David L. Earnest

Lack of Effect of a High-Fiber Cereal Supplement on the Recurrence of Colorectal Adenomas

BACKGROUND The risks of colorectal cancer and adenoma, the precursor lesion, are believed to be influenced by dietary factors. Epidemiologic evidence that cereal fiber protects against colorectal cancer is equivocal. We conducted a randomized trial to determine whether dietary supplementation with wheat-bran fiber reduces the rate of recurrence of colorectal adenomas. METHODS We randomly assigned 1429 men and women who were 40 to 80 years of age and who had had one or more histologically confirmed colorectal adenomas removed within three months before recruitment began to a supervised program of dietary supplementation with either high amounts (13.5 g per day) or low amounts (2 g per day) of wheat-bran fiber. The primary end point was the presence or absence of new adenomas at the time of follow-up colonoscopy. Subjects and physicians, including colonoscopists, were unaware of the group assignments. RESULTS Of the 1303 subjects who completed the study, 719 had been randomly assigned to the high-fiber group and 584 to the low-fiber group. The median times from randomization to the last follow-up colonoscopy were 34 months in the high-fiber group and 36 months in the low-fiber group. By the time of the last follow-up colonoscopy, at least one adenoma had been identified in 338 subjects in the high-fiber group (47.0 percent) and in 299 subjects in the low-fiber group (51.2 percent). The multivariate adjusted odds ratio for recurrent adenoma in tile high-fiber group, as compared with the low-fiber group, was 0.88 (95 percent confidence interval, 0.70 to 1.11; P=0.28), and the relative risk of recurrence according to the number of adenomas, in the high-fiber group as compared with the low-fiber group, was 0.99 (95 percent confidence interval, 0.71 to 1.36; P=0.93). CONCLUSIONS As used in this study, a dietary supplement of wheat-bran fiber does not protect against recurrent colorectal adenomas.

Different bile acids exhibit distinct biological effects: the tumor promoter deoxycholic acid induces apoptosis and the chemopreventive agent ursodeoxycholic acid inhibits cell proliferation.

Epidemiological studies have suggested that the concentration and composition of fecal bile acids are important determining factors in the etiology of colon cancer. However, the mechanism by which these compounds influence tumor development is not understood. To begin to elucidate their mechanism of action, four bile acids, cholic acid, chenodeoxycholic acid, deoxycholic acid (DCA), and ursodeoxycholic acid, were examined for their effects on the growth of several different tumor cell lines. We found that incubating cells with chenodeoxycholic acid or DCA caused morphological changes, seen by electron and light microscopy, that were characteristic of apoptosis, whereas incubating cells with ursodeoxycholic acid inhibited cell proliferation but did not induce apoptosis. Cholic acid had no discernible effect on cells. Notably, the apoptosis induced by DCA could be suppressed by inhibiting protein kinase C activity with calphostin C. These results indicate that different bile acids exhibit distinct biological activities and suggest that the cytotoxicity reported for DCA may be due to its capacity to induce apoptosis via a protein kinase C-dependent signaling pathway.

Esophageal hypersensitivity may be a major cause of heartburn

OBJECTIVE:Little is known about esophageal nociceptive thresholds in chronic heartburn sufferers with normal clinical findings. The aim of this study was to evaluate and to characterize the pathogenesis of heartburn in subjects who chronically use antacids and had not sought medical attention.METHODS:Subjects (N = 152) with chronic heartburn of ≥3 months duration underwent endoscopic grading of the esophagus, esophageal manometry, Bernstein testing, intraesophageal balloon distention (IEBD), and 24-h esophageal pH monitoring.RESULTS:Normal acid contact time (ACT ≤6%) was observed in 43% of these subjects with recurrent heartburn. Of subjects with normal ACT, 64% had normal LES pressure (≥10 mm Hg), 79% had normal esophageal endoscopy, 89% developed heartburn during Bernstein acid infusion, and 52% perceived IEBD as painful.CONCLUSIONS:Approximately 30% of individuals chronically using antacids for heartburn had esophageal sensitivity to mechanical or chemical stimuli despite negative endoscopy and pH monitoring. Our findings suggest that a significant subset of typical heartburn sufferers have a lower threshold for esophageal sensation and pain, which may influence options for pharmacological intervention in such subjects.

Ethanol and cytokine secretion

Cytokines are regulatory polypeptides secreted during the generation of an immune or inflammatory response by lymphocytes, cells of the monocyte/macrophage series, and a variety of other cell types. Alterations in the production, site of action, or metabolism of cytokines by exogenous factors, such as ethanol (EtOH), may have deleterious effects on the immune system as a whole. EtOH has been implicated in the onset of a variety of immune defects in vivo including effects on the production of cytokines critically involved in inflammatory responses (tumor necrosis factor, interleukin 1 and interleukin 6). In this review, we examine current knowledge regarding the effects of EtOH on the release of cytokines in humans and in animal models, in vitro and in vivo, which may help to elucidate the adverse actions of EtOH on mammalian immune systems.

Predictors of the placebo response in functional dyspepsia.

Background  Trials in functional dyspepsia report placebo response rates of 30% to 40%.

Tegaserod treatment for dysmotility-like functional dyspepsia: results of two randomized, controlled trials.

