Effects of plain and controlled-ileal-release budesonide formulations in experimental ileitis.

BACKGROUND: Budesonide combines a topical anti-inflammatory activity with high first-pass hepatic extraction. This study compared the effects of plain and controlled-ileal-release (CIR) formulations of budesonide on intestinal inflammation. METHODS: Ileitis was induced in hamsters by an intraluminal injection of trinitrobenzene sulphonic acid. Inflammation was assessed histologically and by measuring mastocytosis and myloperoxidase activity. Adrenal-pituitary axis suppression was assessed by radio-immunoassay of plasma cortisol. Animals received budesonide (200 or 800 micrograms/kg/day), CIR budesonide (200 micrograms/kg/day), or placebo. RESULTS: Plain budesonide (200 micrograms/kg/day) did not reduce intestinal inflammation despite significantly lowered plasma cortisol levels. Plain budesonide (800 micrograms/kg/day), on the other hand, significantly reduced intestinal inflammation but further decreased plasma cortisol levels. CIR budesonide (200 micrograms/kg/day) was as effective in reducing inflammation as plain budesonide (800 micrograms/kg/day). CONCLUSIONS: CIR budesonide was significantly more effective in reducing intestinal inflammation than plain budesonide. These results suggest that the site of delivery influences the effectiveness of budesonide and that local (topical) rather than systemic action of this compound is primarily responsible for its anti-inflammatory effect.

A randomized trial of a low fat high fibre diet in the recurrence of colorectal polyps. Toronto Polyp Prevention Group.

After polypectomy for adenomatous colorectal polyps, 201 persons were randomized to receive counselling on a diet low in fat (the lesser of 50 g/day or 20% of energy) and high in fibre (50 g/day) (LFHF), or to follow a normal western diet (ND), high in fat and low in fibre. After 12 months of counselling, fat consumption was about 25% of energy in the LFHF group and 33% in the ND group; fibre consumption was 35 g and 16 g respectively. After an average of two years of follow-up, an intention to treat analysis led to a ratio of cumulative incidence rates of 1.2 (95% CL 0.6-2.2) for recurrence of neoplastic polyps, a finding which suggests no significant difference between dietary groups over the period of observation. An exploratory analysis conducted among 142 persons with substantial diet counselling indicated a reduced risk of neoplastic polyp recurrence in women (RR = 0.5), associated with reduced concentrations of faecal bile acids while on the LFHF diet, but indicated an increased risk of recurrence in men (RR = 2.1), associated with increased faecal bile acids. Although a larger study would be needed to rule out the role of chance, these findings of gender-specific associations between diet counselling and both faecal bile acid concentrations and recurrence of colorectal neoplasia are consistent with recently published evidence of differences between genders.

Intestinal microcirculation and leukocyte behavior in ischemia-reperfusion injury.

Polymorphonuclear leukocytes are thought to play a pivotal role in the generation of ischemia-reperfusion-induced mucosal injury; however, their behavior in the intestinal microvasculature following this injury has not been directly examined. In this study intravital microscopy was used to investigate the dynamics of blood flow and leukocyte behavior in the villus, serosal, and mesenteric microcirculation during ischemia-reperfusion in anesthetized hamsters. Thirty minutes of ischemia and 90 min of reperfusion resulted in almost complete microvascular stasis in the villi of control animals, whereas only a few serosal and mesenteric microvessels exhibited stasis. Following reperfusion, there was a significant increase in leukocyte accumulation in all three tissues; however, significantly fewer leukocytes adhered in the villus microvasculature than in the rest of either the mucosa, serosa, or mesentery. Treatment with gamma-hydroxybutyrate (GHB), a compound that we have previously demonstrated to be highly effective in preventing ischemia-reperfusion injury, significantly reduced both the microvascular stasis and leukocyte accumulation in all three vascular beds. This study demonstrates that there are significant differences in the response to ischemia-reperfusion in various intestinal layers and that areas most susceptible to damage are not necessarily those exhibiting the greatest leukocyte accumulation.

gamma-Hydroxybutyrate mediated protection of liver function after long-term hypothermic storage.

