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Since ancient times chronic inflammatory bowel diseases have been known as non-contagious colitis and remain as an unsolved enigma of internal medicine. In the past 50 years it became clear that the incidence is increasing, the cause is multifactorial genetics as well as environment and the intestinal immune reaction is directed against the intestinal microbiota and not tissue antigens. Based on groundbreaking genetic studies the focus has moved from adaptive to innate immunity and thus from autoimmunity to a barrier defect. This paradigm shift will have a major impact on therapies which are traditionally immunosuppressive and will be developed to improve the antibacterial mucosal barrier in the future., (© Georg Thieme Verlag KG Stuttgart · New York.)

The human gut is colonised by about one kilogram of commensal bacteria. These microorganisms are a potential threat, thus an efficient defence system is crucial in preventing bacterial translocation and infection. Besides other mechanisms of protection humans produce antimicrobial peptides (AMPs) that are able to kill a broad range of microorganisms. The human beta-defensin 1 (hBD-1) plays a major role because it is produced constitutively by all human epithelia and some immune cells. In contrast to other AMPs, however, the biological function of hBD-1 has remained unclear since the antibiotic activity of hBD-1 in vitro was only marginal. But still, several diseases have been associated with genetic polymorphisms in the hBD-1 encoding gene. Herein we discuss why the biological role of hBD-1 has been overlooked and how hBD-1 can be activated by chemical reduction. We elaborate on the biological significance of this activation and its importance for inflammatory bowel disease., (© Georg Thieme Verlag KG Stuttgart · New York.)

Double-balloon enteroscopy (DBE) is a newly developed method allowing deep insertion of a thin endoscope into the small bowel, thereby enabling inspection, biopsy and endoscopic treatment of previously inaccessible lesions. This retrospective analysis evaluates the diagnostic and therapeutic efficacy in all patients undergoing DBE at our institution. A total of 109 DBEs were performed in 82 patients (57 patients with suspected small bowel blood loss and 25 patients with other indications). The diagnostic success rate was 51 of 82 (62 %) with a higher rate in bleeders in whom angiodysplasias were the most frequent diagnosis. DBE had therapeutic consequences in 47 patients (57 %), of whom 33 patients (40 %) underwent endoscopic therapy and 6 patients (7 %) surgery. In 4 patients, malignant neoplasias were newly diagnosed (2 gastrointestinal stroma tumors, 1 neuroendocrine tumor, 1 adenocarcinoma). Other diagnostic modalities were helpful in preselecting patients for DBE and choosing the more favorable (oral or anal) access. In 16 of 26 patients, pathological findings in videocapsule endoscopy were substantiated by DBE. In 7 patients, the findings of CT or MRI enteroclysis, and in 4 patients with hematochezia, the results of a preceding erythrocyte bleeding scan were confirmed by DBE. In conclusion, this series indicates that DBE of the small bowel - in concert with other diagnostic modalities - has a high diagnostic and therapeutic efficacy.

Background: Whole gut lavage with a polyethylene glycol electrolyte solution (PEG) is a common bowel cleansing method for diagnostic and therapeutic colon interventions. Absorption of orally administered PEG from the gastrointestinal tract in healthy human beings is generally considered to be poor. In patients with inflammatory bowel disease (IBD), intestinal permeability and PEG absorption were previously reported to be higher than in normal subjects. In the current study, we investigated the absorption of PEG 3350 in patients undergoing routine gut lavage., Methods and Results: Urine specimens were collected for 8 hours in 24 patients undergoing bowel cleansing with PEG 3350 for colonoscopy. The urinary excretion of PEG 3350, measured by size exclusion chromatography, ranged between 0.01 and 0.51 % of the ingested amount, corresponding to 5.8 and 896 mg in absolute amounts, respectively. Mean PEG excretion in patients with impaired mucosa such as inflammation or ulceration of the intestine (0.24 % +/- 0.19, n = 11) was not significantly higher (p = 0.173) compared to that in subjects with macroscopically normal intestinal mucosa (0.13 % +/- 0.13, n = 13)., Conclusion: The results indicate that intestinal absorption of PEG 3350 is higher than previously assumed and underlies a strong inter-individual variation. Inflammatory changes of the intestine do not necessarily lead to a significantly higher permeability of PEG.

