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Etwa 80 % aller palliativmedizinischen Patienten haben unabhangig von der Primardiagnose gastrointestinale Beschwerden, die die Lebensqualitat extrem beeintrachtigen konnen. Es gibt ein breites Portfolio an medikamentosen und nicht medikamentosen Masnahmen zur Symptomkontrolle, moglichst orientiert an der zugrundeliegenden Pathophysiologie.

Differential therapy requires repeated diagnostic assessment for mapping and monitoring of disease activity in Crohn’s disease (CD). The purpose of this prospective study was to evaluate the accuracy of 18F-fluorodexyglucose positron-emission tomography (FDG-PET) for non-invasive assessment of disease activity in CD. 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. 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). 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.

Teaching ultrasound (US) has not been sufficiently standardised yet. Most educational devices in US consist of 2-dimensional B-mode images. However, the identification of anatomic structures in the 3-dimensional space can only be learned by practical hands-on education. In US simulators, US images of real pathologies are created by the examination of a dummy with a mock transducer. The resulting US images were previously recorded in a 3-dimensional format and were processed in a way which facilitates the reconstruction and projection of the images on a screen corresponding to the sectional plane of the mock transducer, simulating the conventional B-mode images. This enables standardised, real-time, hands-on training of US pathology detection. In June 2007, a hands-on workshop on US simulators was performed in the 1st Department of Internal Medicine of the Johannes Gutenberg-University in Mainz/Germany. During 15 days, 209 participants from all parts of Germany were trained. The workshop included an evaluation to elucidate the value and acceptance of this kind of US training. 149 evaluation forms could be analysed (72 %). The participants were fairly heterogeneous and belonged to the following subspecialties: internal medicine (50 %), surgery (11 %), others (18 %). 72 % were residents, 22 % consultants. 40 % of the participants worked in university hospitals, 12 % in hospitals of highest clinical level, and 42 % in hospital of basic care. Baseline knowledge in US was quite different, too, reflected in the number of independently performed US examinations prior to this course: 0 - 400 examinations (44 %), 401 - 1000 examinations (14 %), 1001 - 4000 examinations (7 %), and > 4000 examinations (2 %). Of note, 56 % of the participants had not received any kind of formal training in US. In daily practice 77 % were trained by tutors, whose formal qualification in US was unknown. Only a small proportion of the tutors had received training in US according to the standards of the German Association of US in Medicine (DEGUM). This evaluation shows the high level of acceptance of simulator-based training in US despite the heterogeneity of the participants. 95 % rated the teaching value as "high" and 95 % wished an integration of US simulators in training curricula. In summary, this analysis proves the need for standardised training programmes in US teaching in Germany and a high level of acceptance of simulator-based US training.

Die Palliativmedizin gewinnt in Deutschland aus gesellschaftlichen, medizinischen und okonomischen Grunden zunehmend an Bedeutung. Etwa 80% aller palliativmedizinischen Patienten leiden unter gastrointestinalen Symptomen, die zu teilweise extremer Beeintrachtung fuhren konnen. In einem zweiteiligen Beitrag soll eine Ubersicht uber die Moglichkeiten der Symptomenkontrolle, insbesondere der medikamentosen Kontrolle im hausarztlichen bzw. ambulanten Bereich gegeben werden. Auch im zweiten Teil ist es unser Anliegen aufzuzeigen, wie Schwerkranken in der Endphase eine Betreuung im hauslichen Umfeld ermoglicht werden kann. Im ersten Teil ging es um Beschwerden der Mundhohle sowie Ubelkeit und Erbrechen. In diesem Teil sollen Obstipation, Diarrho, Aszites, Ikterus und die gastrointestinale Obstruktion behandelt werden.

Die Palliativmedizin gewinnt in Deutschland aus gesellschaftlichen, medizinischen und okonomischen Grunden zunehmend an Bedeutung. Etwa 80% aller palliativmedizinischen Patienten leiden unter gastrointestinalen Symptomen, die zu teilweise extremer Beeintrachtung fuhren konnen.

On consideration of current medical and socio-economical factors, palliative care is becoming an increasingly important aspect of modern medicine in Germany. The German Society for Digestive and Metabolic Disorders (DGVS) has taken this into account by founding the working group "Palliative Gastroenterology". Patients with gastrointestinal malignancies or advanced non-malignant liver disease represent an important group that benefits from palliative care. Approximately 80 % of all palliative care patients suffer from gastrointestinal symptoms and endoscopic procedures performed by gastroenterologists play an important role in relieving symptoms such as obstruction. It is the object of this paper to evaluate the role of gastroenterologists in palliative medicine. It will give a brief definition, a historical review and the current legal background for palliative care in Germany and examine special aspects of ethics, decision making and research. Considering the current evidence on palliative endoscopic procedures this paper wants to establish the role of the gastroenterologist in palliative care far beyond the mere practicalities of endoscopy. The gastroenterologist is a crucial element of the interdisciplinary palliative care team and a partner to the patient in the process of decision-making. Finally, it is demonstrated how palliative care structures can be implemented in the setting of a university acute-care hospital.