Liver function was measured after 20 hr of hypothermic preservation in University of Wisconsin (UW) solution and in modified UW (MUW) solution containing gamma-hydroxybutyrate (GHB). Rat livers were rapidly cooled by in situ portal flushing with chilled UW or MUW solution, then removed and stored at 4 degrees C. After 20 hr of storage, liver hemodynamics and function were studied during 90 min of reperfusion in an isolated perfused liver system. Three groups were investigated: livers flushed with and stored in a commercial UW solution for 20 hr (UW group) or in a modified UW solution with 500 mg/L of GHB added (MUW group), and livers flushed with UW solution and reperfused immediately thereafter (control group). Addition of GHB to the cold storage solution significantly improved liver function after 20 hr of cold storage. Livers in the MUW group produced bile at a much higher rate then those in UW group (3.47 +/- 0.34 vs. 0.87 +/- 0.29 ml/100 g liver weight/min at 60 min of reperfusion), while the control livers produced 4.60 +/- 0.40 ml bile/100 g liver weight/min. At the same time, liver blood flow at a perfusion pressure of 11 cm H2O was significantly higher in the MUW group than in the UW group (391 +/- 32 ml/min/100 g liver vs. 177 +/- 33 ml/min/100 g liver) and only slightly lower than in the control group (494 +/- 49 ml/min/100 g liver). Aspartate amino-transferase (AST) and alanine aminotransferase (ALT) levels in perfusate samples taken from the venous effluent were raised during reperfusion in all groups. However, AST and ALT values were significantly lower (503 +/- 88 IU/L/100 g AST, 184 +/- 33 IU/L/100 g ALT) at 90 min of reperfusion in the MUW group than in the UW group (1567 +/- 330 IU/L/100 g for AST and 644 +/- 227 IU/L/100 g for ALT). This study clearly demonstrates that GHB greatly improves liver function and integrity after hypothermic preservation and has the potential to substantially increase the acceptable storage time of donor livers before transplantation.

The cardiovascular effects of gamma-hydroxybutyrate following hemorrhage.

We have previously shown that gamma-hydroxybutyrate (GHB) protects the small intestine against ischemia/reperfusion injury. This study examined the effects of GHB on cardiovascular function and intestinal microcirculation following hemorrhage. Hypotension was induced in control group of hamsters by controlled hemorrhage to a mean arterial pressure (MAP) of 40 mm Hg. Following 60 minutes of hypovolemia the shed blood was returned. This procedure resulted in complete intestinal mucosal microvascular stasis 2 hours following the return of shed blood. A second group of animals was treated with GHB (600 mg/kg body weight) and, despite the loss of 37% of total blood volume, GHB treatment completely prevented the microcirculatory stasis, following the reinfusion of shed blood. In male Wistar rats treated with GHB (200 mg/kg) after the induction of hemorrhage, blood pressure rapidly increased to pre-hemorrhage levels following treatment, even though the shed blood was not returned. Cardiac output (CO) also increased to pre-hemorrhage levels. Sodium chloride solution, in the same molar concentration as GHB (23% NaCl), produced much smaller, but statistically significant, increases in MAP and CO. In animals given an equal volume of normal saline, a gradual increase in MAP was observed, reaching statistical significance at 75 minutes following treatment. Three hours following hemorrhage, serum levels of creatine kinase were 3-fold higher, whereas aspartate aminotransaminase and alanine aminotransferase levels were 2-fold higher in both normal saline and hypertonic saline-treated animals than in GHB-treated animals. These experiments suggest that GHB can prevent ischemic complications following a hypovolemic episode and may improve survival following severe hemorrhage.

Upper gastrointestinal bleeding due to superior mesenteric artery to duodenum fistula: rare complication of metastatic lung carcinoma.

Although metastases from primary carcinoma of the lung to the small intestine appear to be more common than previously suspected, they rarely produce symptoms. Such metastases may present as bowel perforations. Overt gastrointestinal bleeding has been described only as a prelude to perforation. We describe the case of a 55-yr-old man with carcinoma of the lung that had metastasized to the brain and to the third part of the duodenum. The duodenal metastasis presented with massive upper gastrointestinal hemorrhage. The metastasis was seen to be actively bleeding at endoscopy, and a direct fistula from a branch of the superior mesenteric artery to the third part of the duodenum was shown angiographically. Arterial invasion and destruction by tumor was confirmed at postmortem examination. This complication of metastatic carcinoma of the lung has not been previously described in the English literature.

The protective effect of gamma-hydroxybutyrate in regional intestinal ischemia in the hamster.

The purpose of this study was to determine whether gamma-hydroxybutyrate provides protection against intestinal ischemia/reperfusion injury and to compare its effect with that of allopurinol and vitamin E. Thirty minutes of total regional ischemia, followed by 3 hours of reperfusion, produced intestinal damage that was completely prevented by gamma-hydroxybutyrate pretreatment. Naloxone partially blocked this protective effect. Allopurinol provided only partial protection against this injury, whereas vitamin E provided none. Treatment with gamma-hydroxybutyrate after ischemia but before reperfusion also provided significant protection. This study clearly demonstrates that gamma-hydroxybutyrate provides significant protection against intestinal ischemic injury and that it may do so via an opiate receptor-mediated mechanism.

Bowel function of long-term tube-fed patients consuming formulae with and without dietary fiber.

