Nonspecific esophageal motility disorders may be an early stage of a specific disorder, particularly achalasia.

The clinical significance of nonspecific esophageal motility disorder (NEMD) is unclear. Our aim was to investigate the natural history of NEMD. All manometries performed at Meir Hospital from 1997 to 2004 and diagnosed as NEMD were reviewed. Manometric criteria for NEMD included either low-amplitude peristalsis, nonprogression of peristalsis, prolonged retrograde or triple-peaked waves, or incomplete relaxation of the lower sphincter. Patients determined to have NEMD were contacted and asked to complete a questionnaire and undergo a second manometry. NEMD had been diagnosed in 137 patients. Upon review of manometry results, 65 patients were eligible for the study (36 men and 29 women). The other 72 patients did not have NEMD when we reviewed their manometry tracing, applying strict criteria as specified in Table 1. The average age was 64 +/- 16 years (range 24-83 years). The average follow-up period was 7 +/- 2 years. All 65 patients were symptomatic at their initial prestudy visit. By the second visit, symptoms had resolved in 33 (51%) patients and improved in 13 (19%). Dysphagia, chest pain, and food regurgitation had improved, whereas heartburn and respiratory symptoms had not. Of 37 patients with triple-peaked waves, only 11 (30%) had improved clinically. Of the 65 study patients, 17 (26%) had a second manometry during the study, which was normal in 2 (12%), unchanged in 11 (69%), and revealed achalasia in 4 (23%), representing 6% of all study patients. NEMD is generally a benign disorder that improves clinically in most cases. Nevertheless, in about 6% of patients, NEMD may evolve into achalasia.

Cyclosporin for severe ulcerative colitis.

BACKGROUND: About one-third of patients with severe ulcerative colitis do not respond to conventional therapy and require urgent colectomy. It was recently shown that cyclosporin is effective in some of these patients. OBJECTIVES: To review the current experience of six hospitals in central Israel that used cyclosporin in patients with severe ulcerative colitis. METHODS: The files of all 32 patients treated with cyclosporin for corticosteroid-resistant ulcerative colitis were reviewed. Activity of disease was measured by a clinical activity, index colonoscopy and laboratory tests. RESULTS: The average duration of treatment with intravenous cyclosporin was 12.7 days (range 9-28) after which the disease activity index dropped from an average of 14.22 to 4.74. The mean time for response was 7.5 days (4-14). Twelve patients (40%) required surgery within 6 months and another 6 patients (18.8%) were operated on after more than 6 months. Twelve patients (37%) maintained remission for at least 6 months and did not require surgery. In one patient treatment was stopped because of non-compliance and one was lost to follow-up. There were numerous side effects, but in only one case with neurotoxicity was treatment withdrawn. CONCLUSIONS: Cyclosporin is a relatively safe and effective treatment for severe ulcerative colitis. It induced long-term remission in 37% of the patients, and in those who required surgery the treatment resulted in an improved clinical condition before the operation.

Abnormal gallbladder emptying in a subgroup of patients with gallstones.

Gallbladder stasis has been implicated in gallstone formation. Gallbladder filling and emptying were quantitated by computer-assisted cholescintigraphy in 41 normal subjects versus 26 patients with gallstones. Gallbladder contraction was induced by low-dose (1.2 U/kg . h) cholecystokinin infusion. Gallstone patients exhibited normal gallbladder filling, but emptying was significantly (p less than 0.01) reduced compared with controls. On closer inspection, the patients fell into two subgroups, separated by t1/2, the time to empty 50% of gallbladder contents, 19.1 min (mean + 2 SD of control). Fifteen patients (57.7%) with a normal t1/2 (less than 19.1 min) exhibited both normal filling and normal emptying. The remaining 11 patients (43.3%) with t1/2 greater than 19.1 min had grossly abnormal gallbladder emptying, significantly (p less than 0.001) different from both the previous patient subgroup and the controls. There was no significant difference in age, sex, prevalence of obesity, presence or absence of biliary colic, and gallstone size, number, or calcification between these two subgroups. Thus, defective gallbladder emptying is evident in a subgroup of gallstone patients, and is independent of clinical features, stone size, and number. Impaired emptying should be considered when assessing pathogenesis or medical therapy.

Endoscopic sphincterotomy in biliary tract disease.

In many centers endoscopic sphincterotomy is replacing surgery, which has never been an ideal treatment for retained common duct calculi. We attempted endoscopic sphincterotomy in 70 patients, succeeding in 60 (85%). Sixty-one patients had choledocholithiasis (58 postcholecystectomy), 7 had papillary stenosis, 1 carcinoma of the papilla of Vater, and 1 hydatid disease. Repeat cholangiography in 56 patients with gallstones showed spontaneous passage in 44. In three patients the sphincterotomy required extension, and in three the stones were extracted using a Dormia basket. In four patients the stones did not pass, and surgical removal was necessary. Satisfactory biliary drainage was obtained in all the other patients, and the only complications noted were cholangitis and severe pancreatitis. Endoscopic sphincterotomy is reasonably safe and an acceptable, if not preferable, alternative to surgical removal of retained gallstones, and it is also effective in relieving papillary stenosis.

