines seem to be the main effectors in induction and perpetuation of the intestinal inflammation. Beside the local inflammatory effect, there is a very clear defined mechanism where T cells and inflammatory complexes migrate and induce extraintestinal manifestation and complications. This article reviews current knowledge of the pathomorphology of mucosal inflammation in CD focusing especially on the immune mechanisms of T-cell homing, extraintestinal manifestations and fibrogenesis.

The transcription factor IFN regulatory factor-4 controls experimental colitis in mice via T cell-derived IL-6.

The proinflammatory cytokine IL-6 seems to have an important role in the intestinal inflammation that characterizes inflammatory bowel diseases (IBDs) such as Crohn disease and ulcerative colitis. However, little is known about the molecular mechanisms regulating IL-6 production in IBD. Here, we assessed the role of the transcriptional regulator IFN regulatory factor-4 (IRF4) in this process. Patients with either Crohn disease or ulcerative colitis exhibited increased IRF4 expression in lamina propria CD3+ T cells as compared with control patients. Consistent with IRF4 having a regulatory function in T cells, in a mouse model of IBD whereby colitis is induced in RAG-deficient mice by transplantation with CD4+CD45RB(hi) T cells, adoptive transfer of wild-type but not IRF4-deficient T cells resulted in severe colitis. Furthermore, IRF4-deficient mice were protected from T cell-dependent chronic intestinal inflammation in trinitrobenzene sulfonic acid- and oxazolone-induced colitis. In addition, IRF4-deficient mice with induced colitis had reduced mucosal IL-6 production, and IRF4 was required for IL-6 production by mucosal CD90+ T cells, which it protected from apoptosis. Finally, the protective effect of IRF4 deficiency could be abrogated by systemic administration of either recombinant IL-6 or a combination of soluble IL-6 receptor (sIL-6R) plus IL-6 (hyper-IL-6). Taken together, our data identify IRF4 as a key regulator of mucosal IL-6 production in T cell-dependent experimental colitis and suggest that IRF4 might provide a therapeutic target for IBDs.

Spectral Spatial Variation.

Automatic carcinoma detection from hyper/multi spectral images is of essential importance due to the fact that these images cannot be presented directly to the clinician. However, standard approaches for carcinoma detection use hundreds or even thousands of features. This would cost a high amount of RAM (random access memory) for a pixel wise analysis and would slow down the classification or make it even impossible on standard PCs. To overcome this, strong features are required. We propose that the spectral-spatial-variation (SSV) is one of these strong features. SSV is the residuum of the three dimensional hyper spectral data cube minus its approximation with a fitting in a small volume of the 3D image. By using it, the classification results of carcinoma detection in the stomach with multi spectral imaging will be increase significantly compared to not using the SSV. In some cases, the AUC can be even as high as by the usage of 72 spatial features.

CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes.

Azathioprine and its metabolite 6-mercaptopurine (6-MP) are immunosuppressive drugs that are used in organ transplantation and autoimmune and chronic inflammatory diseases such as Crohn disease. However, their molecular mechanism of action is unknown. In the present study, we have identified a unique and unexpected role for azathioprine and its metabolites in the control of T cell apoptosis by modulation of Rac1 activation upon CD28 costimulation. We found that azathioprine and its metabolites induced apoptosis of T cells from patients with Crohn disease and control patients. Apoptosis induction required costimulation with CD28 and was mediated by specific blockade of Rac1 activation through binding of azathioprine-generated 6-thioguanine triphosphate (6-Thio-GTP) to Rac1 instead of GTP. The activation of Rac1 target genes such as mitogen-activated protein kinase kinase (MEK), NF-kappaB, and bcl-x(L) was suppressed by azathioprine, leading to a mitochondrial pathway of apoptosis. Azathioprine thus converts a costimulatory signal into an apoptotic signal by modulating Rac1 activity. These findings explain the immunosuppressive effects of azathioprine and suggest that 6-Thio-GTP derivates may be useful as potent immunosuppressive agents in autoimmune diseases and organ transplantation.

Il-6 signaling in inflammatory bowel disease: pathophysiological role and clinical relevance.

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) occurring in the gut of genetically susceptible individuals independent of a specific pathogen. The interaction between antigen-presenting cells and the local bacterial flora contributes to an uncontrolled activation of mucosal CD4+ T lymphocytes with the consecutive release of proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6, IL-12, IL-23, IL-27, and also IL-17, which is attributed to a specific, differentiated CD4+ lineage called Th17 (TH-IL17, THi). Recent data suggest that IL-6 contributes to Th17 differentiation. However, to clarify the importance of Th17 cells in IBD further data are needed. So far, CD has been attributed to a Th1-mediated disease, whereas UC exhibits a modified Th2 cytokine response. In both diseases CD4+ T cells at the site of inflammation are critically dependent on antiapoptotic IL-6 signaling. Thereby, IL-6 induces the transcription factor STAT-3 via transsignaling (activation of a cell lacking membrane-bound IL-6 receptor via soluble IL-6 receptor). STAT-3 itself induces the antiapoptotic factors bcl-2 and bcl-xL, thus resulting in T-cell resistance against apoptosis. This vicious circle of T-cell accumulation, mediated by apoptosis resistance, finally leading to chronic inflammation, can be blocked by anti-IL-6 receptor antibodies. This review highlights the role of IL-6 in IBD immunopathogenesis and its clinical relevance in IBD therapy and diagnostics.

Computed Tomography-Guided Percutaneous Gastrostomy/Jejunostomy for Feeding and Decompression.

BACKGROUND: An effective method for long-term enteral feeding or stomach decompression is the use of a percutaneous gastrostomy (PEG) or sometimes jejunostomy (PEJ). Under certain circumstances (eg, inadequate transillumination), endoscopic placement of PEG/PEJ tubes is impossible. In these cases, computed tomography (CT)-guided PEG/PEJ may represent an alternative technique. In this study, we evaluate indications, results, and complications of CT-guided PEG/PEJ. MATERIALS AND METHODS: A total of 102 consecutive referred patients were enrolled in the study. Patients came to the endoscopy unit of our department to undergo a CT-guided PEG/PEJ for long-term intragastric/intrajejunal feeding (n = 57) or decompression (n = 45). The majority (n = 98) received a pull-through PEG/PEJ with simultaneous gastroscopy/jejunoscopy. Dose length product and the effective dose for every patient were calculated. RESULTS: PEG/PEJ tube placement was successful in 87.3% (89 of 102). Feeding PEG/PEJ tube placement was successfully completed in 91.2% (52 of 57); decompressive PEG/PEJ tube placement was likewise successfully completed in 82.2% (37 of 45). No procedure-related mortality was observed. Minor complications (eg, tube dysfunction, local bleeding, minimal leakage, local skin infection) were observed in 13 patients. The complication rate was similar between the feeding and decompression groups ( P = .9). CONCLUSIONS: CT-guided PEG/PEJ is a feasible and safe method with a low procedure-related morbidity rate for patients where endoscopic placement via transillumination is not successful. Thus, the procedure is an attractive alternative to surgical tube placement. Long-term complications, mainly tube disturbances, can be treated easily.