Heimo H. Wenzl

Effect of oral tacrolimus (FK 506) on steroid‐refractory moderate/severe ulcerative colitis

Background : Steroid refractory ulcerative colitis is most commonly treated with intravenous ciclosporin to avoid colectomy. In search for an alternative drug that can be administered orally we investigated oral tacrolimus (FK 506) for this indication.

Anti-cardiolipin antibodies in patients with inflammatory bowel disease.

Elevated levels of anti-cardiolipin antibodiesare associated with an increased risk for venous andarterial thrombosis. In patients with inflammatory boweldisease thrombosis is a well known complication. We determined the prevalence of elevatedanti-cardiolipin antibodies in 136 patients withinflammatory bowel disease compared with 136 healthycontrols and analyzed thromboembolic complications inpatients with increased anti-cardiolipin antibodylevels. Anti-cardiolipin antibody titers weresignificantly elevated in patients with Crohns disease(5.7 units/ml) and ulcerative colitis (5.3 units/ml)compared to the control group (2.5 units/ml). We foundno correlation between disease activity andanti-cardiolipin antibody levels. Seven patients haddeep venous thrombosis in their history, in three ofthem this was complicated by pulmonary embolism. In onlytwo of the seven patients with deep venous thrombosiswere anti-cardiolipin antibody levels increased. Inconclusion, anti-cardiolipin antibody titers were significantly increased in patients withinflammatory bowel disease. Elevated anti-cardiolipinantibody levels appear to play no role in thepathogenesis of thromboembolic events in patients withinflammatory bowel disease.

Mycophenolate mofetil in patients with Crohn's disease.

Objective:Intolerance to azathioprine is a rare but important problem in treating chronically active Crohns disease. We performed this study to evaluate mycophenolate mofetil as an alternative immunosuppressive therapy for patients with Crohns disease who did not tolerate azathioprine.Methods:Four patients with highly active perianal Crohns disease and two patients with chronically active, steroid-dependent Crohns disease were included. All patients consumed 2 g/day of mycophenolate mofetil for a median of 8 months (range, 6–12 months). Disease activity was measured by the Perianal Crohns Disease Activity Index in patients with perianal disease and by the Crohns Disease Activity Index in patients with chronically active Crohns disease.Results:Azathioprine-induced side effects disappeared after the drug was discontinued. All patients improved during treatment with mycophenolate mofetil, as shown by a remarkable reduction in the respective clinical scores. Five patients showed no side effects during treatment with mycophenolate mofetil. After 4 months’ treatment one patient developed diarrhea that was probably not due to mycophenolate mofetil.Conclusions:Mycophenolate mofetil could be an alternative therapy to azathioprine in patients with Crohns disease.

Treatment of anemia in inflammatory bowel disease with recombinant human erythropoietin: Results in three patients

Inflammatory bowel disease (IBD) is often associated with anemia. Of 85 patients with IBD, 28 were anemic and had an inadequately low plasma erythropoietin (EPO) concentration. Three patients with a long-standing history of IBD and refractory chronic anemia (hemoglobin values < 10 g/dL, plasma EPO concentrations below 100 mU/mL) were treated with recombinant human EPO, which was administered subcutaneously three times per week at a dose of 200-300 U/kg of body weight. Bone marrow biopsy specimens taken before therapy showed slightly decreased erythropoiesis with a shift of erythroid precursors toward more immature stages. EPO treatment resulted in a marked increase in hemoglobin values in all 3 patients. Bone marrow biopsies after EPO therapy showed quantitatively and qualitatively normal erythropoiesis in all of them. Correction of anemia was followed by improved well-being, and all patients were able to cope much better with their IBD. In all three patients, there was an increase in body weight and their Karnofsky index improved. After a complete workup and exclusion of any other cause for anemia, erythropoietin treatment, although expensive, should be considered in patients with IBD and refractory anemia.