Background and study aims Although various improvements in tissue imaging modalities have recently been achieved, in-vivo molecular and subsurface imaging in the field of gastroenterology remains a technical challenge. In this study we evaluated a newly developed, handheld, miniaturized confocal laser microscopy probe for real-time in-vivo molecular and subsurface imaging in rodent models of human disease. Materials and methods The minimicroscope uses a 488-nm, single line laser for fluorophore excitation. The optical slice thickness is 7 microm, the lateral resolution 0.7 microm. The range of the z-axis is 0-250 microm below the tissue surface. Imaging was performed using different fluorescent staining protocols; 5-carboxyfluorescein-labeled octreotate was synthesized for targeted molecular imaging. Results Cellular and subcellular details of the gastrointestinal tract could be visualized in vivo at high resolution. Confocal real-time microscopy allowed in-vivo identification of tumor vessels and liver metastases, as well as diagnosis of focal hepatic inflammation, necrosis, and associated perfusion anomalies. Somatostatin-receptor targeting permitted in-vivo molecular staining of AR42-J-induced carcinoma and pancreatic islet cells. Conclusions Confocal mini-microscopy allows rapid in-vivo molecular and subsurface imaging of normal and pathological tissue in the gastrointestinal tract at high resolution. Because this technology is applicable to humans, it might impact on future in-vivo microsocpic and molecular diagnosis of diseases such as cancer and inflammation.

Stenoses and fistulas are frequent complications in patients with Crohn's disease (CD). They represent a major diagnostic and therapeutic challenge and surgical intervention is often required. The availability of novel, anti-TNF strategies for therapy has raised the question as to what extent these new treatment options have impact on the clinical decision-making process regarding the necessity for surgery.A short overview of the current pathophysiological understanding of CD, focusing on the immunology of the intestinal mucosa, is given. Then the problems of proper clinical management of stenoses and fistulas are addressed. With regard to symptomatic stenoses, attention will be given to novel diagnostic tools for the distinction between inflammatory and fibrotic stenoses, and our clinical experience with the treatment of symptomatic inflammatory stenoses with infliximab will be discussed. With regard to fistulizing CD, the data that are currently available for medical therapy are summarized with special reference to the studies on the efficacy of anti-TNF treatment.With regard to moderately and severe inflammatory stenoses, medical treatment with infliximab may be an option after careful assessment of the inflammatory nature of the stenosis and exclusion of a septic focus. With regard to fistulas, anti-TNF treatment is a valuable option that is likely to improve the clinical outcome. Based on the available data, however, anti-TNF treatment cannot yet replace surgical intervention when necessary. Prospective trials of medical therapy and a combination of medical and surgical therapy for complex fistulas and internal fistulas are needed to define the potential and the limitations of these novel therapeutic approaches.

TNF-alpha is a pleiotropic cytokine with strong proinflammatory and immunomodulatory properties. TNF-alpha plays a critical role in many acute or chronic inflammatory diseases and anti-TNF-strategies have proven to be clinically effective. Two TNF-specific cell surface receptors TNF-R1 and TNF-R2 have been identified and the function of these receptors and the downstream intracellular signal transduction pathways have been extensively studied in vitro. For a long time TNF-R1 was considered to be the predominant mediator of TNF-signaling, whereas TNF-R2 was ascribed only auxilliary function. However, there is increasing clinical and experimental evidence for an important independent role of p80 signaling in chronic inflammatory conditions. It is conceivable that the multiple TNF-mediated chronic inflammatory disorders differ in terms of the ligand form (soluble TNF-alpha versus membrane bound TNF-alpha), the receptor (TNF-R1 versus TNF-R2) and the downstream signaling cascades utilized. The elucidation of the specific characteristics of TNF-signaling in distinct inflammatory disorders will lead to a better understanding ot the pathogenesis of these diseases and will be the basis for the development of more specific and more efficient therapeutic approaches.

According to the current paradigm both ulcerative colitis (UC) and Crohn’s disease (CD) result from a complex interplay of genetic susceptibility factors, environmental factors, alterations of the physiological intestinal flora and a defective regulation of the intestinal immune system. The objective of this review is to give an overview of these factors and mechanisms, including genetic, environmental and microbial factors, with special alterations of relevant cellular components of the intestinal immune system such as T cells, macrophages and epithelial cells will then be addressed. In addition, the most relevant animal model systems that have contributed to our current pathogenetic understanding will be introduced. Clinically, the natural course of UC with special reference to the risk of colorectal cancer will be addressed. The elucidation of pathomechanisms at the level of the intestinal immune system provides the potential for novel, effective treatment strategies. Best surgical management of patients with UC, however, still remains a challenge.