OBJECTIVES: Therapies for dysmotility-like functional dyspepsia (FD) are limited. We studied tegaserod, a selective serotonin type 4 receptor agonist, in patients with FD.METHODS: Two identical multicenter, double-blind, randomized, placebo-controlled trials enrolled women ≥18 yr with recurring mid-upper abdominal discomfort characterized by postprandial fullness, early satiety, and/or bloating. Patients were randomized to tegaserod 6 mg b.i.d. or placebo. Two patient-reported primary variables were assessed: percentage of days with satisfactory symptom relief, and symptom severity using the composite average daily severity score (CADSS).RESULTS: In total, 2,667 women were randomized with no differences between trials in terms of recruitment method, Helicobacter pylori status, heartburn, or medication use. Mean percentage of days with satisfactory symptom relief for tegaserod versus placebo in Trial 1: 32.2% versus 26.6% (95% CI of treatment difference 2.82, 9.27; P < 0.01), Trial 2: 31.9% versus 29.4% (95% CI of treatment difference −0.21, 6.53; P= 0.066). Mean CADSS in Trial 1: 3.14 versus 3.35 (95% CI of treatment difference −0.29, −0.10; P < 0.0001), Trial 2: 3.15 versus 3.23 (95% CI of treatment difference −0.18, 0.01; P= 0.094). Meta-analysis showed significant benefit for both end points: increase in days with satisfactory relief 4.6% (95% CI 2.29, 6.96); decrease in CADSS 0.14 (95% CI 0.21, 0.07). Treatment effect was greater in patients with severe baseline symptoms. Diarrhea requiring study discontinuation was more common with tegaserod than placebo (4.1% vs 0.3%).CONCLUSIONS: Some improvement in dysmotility-like FD was observed with tegaserod treatment. The clinical implication of this improvement is uncertain.

Tegaserod and the risk of cardiovascular ischemic events: an observational cohort study.

Objectives: Tegaserod, a partial 5-HT4 agonist previously approved for treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation, was suspended from US marketing in 2007, based on pooled clinical trial results which contained a signal suggesting increased risk of cardiovascular ischemic events (CVIEs). We sought to evaluate whether there was an association between tegaserod and CVIE in a setting of routine clinical practice. Methods: This was a matched cohort study conducted within a large US health insurance database, involving 52 229 patients who initiated tegaserod and 52 229 patients with similar characteristics who did not initiate tegaserod. Participants were followed for up to 6 months for the occurrence of CVIE (myocardial infarction, acute coronary syndrome, coronary revascularization, and stroke). Outcomes were identified using insurance claims and were confirmed by review of medical records. We conducted as-matched analyses providing hazard ratios (HRs) along with 95% confidence intervals (95% CI) and as-treated analyses accounting for changes in dispensed therapy. Results: There was no increased risk of CVIE associated with tegaserod treatment. The as-matched association between tegaserod and ischemic cardiovascular outcomes (HR = 0.95, 95% CI 0.73-1.23) and stroke (HR = 0.90, 95% CI 0.46-1.77) did not change substantially in the as-treated analyses (cardiovascular relative risk [RR] = 1.14, 95% CI 0.83-1.56; stroke: RR = 1.09, 95% CI = 0.49-2.02). The results were largely unaffected by adjustment for characteristics or subgroup analyses. Conclusion: In this observational study of tegaserod use, we found no evidence for an increased risk of CVIE in tegaserod users.

Synchronous neoplasms in patients with diminutive colorectal adenomas

The distribution of synchronous neoplasms was retrospectively analyzed in 220 patients undergoing initial colonscopic evaluation for colorectal neoplasms. In 159 of the 220 patients, an index neoplasm was present in the rectosigmoid region. Of these 159 patients, 32 had an index rectosigmoid adenoma < 5 mm in diameter (diminutive), 105 had an index rectosigmoid adenoma ≥ 5 mm in diameter and 22 had an index rectosigmoid adenocarcinoma. Among these patients with different index neoplasms the frequency of synchronous neoplasms was 34%, 53%, and 73%, respectively. The synchronous neoplasm was an adenoma ≥ 5 mm in diameter in 13%, 40%, and 64%, respectively. The synchronous neoplasm was a carcinoma in 0%, 7%, and 5%, respectively. Two or more synchronous neoplasms occurred in 9%, 34%, and 41% of the index neoplasm groups, respectively. Finally, symptoms providing an indication for colonoscopy were present in 31%, 75%, and 86%, respectively. It is concluded that patients with diminutive index adenomas had fewer and smaller synchronous neoplasms (P < 0.025) than patients with larger adenomas or invasive carcinoma as the index lesion. Thus, total colonoscopy does not appear to be necessary in asymptomatic patients with only diminutive adenomas found at flexible sigmoidoscopy.

Omeprazole delays gastric emptying in healthy volunteers: an effect prevented by tegaserod

Background : Proton‐pump inhibitors effectively suppress stomach acidity. They are widely used for treating gastro‐oesophageal reflux disease and related conditions. While generally safe, omeprazole and other proton‐pump inhibitors can delay gastric emptying.

Idiopathic cecal ulcer. Diagnosis by colonoscopy followed by nonoperative management.

Idiopathic ulcer of the cecum has been considered a rare condition requiring surgical treatment because of a high incidence of complications, including bowel perforation. Cecal ulcerations are usually diagnosed at the time of surgery for presumed appendicitis or peritonitis of unknown origin. Preoperative diagnosis of cecal ulcer by barium enema has been unreliable and previous literature cites only one case diagnosed by colonoscopy. We describe four cases in which the diagnosis was made at colonoscopy. Three of our four patients were treated conservatively and did not require laparotomy. Idiopathic cecal ulcer should be considered in the differential diagnosis of lower gastrointestinal hemorrhage as well as atypical appendicitis. If the diagnosis of cecal ulcer is made by colonoscopy in a patient without evidence of an acute abdomen, conservative management may be followed by complete healing, avoiding unnecessary surgery.