Mycophenolate mofetil for Crohn's disease: short-term efficacy and long-term outcome

Aim : To assess the long‐term efficacy of the antimetabolite agent mycophenolate mofetil in patients with Crohns disease.

Effect of Early Nutritional Deprivation and Diet on Translocation of Bacteria from the Gastrointestinal Tract in the Newborn Rat

The gastrointestinal (GI) barrier function is immature in the preterm neonate and might thus facilitate translocation of enteric bacteria and gut-derived septicemia. Circumstantial evidence suggests that bacterial uptake from the intestine may be further enhanced by an alteration of the host nutritional status. To test this hypothesis, neonatal rats were fed normal or restricted amounts of either breast milk or of a rat milk-simulated formula for 3-5 d. At the end of the study, various sections of the GI tract, mesenteric lymph nodes, liver, spleen, and blood were analyzed for bacteria using standard microbiologic procedures. Normal breast feeding was associated with bacterial translocation to mesenteric lymph nodes and in some cases to liver or spleen in 27% of rats, whereas all bacterial cultures were negative in a control group killed immediately after birth. Restricted breast feeding did not increase translocation compared with normal breast feeding. By contrast, feeding normal or restricted amounts of formula increased the numbers of gut bacteria by 2-3 logs, altered the morphology of the small intestinal mucosa, and resulted in ample bacterial translocation to the mesenteric lymph nodes and to systemic organs including the blood. Bacterial translocation may normally occur in suckling neonatal rats and is not increased by food restriction. Artificial feeding dramatically enhances translocation of gut bacteria.

Time course of spontaneous bacterial translocation from gastrointestinal tract and its relationship to intestinal microflora in conventionally reared infant rats.

Whereas the developed gut mucosal barrier prevents luminal bacteria from invading the host, bacterial translocation appears to be facilitated in the neonate. The aim of this study was to determine the extent to which bacteria spontaneously translocate from the gut to extraintestinal organs during the neonatal period and to relate translocation to the evolving intestinal flora in the rat. Newborn Sprague-Dawley rats suckled ad libitum and ate regular chow after weaning. A total of 167 rats were killed either immediately or at 1, 9, 14, 21, 26, or 42 days after delivery. Mesenteric lymph nodes (MLN), liver, heart blood, and the terminal ileal loop were harvested under sterile conditions and analyzed for aerobic and facultatively anaerobic bacteria by standard microbiologic procedures. Bacterial translocation to the MLN and liver began soon after birth and peaked during the second week. On day 14, translocation to any organ was present in 85% of rats. All cultures from the liver were sterile after day 26. By contrast, the fall in translocation to the MLN was incomplete, as 50% of pups still had positive MLN on day 42. Blood cultures were positive in three of the 167 rats. The intensity of translocation as determined by the number of organs infected significantly increased with the number of gram-negative enterics and gram-positive cocci in the gut and was negatively correlated with the percentage of lactobacilli from the total measured intestinal flora (P < 0.0001). In conclusion, bacterial translocation from the gut is a physiological and age-dependent phenomenon in the neonatal rat. Translocation appears to be facilitated when intestinal concentrations of gram-negative enterics and gram-positive cocci are high and when the concentration of lactobacilli is low.