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 block- ade 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-κB, and bcl-xL was suppressed by azathioprine, leading to a mito- chondrial pathway of apoptosis. Azathioprine thus converts a costimulatory signal into an apoptot- ic signal by modulating Rac1 activity. These findings explain the immunosuppressive effects of aza- thioprine and suggest that 6-Thio-GTP derivates may be useful as potent immunosuppressive agents in autoimmune diseases and organ transplantation.

Stenoses are a frequent complication in patients with Crohn's disease and represent a major diagnostic and therapeutic challenge. The proper assessment of the nature of a stenosis as inflammatory or fibrotic is critical for appropriate treatment, since symptomatic fibrotic stenoses require surgical resection. Standard diagnostic procedures to assess the nature of a stenosis include endoscopy, conventional contrast radiography and magnetic resonance tomography. Recent data suggest, that the positron-emission-tomography possesses a high sensitivity and specificity to confirm inflammatory activity in the bowel. The recombinant monoclonal anti-TNF-antibody Infliximab (Remicade) has been approved for the treatment of steroid refractory and steroid dependent Crohn's disease in Germany since 9/2000 and the efficacy of Infliximab is well documented. However, few data exist about the treatment of inflammatory stenoses with Infliximab. We performed a retrospective analysis of our experience with Infliximab in patients with Crohn's disease with special reference to patients with inflammatory stenoses. Among a total of 21 patients treated with Infliximab 11 patients had an inflammatory stenosis. 9 of these patients responded well to Inflimab and became completely asymptomatic for a considerable period of time. Infliximab was tolerated well except for one patient who developed an intrabdominal abscess. The notable clinical response of patients with inflammatory stenoses to Infliximab suggests that treatment with Infliximab might be helpful to postpone or avoid surgical intervention. This finding should be further investigated in a prospective randomized study.

Untersuchungen der letzten 10 Jahre haben zu einem verbesserten Verstandnis der Pathophysiologie von chronisch entzundlichen Darmerkrankungen gefuhrt. Neuere Studien belegen hierbei v. a. die funktionelle Bedeutung einer Aktivierung des mukosalen Immunsystems durch bakterielle Antigene fur die Pathogenese der chronisch entzundlichen Darmerkrankungen (CED). Neben Chemokinen und Adhasionsmolekulen scheinen vor allem Zytokine, die von antigenprasentierenden Zellen und T-Lymphozyten produziert werden, pathogenetisch fur die CED von entscheidender Bedeutung zu sein. So konnte tierexperimentell gezeigt werden, dass Antikorper gegen proinflammatorische Zytokine zu einer Suppression von chronisch intestinalen Entzundungsreaktionen fuhren konnen, was durch eine Induktion von T-Zellapoptose bedingt ist. Basierend auf neuen Erkenntnissen zur Immunpathogenese der CED werden klinisch zzt. innovative Therapiekonzepte getestet, die z. B. rekombinante antiinflammatorische Zytokine und neutralisierende Antikorper gegen proinflammatorische Zytokine und ihre Rezeptoren umfassen. Trotz dieser Fortschritte im Verstandnis der Pathophysiologie und der Bedeutung des mukosalen Immunsystems bleiben jedoch zahlreiche Fragen uber die molekulare Immunpathogenese der CED offen und bedurfen weiterer Untersuchung.

Tumor necrosis factor (TNF) plays a pivotal role in the pathogenesis of Crohn's disease (CD). However, little is known about the role of TNF receptors (TNF-R) in this disease. Here, we found that TNF-R2 (in contrast to TNF-R1) was significantly up-regulated on lamina propria and peripheral blood T cells in CD compared to control patients. To directly test the functional role of TNF-R2 in Th1-mediated experimental colitis in vivo, we took advantage of transgenic animals overexpressing TNF-R2 in T cells. Reconstitution of SCID mice with CD4+ CD62L+ T cells from TNF-R2 transgenic mice led to an earlier wasting syndrome, a more severe colitis and augmented Th1 cytokine production than reconstitution with cells from wild-type littermates. In addition, TUNEL staining revealed a significantly decreased apoptosis rate of lamina propria mononuclear cells in mice reconstituted with TNF-R2 transgenic T cells compared to mice reconstituted with wild-type T cells. In summary, our data suggest a critical regulatory role of TNF-R2 signaling for disease exacerbation in Th1-mediated chronic colitis. Taken together with the increased expression of TNF-R2 inCD, selective targeting of TNF-R2 signaling thus emerges as a potentially novel approach to the treatment of CD.

