Mario Miglioli

Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial

BACKGROUND & AIMS We have recently documented the efficacy of a highly concentrated probiotic preparation (VSL#3) in the prevention of flare-up in patients with chronic pouchitis. The aim of this study was to compare probiotic therapy with VSL#3 versus placebo in the ability to prevent the onset of acute pouchitis during the first year after ileal pouch-anal anastomosis. METHODS Forty consecutive patients who underwent ileal pouch-anal anastomosis for ulcerative colitis were randomized to receive either VSL#3 (1 packet containing 900 billion bacteria/day) (n = 20) or an identical placebo (n = 20) immediately after ileostomy closure for 1 year. The patients were assessed clinically, endoscopically, and histologically after 1, 3, 6, 9, and 12 months. Health-related quality of life was assessed using the Inflammatory Bowel Disease Questionnaire. RESULTS Two of the 20 patients (10%) treated with VSL#3 had an episode of acute pouchitis compared with 8 of the 20 patients (40%) treated with placebo (log-rank test, z = 2.273; P < 0.05). Treatment with VSL#3 determined a significant improvement in Inflammatory Bowel Disease Questionnaire score, whereas this was not the case with placebo. CONCLUSIONS Treatment with VSL#3 is effective in the prevention of the onset of acute pouchitis and improves quality of life of patients with ileal pouch-anal anastomosis.

Effect of an Enteric-Coated Fish-Oil Preparation on Relapses in Crohn's Disease

BACKGROUND Patients with Crohns disease may have periods of remission, interrupted by relapses. Because fish oil has antiinflammatory actions, it could reduce the frequency of relapses, but it is often poorly tolerated because of its unpleasant taste and gastrointestinal side effects. METHODS We performed a one-year, double-blind, placebo-controlled study to investigate the effects of a new fish-oil preparation in the maintenance of remission in 78 patients with Crohns disease who had a high risk of relapse. The patients received either nine fish-oil capsules containing a total of 2.7 g of n-3 fatty acids or nine placebo capsules daily. A special coating protected the capsules against gastric acidity for at least 30 minutes. RESULTS Among the 39 patients in the fish-oil group, 11 (28 percent) had relapses, 4 dropped out because of diarrhea, and 1 withdrew for other reasons. In contrast, among the 39 patients in the placebo group, 27 (69 percent) had relapses, 1 dropped out because of diarrhea, and 1 withdrew for other reasons (difference in relapse rate, 41 percentage points; 95 percent confidence interval, 21 to 61; P < 0.001). After one year, 23 patients (59 percent) in the fish-oil group remained in remission, as compared with 10 (26 percent) in the placebo group (P = 0.003). Logistic-regression analysis indicated that only fish oil and not sex, age, previous surgery, duration of disease, or smoking status affected the likelihood of relapse (odds ratio for the placebo group as compared with the fish-oil group, 4.2; 95 percent confidence interval, 1.6 to 10.7). CONCLUSIONS In patients with Crohns disease in remission, a novel enteric-coated fish-oil preparation is effective in reducing the rate of relapse.

A pilot study of combination therapy with ribavirin plus interferon alfa for interferon alfa-resistant chronic hepatitis C

BACKGROUND/AIMS In chronic hepatitis C, interferon alfa (IFN-alpha) therapy fails to achieve a sustained response in approximately 75% of patients. Similarly, ribavirin induces only a transient response. The aim of this study was to evaluate whether ribavirin and IFN-alpha in combination could be effective in IFN-alpha-resistant chronic hepatitis C. METHODS Twenty patients with chronic hepatitis C resistant to a previous course of IFN-alpha were randomly assigned to receive either ribavirin combined with IFN-alpha or IFN-alpha alone for 6 months. RESULTS Serum alanine aminotransferase levels decreased significantly during therapy in both treatment groups, but after therapy, the levels remained significantly decreased only in the combination therapy group. Nine months after treatment, sustained normalization of aminotransferase levels, associated with sustained loss of serum hepatitis C virus RNA, was observed in 40% of the patients in the combination therapy group but in none of the patients treated with IFN-alpha alone (P < 0.05). The sustained response was accompanied by reduced hepatic necroinflammatory activity on biopsy. CONCLUSIONS These findings suggest that ribavirin plus IFN-alpha combination therapy is able to induce a sustained biochemical and virological response in a significant proportion of patients with IFN-alpha-resistant chronic hepatitis C.