Defensins are endogenous antimicrobial peptides with a broad activity spectrum. Even at micromolar concentrations gramnegative and grampositive bacteria, but also mycobacteria, as well as fungi (candida), viruses (herpes) and protozoa (giardia lamblia) are destroyed. As part of the innate immune system defensins are expressed by the intestinal epithelium and contribute to the maintenance of the mucosal barrier. This barrier appears to be defective in inflammatory bowel diseases since on one hand, the immune response is directed against the "normal" luminal bacterial flora and on the other hand, mucosal adherent and invasive bacteria have been observed in these diseases. A defective defensin expression may well explain these phenomena. Indeed, Crohn's disease of the terminal ileum, especially if associated with a NOD2 mutation, is characterised by a diminished alpha-defensin (human defensin 5 and 6) expression, and in inflamed Crohn's colitis, in contrast to ulcerative colitis, the beta-defensin (human beta-defensins 2 and 3) response is reduced. Through a deficient chemical mucosal barrier this defect could lead to increased bacterial invasion into the intestinal mucosa and might well explain an adequate inflammatory response. Although the final proof that this deficient defensin response leads to a reduced antibacterial activity of the intestinal mucosa is still lacking, the most plausible concept of pathogenesis of Crohn's disease is a defensin deficiency syndrome.

The chimeric antibody directed against tumor necrosis factor- alpha (TNF alpha) Infliximab (Remicade) is effective in the therapy of Crohn's disease. This is rather surprising since it was unlikely that single factor should be effective, considering the complexity and redundance of the mucosal cytokine system. Because of safety reasons and high cost the indication should be restrictive.

Bile salts are reabsorbed from the intestine by active and passive transport mechanisms with great efficacy. Conflicting data do not allow to judge for certainty whether bile salt absorption is under negative or positive feedback control. To address this issue, we analyzed bile salt absorption in vivo along the entire intestinal tract of rats and hamsters that received intraduodenal bile salt infusions for 54 h following interruption of the enterohepatic circulation. Taurocholate absorption in rats was complete, even when unphysiologically high concentrations of taurocholate were given. The combined infusion of taurocholate together with potent inhibitors of bile salt synthesis such as deoxycholate, taurodeoxycholate or taurochenodeoxycholate, failed to inhibit bile salt absorption. In the hamster, taurochenodeoxycholate and taurocholate absorption was complete and could not be inhibited when given in supraphysiological concentrations. Finally, taurocholate absorption was not impaired when deoxycholic acid was infused. These results provide indirect evidence that bile salt absorption is under positive feedback control regulated by luminal bile salt concentrations.

Azathioprine has been found effective in chronic active Crohn's disease. The aim of this open uncontrolled trial was an efficacy analysis in hospitals and private practices versus results of controlled trials. 89 patients with active Crohn's disease (CDAI > 150) were included in a multicenter trial of azathioprine therapy during one year. Follow-up evaluations were scheduled at three, six and twelve months and included self-assessment as well as physicians assessment of disease activity using CDAI and laboratory parameters. 65 patients (73%) completed the study per protocol until twelve months. At the end of the trial 75% of patients were in remission (CDAI < 150), 22% were ameliorated and two patients (3%) deteriorated. Corticosteroid dose was dropped from 0.46 mg/kg bw to 0.18 mg/kg bw during the study. Adverse events, primarily allergy, nausea and hyperlipasemia were frequent (21%), but only two patients had to be withdrawn from the trial. Everyday use of azathioprine for the treatment of chronic active Crohn's disease in hospital and private practice is equally effective compared to results of previous controlled trials. High doses of steroids at the beginning of azathioprine therapy may be associated with higher remission rates at one year.