The effects of prosthetic gallstones on gallbladder function and bile composition.

Diminished gallbladder emptying has been implicated in the pathogenesis of gallstone formation. This study assessed the effect of the physical presence of inert, prosthetic gallstones on gallbladder contractility, histopathology, and bile composition. Three glass beads, each 3 mm in diameter, were implanted in the guinea pig gallbladder. Six weeks later the in vitro contractility was assessed in response to cholecystokinin. Sham-operated animals underwent cholecystotomy without bead implantation. The gross and microscopic appearance of gallbladders from sham-operated and implanted animals was the same. The presence of stones moderately inhibited gallbladder contraction reaching 20.5% (P less than 0.05) at the maximally effective dose of cholecystokinin compared to sham-operated animals. Sham-operated and control (unoperated) animals had similar gallbladder contractility. Thus surgery itself did not alter gallbladder motility. The presence of stones had no effect on biliary lipid composition. It thus appears that gallstones, in the unobstructed gallbladder, cause only a moderate inhibition of gallbladder contractility and have little effect on biliary physiology.

In vitro effects of pancreatic polypeptide and motilin on contractility of human gallbladder.

In vivo studies have indicated that pancreatic polypeptide induces gallbladder relaxation, whereas motilin initiates contraction of the gallbladder. To determine if these two polypeptides act directly on the gallbladder muscle, their effect on strips of human gallbladder was studied in vitro. Preparations were suspended in an organ bath and the isometric tension recorded. Dose-response curves to cholecystokinin and acetylcholine were first established. The ability of pancreatic polypeptide to cause relaxation under basal conditions and during 50% maximal stimulation by cholecystokinin-octapeptide (2 X 10(-8) M) was assessed on four strips at approximate physiological concentration (300 pmol/liter) and on four additional strips at 10(3) higher concentration. Pancreatic polypeptide did not have any effect on the basal or the cholecystokinin-generated tension at either concentration. The response to motilin was evaluated on four gallbladder strips at concentrations ranging from 10(-11) to 6.7 X 10(-7) M. Although the highest concentration was more than 10(5) greater than levels reported in fasting serum, motilin did not initiate any gallbladder strip contraction. Whereas the preparation was unresponsive to pancreatic polypeptide and motilin, it was capable of contracting in a dose-related fashion to the known agonists cholecystokinin and acetylcholine, and the response was blocked by the respective antagonists dibutyryl cyclic GMP and atropine. It thus seems that pancreatic polypeptide and motilin exert their respective actions as sites remote from the gallbladder without directly affecting gallbladder muscle.

Direct determination of the contractility of the guinea pig gallbladder: a new in vivo model.

In vivo methods to study gallbladder contractility either equate gallbladder emptying with contraction or have relied on changes in gallbladder intravesicular pressure to reflect active transmural tension. We therefore devised an animal model in which the contractile force of the intact gallbladder is measured directly while the blood and neural supply remains uncompromised. Under general anesthesia one pole of the guinea pig gallbladder is anchored to the sternum and the other connected to a force displacement transducer. Any contraction--relaxation between these two points is recorded. This model was validated by measuring gallbladder response to both neuronal and humoral stimulation. Nerve stimulation was accomplished by means of two silver collar electrodes placed in contact with the cystic duct. With nerve stimulation, a frequency (0.5-10 Hz) or amplitude (1-10 V) dependent contraction occurred. Intravenous bethanechol (10 X 10(4) ng . kg-1 . h-1) and cholecystokinin (3 X 10(4) ng . kg-1 . h-1) both induced dose-dependent gallbladder contraction. This model should prove useful in assessing the physiologic control of gallbladder contraction.

Effect of chlorpromazine (CPZ) on cholecystokinin-induced gallbladder contraction: the role of calcium.

Smooth muscle contraction is initiated by a rise in intracellular calcium, which binds to calmodulin resulting in myosin phosphorylation. CPZ impairs smooth muscle contraction by either interfering with calcium influx at low concentrations (less than 1.25 x 10(-5) M) or inactivating calcium-calmodulin at higher levels. This chlorpromazine effect was used to determine if gallbladder agonists act through different intracellular mechanisms. Guinea pig gallbladders were mounted in an organ bath and auxotonic contractions induced by bethanechol, KCl and the octapeptide of cholecystokinin (CCK). Bethanechol and KCl-induced contractions were profoundly inhibited by 1.25 x 10(-5) M CPZ throughout the dose-response curve. In contrast, CPZ did not affect CCK-mediated contractions at CCK concentrations less than 5.7 x 10(-8) M. At maximal CCK doses (3 x 10(-7) M), CPZ had only a modest inhibitory effect of 20%, compared with tension losses of 62 and 80% for bethanechol and KCl, respectively. This inhibition with high-dose CCK was offset by increasing extracellular calcium in the organ bath. The resistance of CCK to CPZ inhibition at low doses within the physiologic range implies that CCK acts independently of extracellular Ca2+ unlike the other agonists. Higher CPZ concentrations, greater than or equal to 1.25 x 10(-4) M, markedly suppressed CCK throughout the dose-response curve. Cholecystokinin may act via myosin phosphorylation, but unlike other agonists any rise in cytoplasmic calcium likely originates from an intracellular site.