High eradication rates of Helicobacter pylori with a new sequential treatment

Background : Eradication rates of Helicobacter pylori with standard triple therapy are disappointing, and studies from several countries confirm this poor performance.

Fat-induced heal brake in humans: A dose-dependent phenomenon correlated to the plasma levels of peptide YY

BACKGROUND Upper gastrointestinal motility is regulated by the presence of nutrients in the distal gut. The present study evaluated whether lipid-induced ileal brake on gastric emptying (1) can be elicited by low fat concentrations; (2) is a dose-dependent phenomenon; and (3) is related to gastrointestinal peptide release. METHODS Seven patients were studied in the defunctionalized stage of total colectomy, on three separate occasions. On each study day, patients ate a meal labeled in the solid component; 30 minutes later, one of the following solutions was randomly infused into the ileal pouch: 0.9% saline, 2% oleic acid, and 20% oleic acid. Plasma concentrations of peptide YY (PYY), enteroglucagon, neurotensin, and motilin were measured. RESULTS Both oleic acid solutions slowed gastric emptying compared with saline (P < 0.001), the effect being dose dependent (P < 0.001). Ileal infusions did not modify neurotensin and enteroglucagon levels but induced a dose-dependent increase of PYY (P < 0.01) and a borderline decrease of motilin (P = 0.05) levels. Slower rates of gastric emptying were related to increased plasma concentrations of PYY (r = 0.615; P < 0.05). CONCLUSIONS This study shows that (1) the ileal brake on gastric emptying can be evoked by low doses of lipids in the distal ileum; (2) the delay of gastric emptying is related to the release of PYY; and (3) both phenomena are dose dependent.

Serum interleukin-6, interleukin-8, and beta 2-microglobulin in early assessment of severity of acute pancreatitis. Comparison with serum C-reactive protein.

The aim of this study was to compare the sensitivity, specificity, and diagnostic accuracy of serum interleukin-6, interleukin-8,β2-microglobulin, and C-reactive protein in the assessment of the severity of acute pancreatitis using commercial kits for their respective assays. Thirty-eight patients with acute pancreatitis (25 men, 13 women, mean age 59 years, range 16–97) were studied; the diagnosis was based on prolonged upper abdominal pain associated with a twofold increase of serum lipase, and it was confirmed by imaging techniques. According to the Atlanta criteria, 15 patients had severe illness and 23 had mild disease. The four serum markers were determined in all patients on admission, as well as daily for the following five days. On the first day of the disease, the sensitivity (calculated on patients with severe pancreatitis), specificity (calculated on patients with mild pancreatitis), and the diagnostic accuracy of these serum markers for establishing the severity of acute pancreatitis were 100%, 86%, and 91% for interleukin-6 (cutoff level 2.7 pg/ml); 100%, 81%, and 88% for interleukin-8 (cutoff level 30 pg/ml); 58%, 81%, and 73% forβ2-microglobulin (cutoff level 2.1 mg/liter); and 8%, 95%, and 64% for C-reactive protein (cutoff level 11 mg/dl). The results of our study indicate that, when assayed during the first 24 hr of disease onset, interleukin-6 and interleukin-8 are better markers thanβ2-microglobulin or C-reactive protein for evaluating the severity of acute pancreatitis.

Reversibility of GERD ultrastructural alterations and relief of symptoms after omeprazole treatment.