Currently, evidence-based medicine is subject of a controversial discussion. This review is focused on the different types of evidence in clinical medicine and elaborates the history and context of evidence-based medicine. Evidence-based medicine insists that the theoretical plausibility of a therapeutical concept alone does not substitute for the empirical proof of its efficacy. Evidence-based medicine emphasizes the necessity to complement the individual physician's clinical experience with valid external evidence. This evidence has to be obtained by laborious systematic reviews rather than the traditional fragmentary study of the literature. The Cochrane Collaboration stands for this concept. The application of evidence-based medicine links the individual patient's problems with external evidence by asking defined answerable questions and supplies criteria for the critical evaluation of the evidence found. Evidence-based medicine, however, is not devoid of problems and contradictions. Above all, it has to be subjected to its own criteria and has to prove its efficacy.

Glucocorticoid excess causes insulin resistance i.e. a reduced effectiveness of insulin to suppress hepatic glucose production and to increase glucose uptake in muscle and fat tissue. Persons who cannot compensate for the resulting additional insulin need develop overt diabetes during glucocorticoid therapy. In the field of gastroenterology, glucocorticoids are mainly employed for the therapy of chronic inflammatory bowel diseases, alcoholic and autoimmune hepatitis, and after liver transplantation. The risk of developing steroid diabetes depends among other things on the genetic predisposition, the body composition, the underlying gastrointestinal disease, the age, and the steroid dose. The treatment of glucocorticoid-induced diabetes resembles essentially the treatment of type 2-diabetes. In addition to dietary measures, oral antihypoglycemic drugs and/or insulin are applied. If oral antihypoglycemic drugs are used, specific problems that might result from the gastrointestinal diseases need to be observed. In the short and medium term, the prognosis of glucocorticoid-induced diabetes is good since it is well treatable. If glucocorticoid treatment is continued for a long time, the alterations of glucose metabolism and the resulting hyperinsulinemia may lead to increased cardiovascular risk.

The polyamine dependence of enterocyte growth and differentiation was studied in the human intestinal cell line CaCo-2 using a specific inhibitor of the key enzyme ornithine decarboxylase (ODC), difluoromethylornithine (DFMO). ODC was highest during the initial phase of rapid growth and was inhibited in a dose dependent fashion by DFMO at 0.06-2 mM. At low levels DFMO only delayed cell replication without affecting final cell count whereas at concentrations of 0.125 mM and above the final cell number was diminished by at least 53% compared to controls. In contrast, DFMO even at 0.03 mM reduced sucrase activity to 44% of controls when added at day 2 but was ineffective when supplemented at day 7 of culture or later. The inhibitor also diminished the number and length of microvilli in a dose dependent fashion, although this effect required higher DFMO levels than the reduction of sucrase activity. The DFMO mediated suppression of cell replication, enzymatic and morphologic differentiation was reversible in the presence of the ODC product putrescine. Putrescine alone did not affect any of the above parameters. In conclusion, the present data suggest that ODC and polyamines are involved both in enterocyte growth and differentiation.

We determined the capacity and the profile of prostaglandin synthesis in the antral mucosa of patients with erosive (n = 43) or non-erosive (n = 24) Type B gastritis in comparison with normal controls (n = 24). Prostaglandin synthesis was measured by the incorporation of 14C-labelled arachidonic acid into cyclooxygenase products in mucosal homogenate. There was no significant difference between controls and patients with antral gastritis. Furthermore, there was no correlation of the prostaglandin synthesis with helicobacter colonisation or with the degree of inflammation. In another group of 15 patients there was a 17% increased synthesizing capacity nearby the erosions, compared to a non-erosive area (p = 0.05). In these patients with chronic Type B gastritis the treatment with an antacid (Maalox 70, 4 x 10 ml) for 4 weeks did not affect the synthesizing capacity or the profile of mucosal prostaglandin synthesis.

