This study was undertaken to test the hypothesis that external stimuli acting through the central nervous system perturb the normal gastrointestinal response to meals. Thus, in 4 healthy volunteers we used a multilumen gastroduodenal tube system that allowed simultaneous measurements of gastroduodenal motility, gastric emptying rate, gastric acid secretion, and pancreatic trypsin output. Blood pressure, pulse rate, and skin temperature were also monitored for autonomic response. All subjects were studied on 2 days, receiving on each day two identical test meals. After one of the meals on each day, vertigo was induced by labyrinthine stimulation (ear irrigation with ice water) while the other meal was followed by one of two controls, ear irrigation at 37 degrees C (control stimulation) on 1 day and no stimulation on the other, the order of the tests being randomized. Labyrinthine stimulation at subnauseant levels resulted in a consistent and reproducible delay in gastric emptying of the meal. Further, in 2 of the 4 subjects a marked and reproducible alteration of the postprandial duodenal motility pattern occurred, with a change to one resembling the fasted state, even though nutrients continued to be present in the stomach. Duodenogastric reflux and gastric acid output remained unchanged. Trypsin output decreased initially but later returned to control values. These studies emphasize the role of the central nervous system in the control of gut function after feeding. Labyrinthine stimulation nay be a useful method for investigating inhibitory and disruptive effects of centrally acting stimuli on the human upper gut.

Seventy-eight patients with active Crohn's disease participated in a randomized, double-blind, cross-over trial. The study comprised two 4-mo period. The purpose was to test the efficacy of metronidazole in comparison with that of sulfasalazine. As the main evaluation criteria the Crohn's Disease Activity Index and plasma levels of orosomucoid were chosen. In the first period no difference in efficacy as measured by Crohn's Disease Activity Index was found between the treatment groups. The reduction of the plasma orosomucoid level was significantly more pronounced in the metronidazole group. The hemoglobin concentration increased more in this group than in the sulfasalazine group, possibly due to a toxic effect of sulfasalazine. The erythrocyte sedimentation rate decreased similarly with both drugs. In 15 patients who had active disease throughout the first period, Crohn's Disease Activity Index decreased significantly in the second period for those who switched to metronidazole, but not for those who switched to sulfasalazine. After crossover, no apparent further change in Crohn's Disease Activity Index occurred in either of the treatment groups among patients who had responded favorably in the first period. The plasma concentration of orosomucoid increased significantly among the patients in the sulfasalazine group but not in the metronidazole group. It is therefore concluded that metronidazole is slightly more effective than sulfasalazine in the treatment of crohn's disease. It is worthwhile switching the drug regimen from sulfasalazine, when it fails, to metronidazole, but not from metronidazole to sulfasalazine.

The design and execution of the Cooperative Crohn's Disease Study in Sweden are described in this paper. A double-blind, double-dummy, crossover (2 X 4 mo) technique was used to compare the suppressive efficacy of metronidazole (0.4 g b.i.d.) and sulfasalazine (1.5 g b.i.d.). The number of randomized patients (78) presented approximately one-third of the available population. The Crohn's Disease Activity Index and the plasma level of orosomucoid were the main variables for clinical evaluation. Results were analyzed primarily in the first treatment period by ranking the clinical outcome of every patient according to a uniform and detailed scheme and applying Wilcoxon nonparametric statistics. The cross-over data only served as additional information. Thirty-six patients had had earlier and mostly positive experience with sulfasalazine. Repeated plasma drug analysis indicated good compliance. The blindness of the trial was tested and appeared satisfactory. The coordination of the trial proceeded as planned. A lack of full conformity in the electroimmunoassay of orosomucoid was taken care of satisfactorily.

A trial of neodymium-yttrium-aluminum-garnet laser treatment was conducted in 152 patients with upper gastrointestinal hemorrhage. Laser photocoagulation was applied in 0.5- to 1-s pulses of 55-80 W power. A first part of the trial studying patients with arterial bleeding was uncontrolled. Spurting arterial bleedings could be stopped in 87% of the 23 patients with acute arterial hemorrhage. The recurrence rate after endoscopic treatment of this type of bleeding was high (55%). The operation rate of 61% was, however, lower than the operative indications amounting to 95% in patients with arterial spurters admitted previously to our department. One hundred twenty-nine patients were included in a controlled randomized trial of laser photocoagulation. In 86 patients with active, nonspurting bleeding, the laser was significantly better (p less than 0.001) at stopping the bleeding than conservative treatment in randomized controls, and there was a numerical although not significant reduction of the rate of bleeding recurrence and the necessity for surgery (both p less than 0.1). In 43 patients with fresh stigmata of bleeding (i.e., fresh clot or visible vessel) laser treatment resulted in a numerical reduction in the rate of rebleeding and in the operative indications, but the difference did not reach statistical significance. The mortality rates were not influenced in any of the groups.