BACKGROUND:Dilation of intercellular spaces (DIS) of human esophageal epithelium, evident at transmission electron microscopy (TEM), is an early marker of damage caused by gastroesophageal reflux, but its reversibility after therapy has not been investigated.AIM:To evaluate whether omeprazole can induce the healing of DIS.METHODS:Thirty-eight symptomatic patients, 22 with nonerosive reflux disease (NERD) and 16 with erosive esophagitis (EE), classified on the basis of 24-h pH monitoring, were enrolled. During upper gastrointestinal endoscopy, six biopsies from apparently normal mucosa were taken within the lower 5 cm of the esophagus for histological and TEM analysis. One hundred computer measurements were taken on TEM photomicrographs of the specimens in each patient. After 3 months of omeprazole 40 mg/die a further endoscopy with biopsies was performed. In patients with persistent heartburn and/or incomplete ultrastructural recovery of esophageal epithelium, a new endoscopy was performed after 3 more months of treatment.RESULTS:After 3 months of therapy, 35 patients (92.1%) showed a complete recovery of DIS and resolution of heartburn. Three patients required 3 more months of therapy because of an incomplete recovery of the epithelium correlated with sporadic heartburn. Healing of the mucosa was achieved in two patients, whereas one had an incomplete recovery of DIS with persistent heartburn.CONCLUSIONS:Three and six months of omeprazole therapy led to a complete recovery of DIS in 92.1% and 97.4% of cases, respectively. No significant differences of DIS between NERD and EE were noted. Complete recovery of DIS was accompanied by regression of heartburn in all cases.

Effects of sildenafil on esophageal motility of patients with idiopathic achalasia

BACKGROUND & AIMS Sildenafil shows an intense and prolonged inhibitory effect on the smooth muscle cells of the human corpus cavernosum by blocking phosphodiesterase type 5 that destroys nitric oxide-stimulated cyclic guanosine monophosphate. We investigated if sildenafil possesses a similar effect on the esophageal musculature of patients with achalasia, where there is an impairment of nitric oxide production similar to that of functional impotence. METHODS In 14 patients affected by achalasia with an esophageal diameter of </=5 cm, esophageal motility was recorded with a low-compliance manometric system. After a basal period of 30 minutes, a 50-mg tablet of sildenafil dissolved in water was infused in the stomach in 7 patients and one of placebo in the other 7 patients, randomly and in double-blind manner, continuing the recording for 60 minutes. RESULTS Lower esophageal sphincter tone, residual pressure, and wave amplitude after sildenafil showed a significant decrease compared with both the basal period and the placebo group, with a marked interpatient variability. The inhibitory effect reached its maximum (about -50%) 15-20 minutes after the infusion and lasted <1 hour. Propagation of pressure waves was not modified by sildenafil. CONCLUSIONS Sildenafil inhibits the contractile activity of the esophageal musculature of patients with achalasia, decreasing lower esophageal sphincter tone and residual pressure as well as contraction amplitude.

Oral 5-aminosalicylic acid (asacol) in the maintenance treatment of Crohn's disease

A randomized, placebo-controlled multicenter trial was conducted to evaluate the efficacy and safety of a delayed-release formulation of 5-aminosalicylic acid (5-ASA) (Asacol; Giuliani & Bracco, Milan, Italy) for prevention of clinical relapse in 125 patients with inactive Crohns disease. Patients in remission [Crohns Disease Activity Index (CDAI) less than 150] between 3 months and 2 years were randomly allocated to receive either 800 mg 5-ASA three times daily (n = 64) or placebo (n = 61) for up to 12 months or until relapse of symptoms. Relapse was defined by a CDAI greater than 150, with a minimum increase of 100 points over the baseline value. The cumulative relapse rates were 12% in the 5-ASA group and 22% in the placebo group at 3 months [95% confidence interval (CI) for the difference, -4 to 24]; 28% and 41%, respectively, at 6 months (95% CI, -4 to 30); and 34% and 55%, respectively, at 12 months (95% CI, 3-39; P = 0.02, log rank test). Significant decrease in the risk of relapse was found in patients with ileitis, in those with previous bowel resection and, in those with prolonged prestudy remission. Eight patients (5 on 5-ASA, 3 on placebo) withdrew from the study because of adverse reactions, but no major clinical or laboratory adverse effect was observed. It is concluded that oral 5-ASA coated with Eudragit S (Rohn Pharma GmbH, Wieterstadt, Germany), 2.4 g daily, is safe and seems superior to placebo in preventing or delaying clinical relapse in Crohns disease, especially in milder cases and in ileal disease.