Diarrhea, constipation and subsequent laxative use are chronic problems in long-term enterally fed patients. We have conducted a double-blind randomized crossover study to evaluate the effects of two enteral formulae (Enrich, 12.8 g of dietary fiber per 1000 kcal and Ensure, fiber-free) on stool frequency, fecal weight, laxative use, gastrointestinal tolerance and bowel function in chronic care tube-fed patients. Twenty-eight subjects (24 male, 4 female) completed the study. Mean daily number of stools and mean daily fecal wet weight in Enrich-fed patients were not significantly different from those of patients receiving Ensure. Ensure-fed patients required significantly more laxatives (p = 0.02) than those receiving Enrich. There were 26 reports of diarrhea in the Ensure-fed group as compared to 6 in the Enrich-fed group, and this difference was significant (p = 0.006). Reporting rates for constipation were not significantly different in the two groups. At the end of the study, the bowel function of 57.1% of patients receiving Enrich was improved when compared with that of 14.3% of Ensure-fed patients, and this difference was significant (p = 0.005). These results suggest that the addition of dietary fiber to enteral formulae improves gastrointestinal tolerance and bowel function, and reduces laxative use in long-term enterally fed patients.

Dorsal duct sphincterotomy is effective long-term treatment of acute pancreatitis associated with pancreas divisum.

Nonbiliary, nonalcoholic pancreatic inflammatory disease was investigated by biochemical investigation, ultrasonography, endoscopic retrograde cholangiopancreatography, and secretin tests. Twenty-five consecutive cases were followed up for 12 months to 10 years after treatment of disease associated with pancreas divisum, diagnosed by endoscopic retrograde cholangiopancreatography. Thirteen patients had no recurrence of acute pancreatitis after dorsal duct sphincterotomy alone, during long-term follow-up (mean, 54 months); one patient had recurrent pancreatitis during 33 months after failed sphincterotomy. Eight patients had variable results 12 months to 8 years (mean, 49 months) after dorsal duct sphincterotomy for pancreatic pain syndrome (without amylase elevation), three were pain free, and one had recurrent pancreatitis. For 10 years after dorsal duct sphincterotomy for chronic pancreatitis, one patient had no pain relief; after subtotal pancreatectomy and pancreaticojejunostomy of the dorsal duct, both for chronic pancreatitis, one patient each was pain free and normoglycemic after 54 and 12 months, respectively. Dorsal duct sphincterotomy alone is successful in achieving long-term freedom from recurrence of acute pancreatitis associated with pancreas divisum. Pancreatic pain syndrome is not consistently improved by dorsal duct sphincterotomy. Chronic pancreatitis associated with pancreas divisum should be treated by resection or drainage procedures, not by dorsal duct sphincterotomy.

Treatment of chronic alcoholic pancreatitis by pancreatic resection.

Forty-one patients with chronic pancreatitis caused by alcoholism were selected for resective surgery on the basis of clinical criteria and findings on pancreatography. Five patients had Whipple resections, 32 had 80 percent resections, and 7 had total pancreatectomies (3 previously had subtotal pancreatectomies). One perioperative and three late deaths accounted for the overall mortality of 10 percent. Complete freedom from pain on long-term follow-up was achieved in all of the patients who had total pancreatectomy, in half of the patients who had 80 percent resection, and in only one of five patients who had Whipple resection. Diabetes occurred in only one patient after Whipple resection, in nearly half of the patients after 80 percent pancreatectomy, in a gradually accelerating manner, up to 5 years, and in all patients after total resection, where it was frequently complicated by recurrent alcoholism. Jaundice was a rare complication of disease progression in the overall treatment group; none of these patients presented with cholestasis preoperatively. Recurrent alcoholism was reported in 32 percent of the patients and contributed to two deaths.

New options in the surgical management of Crohn's disease.

Conventional surgical treatment of Crohn's disease involves multiple or extensive resections or bypass procedures. These contribute to the morbidity and mortality of the disease. Minimal resection with appropriate "strictureplasty" is proposed as an alternative approach. Strictureplasty is analogous to pyloroplasty. The authors performed 15 strictureplasties in three patients, all of whom had previously undergone small-bowel resection for Crohn's disease. They presented with symptoms of chronic bowel obstruction resistant to medical therapy. There were two minor postoperative complications. Two patients were asymptomatic 20 months postoperatively; the third required reoperation for recurrent enterovesical fistula. The technique is safe. Its efficacy will be determined by long-term follow-up.

Monocyte procoagulant activity in Whipple's disease.