A multicenter study was conducted on 173 patients with active, endoscopically proven duodenal ulcers (158 men, 15 women). They were randomly assigned, in a double-blind manner, to two groups: those receiving placebo capsules (91 patients) and those receiving capsules containing 100 microgram of 15(R)-15-methyl prostaglandin E2 (arbaprostil) (82 patients). Each drug was ingested four times a day (1 h before meals and at bedtime) for 28 days. Endoscopy was performed on days 0, 14, and 28 after the trial began. At each examination, the ulcer size was measured and whether the ulcer had healed was recorded. Arbaprostil increased the incidence of ulcer healing to approximately the same degree as reported in most extensive studies with cimetidine. At 14 days, three times as many patients were totally healed in the arbaprostil-treated as in the placebo-treated group (37% vs. 12%, p less than 0.001). At 28 days, 67% of patients receiving arbaprostil were healed compared with 39% in the group receiving placebo (p less than 0.001). Similarly, the ulcer size, measured endoscopically, was much smaller after arbaprostil administration than in the group receiving placebo after both 14 and 28 days (p less than 0.001). Side effects attributable to treatment consisted primarily of loose stools and diarrhea (34%). Smoking retarded healing in the placebo-treated group (p less than 0.05), but did not significantly retard healing in patients treated with arbaprostil. We conclude that arbaprostil markedly accelerates the healing rate of active duodenal ulcers. This effect may be due to inhibition of acid secretion as well as gastric cytoprotection.

To determine the value of bethanechol in the treatment of erosive esophagitis, a double-blind study was undertaken in which 28 patients were randomized to either bethanechol and antacid, or placebo and antacid. Patients were evaluated clinically, endoscopically, and by esophageal manometry before and after 8 wk of therapy. After treatment both groups showed significant improvement in heartburn and in healing of esophageal lesions. Patients who received bethanechol plus antacids did not show a greater improvement than patients who received placebo plus antacids in any category, nor did patients in the bethanechol-treated group have a greater incidence of complete healing. In addition, pretreatment mean lower esophageal sphincter pressure was normal in approximately 30% of patients with erosive esophagitis and this finding was associated with a greater chance for complete healing of esophageal lesions. These results fail to show that the addition of bethanechol to an intensive antacid regimen is more effective than the antacid regimen alone in the treatment of erosive esophagitis and that patients with esophagitis and normal lower esophageal sphincter pressures respond more favorably to medical treatment.

Four hundred and ten patients with severe watery diarrhea; including 316 patients with cholera, were studied in a double-blind, randomized, placebo controlled trial to determine if chlorpromazine (1 mg/kg) would be useful in the management of such patients. All patients were at least 7.5% dehydrated on admission into the study; all received intravenous fluids followed by oral rehydration solution and all received tetracycline. In addition, one-half of the patients received chlorpromazine, 1 mg/kg, orally as a single dose 2 h after admission. Effectiveness of the chlorpromazine was determined by comparing oral therapy failure rates, purging rates, vomiting rates, i.v. fluid requirements and hospitalization time in groups of the patients receiving and not receiving the drug. In children with severe cholera, e.g., with shock on admission or with very high purging rates, chlorpromazine lowered the oral therapy failure rate by about 50%. However, children with less severe cholera, adults with cholera, and patients of all ages with noncholera diarrhea could not be demonstrated to benefit significantly from the drug. In these groups of patients, oral therapy failures were rare irrespective of whether or not chlorpromazine had been given. We, therefore, do not recommend chlorpromazine in the routine management of patients with watery diarrhea, however, it may be useful in treatment of children with severe cholera when added to standard treatment of hydration and tetracycline.

The most promising endoscopic hemostatic techniques all depend upon heat to coagulate. Four thermally active techniques under similar controlled conditions in this endoscopic study were compared. The study was undertaken to compare the efficacy and histologic damage of monopolar electrocoagulation (MPEC), bipolar electrocoagulation (BPEC), argon laser photocoagulation (ALP) and neodymium-yytrium-aluminum-garnet (YAG) laser photocoagulation applied endoscopically to control bleeding from standard canine gastric ulcers. An open-closed model utilizing a nontraumatic intestinal clamp in heparinized adult mongrel dogs was used. Bleeding ulcers were randomly assigned to an endoscopic treatment modality or control. The endoscopic techniques and parameters of treatment for this study were established from a previous experience with each modality and from endoscopic treatment in pilot studies. Quantitative efficacy and subjective ease of endoscopic treatment were evaluated acutely; gross and histologic injury were determined after 7 days. Our conclusions were that more energy or greater power was required with each method to treat bleeding standard ulcers efficiently through the endoscope than at laparotomy. It was also concluded that each method was 93% or more effective in halting bleeding in this canine ulcer model but there were differences in ease of endoscopic use. Both lasers were much easier to apply than electrocoagulation. The order of decreasing ease of application was YAG, ALP, MPEC, BPEC. Argon laser and BPEC caused significantly less tissue injury than either MPEC or YAG. The order of increasing injury or decreasing margin of safety was ALP, BPEC, YAG and MPEC. In contrast to electrocoagulation, especially monopolar, laser related tissue injury was generally predictable and correlated with total treatment energy, animal weight or gastric overdistension, or both. The limitations, advantages, and disadvantages of each hemostatic technique are discussed and compared.