For a long time corticosteroids, aminosalicylic acid preparations and antibiotics have represented the principal approaches in evidence-based drug therapy for chronic inflammatory bowel diseases (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC), and are able to suppress disease activity in most cases. However, there are cases that do not respond to conventional drug therapy or remain dependent on high doses of steroids associated with severe side effects in the long run. It is generally accepted now that IBD has an immunological basis and results from a hyperresponsive state of the intestinal immune system. Although the primary etiological defect respectively immunogenic agent still remains to be identified, substantial progress has been made in our understanding to regulatory mechanisms of the intestinal immune system and their alterations in IBD at the molecular level. Due to the concurrent advent of biotechnological processes it has been possible to utilise these insights for the development of novel immunomodulatory therapeutic strategies ranging from recombinant cytokines and blocking antibodies to oligonucleotide antisense strategies and gene therapeutic approaches. This review will present the current status of the development of these novel immunomodulatory therapeutic strategies in IBD and the status of their use in clinical practice. For a better understanding, it will be necessary to address the recent advances in the elucidation of pathogenetic mechanisms of IBD from studies in human specimen and experimental colitis models that have provided the basis for these novel therapeutic approaches.

The pro-inflammatory cytokine interleukin (IL)-6 (refs. 1-5) can bind to cells lacking the IL-6 receptor (IL-6R) when it forms a complex with the soluble IL-6R (sIL-6R) (trans signaling). Here, we have assessed the contribution of this system to the increased resistance of mucosal T cells against apoptosis in Crohn disease (CD), a chronic inflammatory disease of the gastrointestinal tract. A neutralizing antibody against IL-6R suppressed established experimental colitis in various animal models of CD mediated by type 1 T-helper cells, by inducing apoptosis of lamina propria T cells. Similarly, specific neutralization of sIL-6R in vivo by a newly designed gp130-Fc fusion protein caused suppression of colitis activity and induction of apoptosis, indicating that sIL-6R prevents mucosal T-cell apoptosis. In patients with CD, mucosal T cells showed strong evidence for IL-6 trans signaling, with activation of signal transducer and activator of transcription 3, bcl-2 and bcl-xl. Blockade of IL-6 trans signaling caused T-cell apoptosis, indicating that the IL-6-sIL-6R system mediates the resistance of T cells to apoptosis in CD. These data indicate that a pathway of T-cell activation driven by IL-6-sIL-6R contributes to the perpetuation of chronic intestinal inflammation. Specific targeting of this pathway may be a promising new approach for the treatment of CD.

Secretin is a 27-amino acid long peptide hormone that regulates pancreatic water, bicarbonate, enzymes, and potassium ion secretion. The human secretin receptor (hSR) is a glycoprotein consisting of 440 amino acids, of which there are 5 putative N-linked glycosylation sites at positions Asn 72 , Asn 100 , Asn 106 , Asn 128 (N-terminal ectodomain), and Asn 291 (second exoloop). Through functional analysis of the hSRtransfected cells cultured in the presence of various glycosylation inhibitors, it was found that tunicamycin and castanospermine were able to significantly reduce the secretin-stimulated cAMP response. On the other hand, the effects of other inhibitors, swainsonine and deoxymannojirimycin, were much lower, suggesting that the high mannose-type carbohydrate side-chain is essential to the expression of a fully functional hSR. The role of individual N-linked glycosylation sites was studied by mutation analysis (Asn to Leu or Ser to Ala) coupled to measurements of cAMP accumulation and extracellular acidification rate. The ED50 values of the wild-type receptor in these two assay systems were 0.25 and 0.11 nM, respectively, and mutation at position 100, 106, or 291 did not affect either the ED50 values or the maximal responses in the two assays. However, the Asn 72 Leu and Ser 74 Ala mutations reduced the maximal responses and increased the ED50 values in both assays, suggesting that this site is a true glycosylation signal. This hypothesis was further supported by competitive binding studies, the same mutants were found to be defective in binding with [ 125 I]secretin. To evaluate whether the change in receptor function of the mutants is caused by the change in the process of presenting the receptor to the cell surface, the mutants and the wild-type receptor were tagged with a c-Myc epitope at the C-termini. Using an anti-c-Myc monoclonal antibody and confocal microscopy, all of the mutant receptors were found to be expressed and delivered to the plasma membrane. (Endocrinology 140: 5102‐5111, 1999)

We report on a 67-year-old female patient who presented in July 2005 with sudden onset of pain in the right upper abdomen. The patient had undergone cholecystectomy in 1987. Because of recurrrent complaints in the right upper abdomen, a pigtail stent was placed into the common hepatic duct in 2001. When the patients presented now, the laboratory tests including liver enzymes were within normal ranges. Endoscopic retrograde cholangiogi aphy, however, revealed a remaining 10-French, impacted double pigtail endoprothesis that was obstructed by sludge as well as multiple giant bile duct stones of 20 to 30 mm in size. The giant stones could be finally removed by the combined use of ESWL and endoscopic techniques. This case demonstrates that impacted stents may favour the development of giant bile duct stones that may result in clinical symptoms only after prolonged periods of time.