The Stool Antigen Test for Detection of Helicobacter pylori after Eradication Therapy

Context Standard treatment regimens do not eradicate infection in approximately 10% to 20% of people with ulcers or gastritis caused by Helicobacter pylori. Symptoms do not reliably identify patients who have persistent infection despite treatment. Although positive results on a urea breath test done 4 weeks after treatment reliably identify persistent infection, a noninvasive test that detects successful eradication earlier would be useful. Contribution This multicenter study shows that a positive finding on a stool antigen test done as early as 1 week after treatment identifies about 95% (range, 70% to 100%) of cases of persistent infection. Generalization Cautions Findings are from patients with dyspepsia who were referred for endoscopy; 20% of patients were still infected at 1 month despite eradication therapy. The Editors Noninvasive tests for Helicobacter pylori are important in primary care, both for initial diagnosis of H. pylori infection and for confirmation of eradication. Current guidelines recommend noninvasive testing and treatment of young dyspeptic patients without alarm symptoms (such as dysphagia or weight loss that suggest underlying malignant disease) in a primary care setting by using low-cost noninvasive tests (1, 2). Randomized, controlled trials have shown that a test and eradicate strategy toward H. pylori is effective in patients with dyspepsia seen in primary care settings who have not undergone investigations such as endoscopy or radiographic studies (3). Post-therapy testing is also growing in importance. Resistant strains of H. pylori are now widely prevalent in the United States and Europe, and eradication therapy with current regimens fails in 10% to 20% of patients (4, 5). Furthermore, some patients with ulcer disease remain symptomatic despite successful eradication of H. pylori and healing of the ulcer (6). In patients with persistent symptoms, testing for persistent H. pylori infection is important to direct further therapy. Routine testing to confirm eradication in patients with complicated ulcer disease, such as bleeding peptic ulcer, is necessary because the risk for rebleeding is greatly increased in patients with persistent infection (7). The choice of tests in the post-therapy setting is limited. Serologic tests are unreliable in determining eradication (8). Endoscopic tests (rapid urease test, histologic examination, or culture) are reliable, but endoscopy is expensive and inconvenient. Until recently, the only noninvasive test that reliably demonstrated whether eradication was successful was the urea breath test (9). This test has high sensitivity and specificity in the post-therapy setting but cannot be used until 4 weeks after treatment. Moreover, the breath test is still not widely available in the United States. The fecal antigen test is a relatively new noninvasive test for detection of H. pylori (10). This test detects the presence of infection by measuring the fecal excretion of H. pylori antigens. It has been approved by the U.S. Food and Drug Administration for detection of H. pylori before and after therapy. We sought to determine whether a stool antigen test administered at various times after treatment correctly identifies persons in whom H. pylori infection persists despite eradication therapy. Methods We prospectively studied 84 patients infected with H. pylori at six clinical centers (31 in Bologna, Italy; 29 in Amsterdam, the Netherlands; 9 in Rome, Italy; 8 in Lisbon, Portugal; 4 in Madrid, Spain; and 3 in Milwaukee, Wisconsin). The sample consisted of consecutive patients with dyspepsia (defined as pain or discomfort centered in the upper abdomen) who were referred by primary care physicians for upper endoscopy (11). Consenting patients were enrolled if they tested positive for H. pylori on endoscopic tests. Patients enrolled in this study have not been enrolled in other studies. Patients were excluded if they had taken proton-pump inhibitors, H2-receptor antagonists, nonsteroidal anti-inflammatory agents, or antibiotics in the 4 weeks before the study. Failure to return for follow-up endoscopy was an a priori exclusion criterion. All patients gave written informed consent, and the study was approved by the human subjects review committee or equivalent at each participating institution. At baseline, patients underwent endoscopy with biopsy sampling for histologic examination (two samples from the antrum and two from the corpus), culture (two samples from the antrum and two from the corpus), and a rapid urease test (one sample from the antrum). All patients were infected with H. pylori at baseline, as demonstrated by positive results on both rapid urease testing and histologic examination or a positive culture for H. pylori. Within 24 hours of the endoscopy, all patients underwent a 13C or 14C urea breath test. The breath test was chosen according to local availability and experience, but in all cases a