Two point analysis 15-minute 14C-urea breath test for diagnosing Helicobacter pylori infection.

The value of a two point analysis (double sample) 14C-urea breath test in diagnosing Helicobacter pylori (HP) infection in patients with suspected acid peptic disease has been studied and compared to histology and to a rapid agar plate urease test in 76 patients. Using the histological finding of HP as the gold standard, the 14C-breath test was positive in 59 of the 61 histologically confirmed infected patients and in 3 of the 15 noninfected ones, giving a sensitivity of 97% and specificity of 80%. In 12 patients, a smaller dose of 3 mu Ci 14C-urea was used. The results correlated well with those in whom the higher dose of 10 mu Ci was used. We conclude that a two point 14C-urea breath test with analysis at 5 and 15 min is effective in diagnosing HP infection thus obviating the need for endoscopy and biopsy.

Retroperitoneal perforation during endoscopic sphincterotomy: imaging findings.

BACKGROUND: Endoscopic retrograde cholangiopancreatography with sphincterotomy has become an important technique in the diagnosis and treatment of biliary and pancreatic diseases. Serious complications, although rare, may occur, and their early recognition and treatment are of the utmost importance. We encountered several such cases. This study reviews the imaging findings in patients with retroperitoneal perforation detected after the procedure. METHODS: Of 796 patients who had endoscopic sphincterotomy at our institution during a 9-year period, retroperitoneal perforation occurred in nine (1.13%). Imaging findings and clinical outcome were assessed. RESULTS: In eight patients, routine abdominal radiographs taken during the procedure disclosed retroperitoneal air, associated with extravasation of contrast material in six patients. This was further confirmed on computed tomography (CT) in three patients. In the ninth patient, the diagnosis was established by an emergent abdominal CT performed a day after the sphincterotomy, because of severe abdominal pain. Two patients died of overwhelming sepsis. CONCLUSIONS: Retroperitoneal perforation during endoscopic sphincterotomy is a rare complication, which occurred in 1.13% of our patients. It can be usually clearly recognized radiographically by an abdominal film and in doubtful cases by CT. We emphasize the importance of recognizing this potentially serious complication with imaging studies.

Expression of bcl-2 in autoimmune and Helicobacter pylori-associated atrophic gastritis.

Chronic atrophic gastritis can be induced either by H. pylori or by an autoimmune process. The protein product of bcl-2, which is a protooncogene, blocks apoptosis. Aberrant bcl-2 expression has been found in 68% of atrophic gastritis patients. The aim of this study was to compare bcl-2 expression in 20 autoimmune atrophic gastritis patients to that in 20 H. pylori-associated atrophic gastritis patients. Twenty patients with H. pylori antral gastritis but without atrophy served as controls. The bcl-2 expression was assessed by immunohistochemical staining of gastric biopsies, using mouse anti-human bcl-2 monoclonal antibodies. Autoimmune atrophic gastritis patients were younger, mainly females, with a significantly higher serum gastrin level than the H. pylori-associated atrophic gastritis group (P < 0.001). The bcl-2 was expressed in 10/20 (50%) of autoimmune atrophic gastritis patients, in 9/20 (45%) of H. pylori-associated atrophic gastritis patients (P = 0.73), and in 2/20 (10%) of controls. There was no correlation between bcl-2 expression and the presence of intestinal metaplasia (P = 0.35). Our findings confirm that H. pylori-associated atrophic gastritis and autoimmune atrophic gastritis are two different conditions, but with equal expression of bcl-2. Excessive expression of bcl-2 is found only in atrophic gastritis, but not in H. pylori antral gastritis without atrophy.

Methotrexate in chronic active ulcerative colitis: a double-blind, randomized, Israeli multicenter trial.

BACKGROUND & AIMS: Uncontrolled studies have suggested that methotrexate may be effective in patients with active ulcerative colitis. The aim of this study was to evaluate the effectiveness of oral methotrexate in chronic steroid-dependent ulcerative colitis in a randomized, double-blind multicenter trial. METHODS: Patients with active ulcerative colitis who have received steroids and/or immunosuppressives for at least 4 months during the preceding 12 months with a current Mayo Clinic score of > or = 7 were included in the study. Methotrexate (12.5 mg) or placebo was added to their treatment once weekly for 9 months. RESULTS: Sixty-seven patients were included (methotrexate, 30 patients, placebo, 37 patients). The proportion of patients entering first remission (methotrexate, 46.7%; placebo, 48.6%), the time to reach first remission (methotrexate, 4.1 +/- 1.9 months; placebo, 3.4 +/- 1.7 months), as well as the proportions of patients having a relapse after first remission (methotrexate, 64.3%; placebo, 44.4%) were not significantly different between the two groups. The mean Mayo Clinic score, the mean monthly steroid dose, and the proportion of abnormal laboratory results during the study were also similar. CONCLUSIONS: Methotrexate at a weekly oral dose of 12.5 mg was not found to be better than placebo in the induction or maintenance of remission in patients with chronic active ulcerative colitis.