We report five instances of local lysis with rt-PA (recombinant tissue type plasminogen activator) in three patients with thrombotic occlusions of their peritoneovenous Denver shunts (PVS). In all cases liver cirrhosis was alcohol-induced and ascites was refractory to all medical measures. Because of rethrombosis two patients were treated again after 13 months. The occlusion had occurred 2-30 days before treatment. In four of the five instances the local lysis was successful. Complications were rare. This scintigraphic visualization of the catheter system allowed assessment of shunt patency under physiological flow conditions. The local lysis of a thrombotic shunt with rt-PA and scintigraphic monitoring is a low-risk alternative to reoperation. Possible benefits compared to other fibrinolytics must be confirmed by a greater patient collective.

In a controlled study patients with Crohn's disease received an exclusion diet or an diet low in refined carbohydrates and rich in fiber. A total of 26 patients was observed for 1 year. The exclusion diet was not significantly superior to the standard diet with respect to the clinical course (Crohn's disease activity index according to Best or van Hees) or laboratory parameters of inflammatory activity. During dietary counselling relapses were infrequent and symptoms improved in both dietary groups.

The changes in the structure and proliferative activity of rabbit ileal mucosa have been studied with morphometric and stathmokinetic techniques during 24 h organ culture. Under control conditions the villus base diameter and villus height decreased by 34 and 53%, respectively, whereas the number of villi per mm2 remained constant. The reduction of crypt depth was less pronounced than the loss in villus height, leading to a decrease in the villus height to crypt depth ratio from 3.4 to 2.3. The likely reason for this culture induced hypoplasia was a significant drop in mitotic activity as early as 2 h after starting the culture. Inhibition of HMG-CoA reductase, the key enzyme of cholesterogenesis, lead to a further reduction in mucosal dimensions and a near complete suppression of crypt cell regeneration. These data imply that despite the well-known preservation of differentiated function mucosal cell renewal during organ culture is impaired.

During a 7 years study, the endoscopically determined prevalence and incidence of peptic gastroduodenal ulcer in 305 patients with portal hypertension (72% alcoholic cirrhosis, 21.3% non-alcoholic cirrhosis, 6.7% non-cirrhotic portal hypertension) were 4.3% and 3.9% per year, respectively. The yearly risk per patient of suffering from peptic ulcer was 7.4% if both, first and recurrent ulcers (total: 49) were considered. No association was disclosed of peptic ulcer with sex, age, etiology or severity of liver disease. Although an adequate control group was not yet available for comparison, the data do not support the previously postulated relationship between liver cirrhosis and peptic ulcer.

A decreased PG E2 content in gastric mucosa of humans receiving a longterm antirheumatic therapy has been reported to be partially reversed after a one week treatment with an antacid (Reimann et al., Fortschr Med 102 [1984], 25-26). Therefore the effect of an Aspirin treatment of healthy volunteers with or without an antacid on the prostaglandin synthesis in gastric or duodenal mucosa was investigated. 14C-labelled arachidonic acid was used as substrate during in vitro incubation of the mucosal homogenate for determination of the endogenous formation of prostaglandins. Aspirin suppressed the total prostaglandin synthesis to less than 10% of control after one week treatment. The addition of a high dose antacid did not influence this inhibition, and no significant effect on the prostaglandin profile was detectable. It is concluded that antacids do not influence the suppression of the endogenous prostaglandin synthesis by NOSAC's, however another effect, eg a prolonged stability of PG E2 in a less acidic environment is more likely.

Prostaglandins are involved in many physiological functions of the gastrointestinal tract, e.g. the secretion of acid, mucus and bicarbonate, the motility, the microcirculation and cytoprotection. The diverse prostaglandins as well as prostacyclin and thromboxane are synthesized by a complex enzymatic system, which is affected by a multitude of possibly regulatory influences. Such mechanisms are the availability of dietary essential fatty acids, the calcium, dependent activation of the phospholipase A2, the self-inactivation of the prostaglandin cyclooxygenase, the availability of cofactors, the catabolism of the prostanoids and others. A minireview concerning these potentially regulatory mechanisms in the upper gastrointestinal tract is presented.