We have studied the expression of procoagulant activity by the circulating mononuclear cells of four patients with Whipple's disease. There was a spontaneous expression of procoagulant activity in two patients with active untreated Whipple's disease. This activity was shown to originate in the monocyte fraction of the mononuclear cells and was demonstrated to cleave prothrombin directly. This prothrombinase activity was not Factor Xa, because it was not neutralized by anti-Factor X serum and was not inhibited by an established panel of Factor Xa inhibitors. The prothrombinase activity was not expressed by the monocytes of these patients following 8 weeks of antibiotic therapy, by which time the patients' symptoms resolved, and was not found in two patients previously treated for Whipple's disease who were in clinical remission or in normal subjects. Serial studies in one patient with active disease showed that monocytes failed to express increased prothrombinase within 2 weeks of antibiotic therapy. A second procoagulant activity was produced in response to endotoxin (LPS) by cells from controls and patients with Whipple's disease and was identified as thromboplastin. These observations suggest that circulating monocytes of patients with active Whipple's disease are endogenously stimulated to express prothrombinase activity, which may contribute, at least in part, to the pathophysiology of this condition.

Zollinger-Ellison syndrome, prolonged cimetidine administration and nasopharyngeal carcinoma:--a coincidence?

A patient with Zollinger-Ellison syndrome who developed an undifferentiated nasopharyngeal carcinoma (NPC) after 3 years of daily treatment with a least 1.0 g cimetidine is described. The question is raised whether large doses of cimetidine, administered for long periods to patients perhaps already immunologically compromised, may change T-suppressor cell functions so as to enable proliferation of oncogenic viruses (e.g. EB virus) and the appearance of tumor. We feel that when the population at risk is small, even a solitary case should alert all concerned.

Treatment of pancreatitis associated with pancreas divisum by dorsal duct sphincterotomy alone.

Of 480 patients seen with pancreatitis at the Sunnybrook Medical Centre, Toronto, in the past 5 years, 5 had pancreas divisum, demonstrated by pancreatography. Clinical presentations included recurrent acute pancreatitis, chronic pancreatitis and recurrent subcutaneous fat necrosis with steatorrhea. Pancreatography demonstrated dorsal pancreatic drainage through the duct of Santorini in all cases. The luminal diameter at the orifice of the duct of Santorini, assessed at operation, was inadequate to provide normal drainage from the gland. Sphincterotomy of the duct of Santorini alone, without surgery to the duct of Wirsung or sphincter of Oddi, was performed in four patients. This relieved the pain of chronic pancreatitis, eliminated recurrent attacks of acute pancreatitis and curtailed recurrence of subcutaneous fat necrosis and steatorrhea during follow-up periods of 51, 27, 17 and 28 months respectively. One patient who refused operation continued to have recurrent pancreatitis 41 months after diagnosis.

Resection for chronic alcoholic pancreatitis.

Nineteen patients with chronic alcoholic pancreatitis have been followed up for 7 to 81 months (mean 45 months) since resection for the relief of pain. Five had distal pancreatectomy, three had a Whipple resection, seven had 75% pancreatectomy and four had total pancreatectomy. Pain was completely relieved in all patients after total pancreatectomy and in four patients after 75% pancreatectomy. Recurrent acute pancreatitis was frequent after distal pancreatectomy. Alcoholism recurred in six patients. Steatorrhea was noted grossly in 14 patients after operation. It was corrected by enzyme replacement. All patients had long-term weight gain, except one who had undergone a Whipple resection. Diabetes developed in one patient who underwent 75% pancreatectomy, in one after distal pancreatectomy and in all patients who underwent total pancreatectomy; management of the diabetes was complicated by heavy alcohol consumption in one patient who underwent total pancreatectomy.

Fine structural changes in the liver of methotrexate-treated psoriatics.

Ultrastructure of 55 liver biopsies obtained from 52 patients, all but 1 with psoriasis and all but 5 treated with methotrexate (MTX), have been studied. In MTX-treated psoriatics, liver cell nuclei showed reduced electron opacity with frequent cytoplasmic invaginations and glycogen inclusions. In the mitochondria nonspecific changes, such as pleomorphism, gigantism, paracrystalline inclusions, compartmentalization, signs of division and sequestration via autophagosomy were noted. The pericanalicular ectoplasm exhibited widening with accumulation of microfilaments. Detachment of desmosomal plaques between hepatocytes was common. A striking finding was the hyperplasia of fat-storing perisinusoidal (Ito) cells. No definite correlation was found between morphology, duration of disease, treatment as well as cumulative dose of MTX.

Antibiotic-associated pseudomembranous colitis.

Two cases of pseudomembranous colitis, one associated with administration of ampicillin and the other associated with administration of ampicillin and trimethoprim-sulfamethoxazole, are reported. Both patients presented with diarrhea, abdominal pain, fever and an elevated leukocyte count. Pseudomembranous colitis was diagnosed by sigmoidoscopy and biopsy. Both patients recovered with conservative management.

Factitious diarrhea.

The causes of diarrhea are legion. In any diagnostic problem a factitious etiology must be carefully considered. Three cases are presented, in two of which daily ingestion of prunes and prune juice was found to be the cause of chronic diarrhea. In the third case an edible oil product, Coffee Rich, was determined by dietary manipulation to be the cause, carrageenan possibly being the laxative principle.