The secretin receptor is prototypic of a recently described family of G protein-coupled receptors. We recently demonstrated its phosphorylation in response to agonist stimulation and elimination of this covalent modification by C-terminal truncation (F. Ozcelebi et al. (1995) Mol. Pharmacol. 48, 818-824). Here, we explore the functional impact of receptor phosphorylation and structural determinants for desensitization by comparing receptor behavior after agonist exposure in cell lines expressing wild-type and truncated receptor. To characterize receptor internalization, a novel fluorescent full agonist, [rat secretin-27]-Gly-rhodamine, was developed, which bound specifically and with high affinity. Both receptor constructs bound secretin normally, leading to normal G protein coupling and cAMP accumulation and prompt receptor internalization. Exposure to 10 nM secretin for 5 min or 12 h prior to washing and restimulation with a full range of concentrations demonstrated absent cAMP responses in wild-type receptor-bearing cells and responses 25 to 30% of control and shifted 1 order of magnitude to the right in the truncated receptor-bearing cells. Thus, the major mechanism of desensitization was phosphorylation-independent receptor internalization. Phosphorylation was associated with a distinct process that likely represents interference with G protein coupling, manifest as a reduced rate of cAMP stimulation. Thus, dual distinct mechanisms of desensitization exist in the secretin receptor family that should help protect receptor-bearing cells from overstimulation.

The aim of this study was to assess the potential of leflunomide, an immunosuppressant in rheumatoid arthritis, as a second-line immunosuppression treatment of patients with Crohn's disease refractory or intolerant to azathioprine. The study cohort consisted of 24 patients. The primary end point was steroid-free remission, and secondary end points were changes in the Crohn's disease activity index (CDAI) and steroid intake, responsiveness of arthralgias and adverse events. Results were expressed in medians (quartiles). The remission rate increased from 21 to 42% by week 16 (P < 0.05). In the intention-to-treat analysis, the CDAI decreased from 219 to 87 (P = 0.018) and the steroid intake from 25 to 3 mg/day (P = 0.033). In the per-protocol analysis, the CDAI decreased from 182 to 87 (P = 0.0183) and the steroid intake from 45 to 4 mg/day (P = 0.0778). Patients with arthralgias improved significantly. However, adverse side effects were frequent. Leflunomide may improve disease activity, especially in terms of arthralgias, and reduce steroid intake. Adverse events were more frequent in our patients than has been reported in controlled studies for rheumatoid arthritis but corresponded to those found in post-marketing studies.

Crohn's disease (CD) and ulcerative colitis (UC) are the two most common forms of chronic inflammatory bowel disease (IBD). The etiology of IBD is still unclear and should be considered as multi-factorial according to recent studies. Genetic factors seem to play a pathogenetic role as well as environmental, infectious and immulogical factors. Substantial progress, however, has been made in the understanding of the pathogenesis of IBD during the past years persuing the view, that IBD could result from disturbances of the intestinal barrier and a pathologic activation of the intestinal immune response towards luminal, bacterial antigens. This paradigm has led to the identification of key players of the intestinal immune system, which represent promising targets for novel therapeutic approaches. The objective of this chapter is to provide an overview over recent advances in the elucidation of the intestinal immune system in IBD and novel therapeutic approaches that have been derived from these results. Molecular biological techniques have revealed, that many of the established conventional antiinflammatory drugs such as salicylic acids, steroids or immunuosuppressants act at the same molecules that are the target for modern biologicals, i.e., the cytokine TNF or the transcription factor NFkappaB. This chapter, however, focusses on novel experimental approaches such as recombinant antiinflammatory cytokines, neutralizing antibodies or antisense oligonucleotides.

Crohn’s disease (CD) and ulcerative colitis (UC) are the two most common forms of chronic inflammatory bowel disease (IBD). The etiology of IBD is still unclear and should be considered as multi-factorial according to recent studies.1 Genetic factors seem to play a pathogenetic role as well as environmental, infectious and immulogical factors. Substantial progress, however, has been made in the understanding of the pathogenesis of IBD during the past years persuing the view, that IBD could result from disturbances of the intestinal barrier and a pathologic activation of the intestinal immune response towards luminal, bacterial antigens. This paradigm has led to the identification of key players of the intestinal immune system, which represent promising targets for novel therapeutic approaches. The objective of this chapter is to provide an overview over recent advances in the elucidation of the intestinal immune system in IBD and novel therapeutic approaches that have been derived from these results. Molecular biological techniques have revealed, that many of the established conventional antiinflammatory drugs such as salicylic acids, steroids or immunuosuppressants act at the same molecules that are the target for modern biologicals, i.e., the cytokine TNF or the transcription factor NFκB. This chapter, however, focusses on novel experimental approaches such as recombinant antiinflammatory cytokines, neutralizing antibodies or antisense oligonucleotides.