A Comparison of Stool Characteristics from Normal and Constipated People

In people with constipation, it is not known if decreased frequency of defecation is associated with abnormalities in the weight or in the consistency of stools or if the weight or the consistency of stools correlates with the severity of various discomforts associated with bowel movements. In neither normal nor constipated subjects has the consistency of stools been carefully correlated with their relative contents of water and solids. Our aim was to gain insight into these questions. Twenty subjects with idiopathic chronic constipation and 20 age- and sex-matched control subjects were recruited by advertisement. Stools were collected for one week. After each bowel movement, the subjects perception of various discomforts associated with the bowel movement were recorded. The stools were then analyzed. The results and conclusions were as follows: (1) Stool weight per bowel movement was similar in the two groups but stool weight per week was markedly reduced in constipated subjects. (2) Reduced stool weight per week in constipated subjects was due to a nearly proportional reduction in stool water and stool solids output. (3) Using data from both groups, there was a curvilinear correlation between percent insoluble stool solids and stool hardness, as measured by a texture analyzer; hardness increased only slightly as percent insoluble solids increased between 7 and 20%, but hardness increased dramatically when percent insoluble solids exceeded 25%. (4) Only 6% of stools from constipated subjects (2 of 34) had abnormally high values for percent stool solids and physical hardness. (5) In subjects with constipation, the severity of various discomforts associated with bowel movements (such as straining) correlated poorly with the weight or the hardness of stool that was produced by the bowel movement.

Gut-Derived Bone Infection in the Neonatal Rat

The risk of osteomyelitis is increased in the premature and critically ill neonate. Although potential sites of bacterial entry are present in many of these infants, the source of infection frequently cannot be established. This study was performed to assess the possible role of bacterial translocation from the intestine in the origin of bone infection using models of breast-fed and formula-fed rat pups. Newborn Sprague-Dawley rats suckled either ad libitum by the dam (n = 30), or were fed a rat milk-simulated formula (n = 30). After 3 d, the animals were killed, and the left femur, heart blood, mesenteric lymph nodes, liver, spleen, and terminal ileum were excised. Organs were analyzed for bacteria by standard microbiologic procedures. Bacterial translocation occurred in 23% of breast-fed rats; the bone was not infected in any of these animals. After feeding of formula diet, bacterial counts of the ileum were markedly elevated (p < 0.001), and the composition of the gut flora was disrupted. Bacterial translocation was noted in all formula-fed rats. Bone cultures were positive in 23 of 30 (77%) rats after formula-feeding (p < 0.001 versus breast-feeding). Organisms translocated to the bone included Enterococci, Proteus, Enterobacter, and Escherichia coli. Bacterial species cultured from the bone correlated with the individual colonization pattern of other extraintestinal organs and with the composition of the ileal flora. Members of the gut flora can escape the intestine and colonize the bone in formula-fed rats. The gut should be considered as a potential source for osteomyelitis in the neonate.

Effect of prenatal cortisone on spontaneous bacterial translocation from gastrointestinal tract in neonatal rat

The immature host is prone to the passage of bacteria across the gut mucosal barrier. Corticosteroids accelerate the maturation of the intestinal mucosa and alter the composition of the gut bacterial flora. The present study was performed to assess the effect of prenatal cortisone on bacterial translocation in the neonatal rat. Time-pregnant Sprague Dawley rats were randomized on the 19th day of gestation for intraperitoneal injection of either 20 mg/100 g body weight of hydrocortisone or saline. Rats delivered spontaneously and the offspring were suckled ad libitum by the dam. Rat pups (N = 82) were killed 1 or 9 days after delivery. Mesenteric lymph nodes, liver, heart blood, and the terminal ileal loop were excised and quantitatively analyzed for bacteria. After one day, the proportion of rats with positive translocation was not significantly different between the two treatment groups (saline 62%, cortisone 80%, P = NS). By day 9, translocation had increased in the saline group (P = 0.03 vs day 1), did not significantly change in the cortisone group, and was significantly lower in rats treated with cortisone compared with the saline control (saline 90%, cortisone 60%, P = 0.02). The decrease in bacterial translocation after treatment with cortisone was associated with significantly lower total bacterial counts in the ileum (P < 0.05). Cortisone did not reduce bacterial counts in extraintestinal organs with positive translocation. In conclusion, prenatal treatment with cortisone reduces the incidence of spontaneous bacterial translocation from the intestine but not the concentration of translocated bacteria in extraintestinal organs of 9-day-old rats. Cortisone-induced changes of the intestinal microflora may have contributed to the reduction in translocation frequency.