validated breath test analysis system was used. Cut-off values were determined according to the recommendations of the various manufacturers of these tests. Patients collected stool using a kit consisting of a plastic spoon that is used to scoop a small amount of stool from the toilet paper or toilet bowl into an airtight container. At all sites, the stool assay was performed by using the Premier Platinum HpSA test (Meridian Diagnostics, Inc., Cincinnati, Ohio). The assay is a microwell-based enzyme immunoassay that uses polyclonal antiH. pylori capture antibody adsorbed to microwells. Diluted patient samples and a peroxidase-conjugated polyclonal antibody were added to the wells and incubated at room temperature for 1 hour. A wash was performed to remove unbound material. Substrate was added and incubated for 10 minutes at room temperature. Color develops in the presence of bound enzyme. Stop solution was added, and the results were inspected spectrophotometrically at 450 nm within 15 minutes of adding the stop solution. Visual determination can also be used; this has been shown to have similar results (12). A positive control and a negative control are built into the test. The cut-off values were classified as negative (<0.140), indeterminate (0.140 to 0.159), or positive (>0.160). After completion of the baseline procedures, treatment was begun with ranitidine bismuth citrate (400 mg twice daily) or omeprazole (20 mg twice daily) in combination with amoxicillin (1 g twice daily) and clarithromycin (500 mg twice daily) for 7 to 10 days. Seven-day eradication therapy was used in Europe, where it is approved by the European Union and has been shown to be effective (5). Ten-day triple therapy with proton-pump inhibitors was used in the United States, where it is approved by the U.S. Food and Drug Administration. Patients collected stool for the stool antigen test on days 3, 7, 15, 21, 28, and 35 after completion of H. pylori eradication therapy. On day 35 after completion of eradication therapy, endoscopy was repeated and biopsy samples were again obtained for histologic examination, culture, and the rapid urease test, as performed at the baseline visit. The 13C or 14C urea breath test was repeated on day 35 by using the same method and cut-off values as at baseline. Patients were classified as being infected with H. pylori at baseline and having persistent infection on day 35 if culture of gastric biopsy specimens was positive for H. pylori or results of the rapid urease test and histologic examination were positive. All other patients were classified as negative. These criteria have been recommended by an expert panel for use in clinical trials of H. pylori eradication (13). At baseline, the sensitivity of the stool test and urea breath test were calculated by using the presence of infection (defined above) as the gold standard. At each time point after completion of therapy (days 3, 7, 15, 21, 28), predictive values were calculated by using continued infection on day 35 as the gold standard (positive result on culture or on rapid urease test and histologic examination). Trained investigators who were blinded to the results of the other diagnostic studies performed the stool assays. The first endoscopy procedure was performed before the stool and breath tests. Therapy was given on the basis of results on endoscopic testing. Endoscopists were blinded to the results of post-treatment stool studies and the breath test until all evaluations were completed. Long-Term Follow-up Patients in whom eradication of H. pylori was successful were eligible for entry into a long-term study evaluating the stool antigen test. For 6 months, stool antigen tests were done monthly and a urea breath test was obtained every 3 months. Statistical Analysis Statistical analysis was performed by using StatView for Windows, version 5.01 (SAS Institute, Inc., Cary, North Carolina). Results are presented as the mean (SD). Sensitivity, specificity, probabilities, and predictive values are presented with 95% exact binomial CIs. Equivocal stool tests are considered by inclusion in the denominator of sensitivity and specificity. Stool antigen concentrations at individual time points were compared by using theMannWhitney test with downward adjustment of the P values for repeated observations (14). Role of the Funding Source The manufacturer (Meridian Diagnostics, Inc.) provided the stool kits. The study had no other funding source. Collection, analysis, and interpretation of the data, including the decision to publish, were solely the decision of the authors; the manufacturer of the test had no role in this process. Results The mean age of the 84 study patients was 52 years (range, 18 to 81 years). Fifty-three patients were women, and 31 were men. Endoscopic findings were as follows: normal (7 patients), esophagitis (2 patients), erythema in the antrum (45 patients), erosions in the antrum (11 patients), erosive duodenitis (9 patients), duodenal ulcers (8 patients), gastric ulcer (2 p