Recent data strongly support the view that coeliac disease is a Th1 mediated inflammatory disease as both interferon γ production and T-bet levels in gut infiltrating cells are upregulated The puzzling observation on high interferon γ (IFN-γ) but low interleukin (IL)-12 levels in coeliac disease (CD) has resulted in questions about the underlying principles of T helper cell polarisation. In this issue of G ut ,1 the molecular basis of T helper cell polarisation in CD has been illuminated by the finding that T-bet, the master transcription factor of T helper cell type 1 (Th1) cells, is upregulated in this disease [see page 1090] . The past decade has witnessed a dramatic improvement in our pathophysiological understanding of inflammatory disorders of the intestinum due to extensive research efforts focusing on regulatory mechanisms of the immune system. This has been greatly facilitated by the advent of molecular biological techniques which have allowed for the identification and characterisation of distinct factors in the complex regulatory network of the immune system. General themes have thus been recognised and an attempt is being made to classify diseases according to common immunological features. One crucial emerging theme is the Th1/Th2 polarisation of T helper cells.2,3 On activation with distinct immunological stimuli, naive CD4+ precursor T helper cells differentiate into mature T cells which either produce a so called Th1 cytokine profile characterised by tumour necrosis factor α (TNF-α) and IFN-γ, or a T helper cell type 2 (Th2) cytokine profile including IL-4, IL-5, IL-9, and IL-13. While these T cell subsets produce proinflammatory cytokines that can cause substantial tissue injury in vivo, more recent data suggest that additional subsets of CD4+ T helper cells exist with anti-inflammatory functions. These subsets include T helper 3 (Th3) cells producing transforming growth …

Timely diagnosis of intraepithelial neoplasias (IN) and colitis-associated colon carcinomas (CRC) is crucially important for the treatment of ulcerative colitis (UC). We performed a randomized, controlled trial to test whether chromoendoscopy (CE) might facilitate early detection of IN and CRC in UC.A total of 263 patients with long-standing UC (or=8 years) were screened for potential inclusion in the study, 165 of whom were randomized at a 1:1 ratio to undergo conventional colonoscopy or colonoscopy with CE using 0.1% methylene blue. Five mucosal biopsy specimens were taken every 10 cm between the rectum and cecum. Circumscript lesions in the colon were evaluated according to a modified pit pattern classification.In the CE group, there was a significantly better correlation between the endoscopic assessment of degree (P = 0.0002) and extent (89% vs. 52%; P0.0001) of colonic inflammation and the histopathologic findings compared with the conventional colonoscopy group. More targeted biopsies were possible, and significantly more IN were detected in the CE group (32 vs. 10; P = 0.003). Using the modified pit pattern classification, both the sensitivity and specificity for differentiation between non-neoplastic and neoplastic lesions were 93%.Based on our prospective randomized trial, CE permits more accurate diagnosis of the extent and severity of the inflammatory activity in UC compared with conventional colonoscopy. In addition, CE with methylene blue is a novel tool for the early detection of IN and CRC in patients with UC. These findings have important implications for medical and surgical interventions.

Tumor necrosis factor (TNF) plays a pivotal role in the pathogenesis of Crohn's disease (CD). However, little is known about the role of TNF receptors (TNF-R) in this disease. Here, we found that TNF-R2 (in contrast to TNF-R1) was significantly up-regulated on lamina propria and peripheral blood T cells in CD compared to control patients. To directly test the functional role of TNF-R2 in Th1-mediated experimental colitis in vivo, we took advantage of transgenic animals overexpressing TNF-R2 in T cells. Reconstitution of SCID mice with CD4+ CD62L+ T cells from TNF-R2 transgenic mice led to an earlier wasting syndrome, a more severe colitis and augmented Th1 cytokine production than reconstitution with cells from wild-type littermates. In addition, TUNEL staining revealed a significantly decreased apoptosis rate of lamina propria mononuclear cells in mice reconstituted with TNF-R2 transgenic T cells compared to mice reconstituted with wild-type T cells. In summary, our data suggest a critical regulatory role of TNF-R2 signaling for disease exacerbation in Th1-mediated chronic colitis. Taken together with the increased expression of TNF-R2 in CD, selective targeting of TNF-R2 signaling thus emerges as a potentially novel approach to the treatment of CD.

Tumor necrosis factor alpha (TNF-alpha) is a pleiotropic cytokine with strong proinflammatory and immunomodulatory properties. TNF-alpha plays a critical role in many acute or chronic inflammatory diseases and anti-TNF strategies have proven to be clinically effective. Two TNF-specific cell surface receptors, TNF-R1 (p60) and TNF-R2 (p80), have been identified and the function of these receptors and the downstream intracellular signal-transduction pathways have been extensively studied in vitro. For a long time p60 was considered to be the predominant mediator of TNF signaling, whereas p80 was ascribed only an auxilliary function. However, there is increasing clinical and experimental evidence for an important independent role of p80 signaling in chronic inflammatory conditions. To date, most data exist for Crohn's disease. Upregulation of p80 and increased p80 signaling aggravates experimental colitis and is likely to contribute to the chronicity of inflammation in vivo. Further studies are required to elucidate critically important steps in TNF signaling that might be dysregulated. This will lead to a better understanding of the pathogenesis of these diseases and potentially reveal new, more specific therapeutic targets.

As a result of extensive clinical and basic research, the pivotal role of tumour necrosis factor (TNF) in the pathogenesis of chronic inflammatory diseases such as inflammatory bowel disease (IBD) has now generally been acknowledged. This has led to promising clinically effective anti-TNF-strategies. Of note, there is more and more evidence that TNF seems to play a key role in other gastrointestinal diseases including Helicobacter pylori infection, pancreatitis, viral hepatitis and toxic liver damage, too. The action of TNF at the cellular level is mediated by two cell surface receptors, TNF-R1 (p60) and TNF-R2 (p80). The function of these receptors and the downstream intracellular signal transduction pathway have been extensively studied in vitro and it can be expected, that there are critically important steps in TNF-signal transduction that might be dysregulated in these disease states. Their elucidation could lead to a better understanding of the pathogenesis of these diseases, in particular IBD and potentially reveal new, more specific therapeutic targets. Objective of this review is to give an overview about the current knowledge on TNF signal transduction in relationship to selected examples of important gastrointestinal disorders with special focus on IBD. Finally, the implications for future research efforts will be discussed.

Detection of disease activity in Crohn's disease (CD) is of crucial importance for diagnosis and management of the disease. Noninvasive methods for monitoring are desirable and comprise hydromagnetic resonance imaging (hydro-MRI) and leukocyte scintigraphy. In addition, a recent case report indicated the potential of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to assess CD activity. However, comparative prospective studies are lacking.Between February, 1999 and August, 2000, 59 patients with CD were enrolled in a prospective study to assess disease activity by FDG-PET, hydro-MRI, and immunoscintigraphy with anti-nonspecific cross-reacting antigen 95 antigranulocyte antibodies. In 28 of these patients, colonoscopy could be performed. Twelve patients with irritable bowel syndrome and 20 tumor patients without gut inflammation served as controls. Results were compared by statistical analysis.FDG-PET detected 127 pathological findings (average maximum standardized uptake value = 4.4 +/- 1.1) in the terminal/neoterminal ileum (37), small bowel (24), and colon (66) of 54 patients with CD, whereas no pathological findings were seen in five patients with CD, the control patients with irritable bowel syndrome, and the tumor patients without gut inflammation. In contrast, examination with hydro-MRI or granulocyte antibodies detected less pathological findings in CD patients. Forty-five of the detected foci were accessible to endoscopic verification. The correlation of the foci with endoscopic findings showed a high specificity (89%) of all three methods to detect inflamed areas in the terminal ileum and colon of patients with CD, although analyses by hydro-MRI and granulocyte antibody scan had strikingly lower sensitivities (40.9% and 66.7%) than FDG-PET analysis (85.4%).FDG-PET appears to be a reliable noninvasive tool for simultaneous detection of inflamed areas in the small and large bowel of patients with CD. FDG-PET can be used to detect disease activity in the terminal ileum and colon of CD patients with high sensitivity and specificity.

The superfamily of guanine nucleotide–binding protein (G protein)-coupled receptors represents the largest group of receptor molecules yet identified. They bind ligands as structurally diverse as photons, odorants, biogenic amines, peptides, and large glycoproteins. This entire spectrum of natural agonists is accommodated by members of the largest, most extensively studied, and best understood family of such receptors, the rhodopsin/ b-adrenergic receptor family. Recently, another distinct family within this superfamily was identified.1 Known as the secretin receptor family, this family shares few of the specific sequence motifs of the rhodopsin/b-adrenergic receptor family and has less than 12% sequence homology with it, but still possesses the same predicted molecular architecture with seven transmembrane helices and appears to signal via a similar sequence of molecular events (Figure 1).1 Among the members of this family are receptors for two extremely important regulators of pancreatic, biliary, and gastrointestinal physiology: secretin and vasoactive intestinal polypeptide (VIP). Because of their clear physiological relevance to gastroenterology, they are the focus of this review. Also included in the secretin receptor family are receptors for pituitary adenylate cyclase–activating polypeptide (PACAP),2 gastric inhibitory polypeptide (GIP),3 glucagon,4 glucagon-like peptide 1,5 calcitonin,6 calcitonin gene-related peptide,7 parathyroid hormone,8 growth hormone–releasing factor (GHRF),9 corticotropin-releasing factor,10 insect diuretic hormone,11 and a few orphan receptors or more distantly related molecules. These receptors share substantial homology with each other, and all bind moderately large peptides possessing diffuse pharmacophoric domains. Some of these receptors are probably important in digestive physiology, but our current understanding of them does not suggest the presence of unique themes distinct from those that are developed in the following discussion. Biochemical and Molecular Characterization of Gastrointestinal Hormone Receptors

Distinct themes exist for ligand-binding domains of G protein-coupled receptors. The secretin receptor is prototypic of a recently described family in this superfamily which binds moderate-sized peptides possessing a diffuse pharmacophore. We recently demonstrated the importance of the N terminus and first loop of this receptor for secretin binding (Holtmann, M. H., Hadac, E. M., and Miller, L. J. (1995) J. Biol. Chem. 270:14394-14398). Here, we extend those findings to define another receptor domain important for agonist recognition and to focus on critical determinants within each of these domains. Extending the secretin-vasoactive intestinal polypeptide (VIP) chimeric receptor approach, we confirmed and refined the critical importance of the N terminus and the need to complement this with other domains of the secretin receptor. There was redundancy in the complementary determinants required, with the second extracellular loop able to compensate for the absence of the first loop. The first 10 residues of the N terminus of the secretin receptor were critical. Sequential segmental and site replacements permitted focusing on the His189-Lys190 sequence at the C terminus of the first extracellular loop, and on four residues (Phe257, Leu258, Asn260, and Thr261) in the N-terminal half of the second loop as providing critical determinants. All receptor constructs which expressed sensitive cAMP responses to secretin (EC50

Secretin and vasoactive intestinal polypeptide (VIP) receptors are closely related G protein-coupled receptors in a recently described family possessing a large amino-terminal ectodomain. We postulated that this domain might be critical for agonist recognition and therefore constructed a series of six chimeric receptors, exchanging the amino terminus, the first extracellular loop, or both in secretin and VIP receptors. Constructs were expressed in COS cells and characterized by cAMP generation and binding of both secretin and VIP radioligands. Wild type receptors demonstrated high affinity binding of respective ligands (IC50 values (in nM): at the secretin receptor: 2.2 for secretin, >1000 for VIP; at the VIP receptor: 2.2 for VIP, >1000 for secretin) and appropriately sensitive and selective biological responses (EC50 values (in nM): at the secretin receptor: 1.5 for secretin, 127 for VIP; at the VIP receptor: 1.0 for VIP, 273 for secretin). Replacement of the secretin receptor amino terminus with that of the VIP receptor resulted in biological responsiveness typical of the VIP receptor (EC50 = 120 nM for secretin, 1.7 nM for VIP). The converse was not true, with this domain of the secretin receptor not able to provide the same response when incorporated into the VIP receptor (EC50 = 50 nM for VIP, 30 nM for secretin). The addition of both the first loop and the amino terminus of the secretin receptor was effective in yielding a secretin receptor-like response (EC50 = 2.0 nM for secretin, 47 nM for VIP). All chimeric constructs expressing selectivity for secretin-stimulated activity bound this hormone with high affinity (IC50 = 0.2-2.2 nM); however, there was divergence between VIP binding and biological activity. Thus, the amino terminus of secretin and VIP receptors plays a key role in agonist recognition and responsiveness, with the first loop playing a critical complementary role for the secretin receptor.

Treatment of Patients With Crohn's Disease and Concomitant Chronic Hepatitis C With a Chimeric Monoclonal Antibody to TNF

AIM: To define the (co-)expression pattern of target receptor-tyrosine-kinases (RTK) in human gastric adenocarcinoma. METHODS: The (co-)expression pattern of VEGFR1-3, PDGFRα/β and EGFR1 was analyzed by RT-PCR in 51 human gastric adenocarcinomas. In addition, IHC staining was applied for confirmation of expression and analysis of RTK localisation. RESULTS: The majority of samples revealed a VEGFR1 (98%), VEGFR2 (80%), VEGFR3 (67%), PDGFRα (82%) and PDGFRβ (82%) expression, whereas only 62% exhibited an EGFR1 expression. 78% of cancers expressed at least four out of six RTKs. While VEGFR1-3 and PDGFRα revealed a predominantly cytoplasmatic staining in tumor cells, accompanied by an additional nuclear staining for VEGFR3, EGFR1 was almost exclusively detected on the membrane of tumor cells. PDGFRβ was restricted to stromal pericytes, which also depicted a PDGFRα expression. CONCLUSION: Our results reveal a high rate of receptor-tyrosine-kinases coexpression in gastric adenocarcinoma and might therefore encourage an application of multiple-target RTK-inhibitors within a combination therapy.

In October 2004, a 69 year female patient presented with melena and anaemia (haemoglobin level 9 g/dl). The patient had been on warfarin due to construction of an aorto-bifemoral graft because of an aortic aneurysm and an …