Treatment of variceal hemorrhage is one of the most controversial subjects in medicine. The resurgence of old therapies (endoscopic sclerotherapy) and the introduction of new modalities (obliterative angiotherapy) has exacerbated the controversy. No widely accepted controlled therapeutic trial is available. The problem related to survival analysis has been studied in the light of the available information concerning the natural history of variceal bleeding. It is believed that controlled trials can be designed which will prove the efficacy, or lack of it, for any proposed treatment; however, valid conclusions based on previous studies are limited, largely because of the many confounding variables. Time, as a variable factor both for randomization and therapeutic intervention, has been largely ignored, yet, we believe it is the major variable in this setting. For the population of variceal bleeders, risk of rebleeding or death rapidly diminishes over the first few days after a bleed, and early survival may be the best marker for later survival. Neither presentation nor treatment seems to alter this fundamental behavior. Variceal hemorrhage may serve as a prototype for problems of survival analysis of diseases with early high mortality.

Sixty-seven patients entered a double-blind, controlled trial to evaluate the efficacy of propylthiouracil treatment in severe alcoholic hepatitis. Twenty-three percent (7 of 31) given propylthiouracil and 19% (7 of 36) given placebo died during the 6-wk study. Propylthiouracil treatment did not reduce the frequency and incidence of complications in alcoholic hepatitis, but induced hypothyroidism in 4 patients. Treatment produced no beneficial effect on any of the hepatic biochemical tests. We were unable to show any beneficial effect of propylthiouracil treatment on morbidity and mortality in patients with severe acute alcoholic hepatitis.

Subjects in the National Cooperative Gallstone Study undergoing 12 mo of therapy with chenodeoxycholic acid for the dissolution of gallstones (low-dose, 375 mg/day, n =252; high-dose, 750 mg/day, n = 253) had a mean increase in serum cholesterol of 20 mg/dl as compared with a 5 mg/dl increase in the placebo group (n = 258). The effect of chenodeoxycholic acid on lipoproteins was determined in a random subset of the high-dose (n = 136) and placebo (n = 143) groups. For men, the mean baseline adjusted estimated low-density lipoprotein cholesterol level at 12 mo was significantly higher in the high-dose group than in the placebo group (159 vs. 148 mg/dl, p less than 0.01), whereas among women this difference was not demonstrated. Change in low-density lipoprotein cholesterol level was inversely related to baseline cholesterol to an equivalent degree in each group among men and women. Women in the high-dose group had significantly lower very-low-density lipoprotein cholesterol levels than did the corresponding placebo group (27 vs. 32 mg/dl, p less than 0.003). Very-low-density lipoprotein cholesterol levels did not differ significantly between the high-dose and placebo group in men. Treatment did not significantly affect the levels of high-density lipoprotein cholesterol or apoproteins A-I, A-II, or B. Chenodeoxycholic acid therapy produces an increase in total cholesterol and low-density lipoprotein cholesterol but does not alter high-density lipoprotein cholesterol levels.

An oral electrolyte solution containing 125 mM/L sodium, 10 mM/L potassium, 80 mM/L sulfate, 20 mM/L bicarbonate, and 80 mM/L of polyethylene glycol, and associated with little water or electrolyte absorption from the gut was recently described in this journal. To determine the efficacy of this solution (Golytely) for colonoscopy, 20 consecutive patients were randomized to either a standard colonoscopy prep or Golytely. Both preps resulted in a feces-free colon, allowing colonoscopy to the cecum in most cases. Although Golytely produced mild cramps (3 of 12) and transient fullness (6 of 12 vs. 0 of 8 with standard prep, p less than 0.02), 11 of 12 were willing to repeat Golytely vs. 3 of 8 with the standard prep (p less than 0.02). It is concluded that Golytely is an effective prep for colonoscopy and well tolerated by patients. It is especially useful for those requiring repeated examinations because of patient acceptance and efficacy.

Fifty-nine outpatients with endoscopically proven duodenal ulcer were evaluated for 4-8 wk in a randomized, double-blind trial comparing sucralfate, a sulfated disaccharide, (1 g, 0.5 h before each meal and at bedtime) with cimetidine (300 mg, 0.5 h before each meal and at bedtime). Ulcer symptoms and their relief were recorded by patients in a diary, along with data on cigarette, alcohol, coffee, and drug intake. Duodenoscopy was performed after 4 wk to assess healing, and was repeated after 8 wk if healing had not occurred by the 4-wk evaluation. Twenty-four of 30 patients taking sucralfate (80.0%) and 22 of 29 patients taking cimetidine (75.9%) had their ulcer completely healed after 4 wk. The overall healing rates after 8 wk for the sucralfate and cimetidine groups were 90.0% (27 of 30 patients) and 86.2% (25 of 29 patients), respectively. There were no significant differences between the two treatment groups in ulcer healing, symptom relief, and side effects. Symptoms were relieved equally with respect to time and efficacy. Minor adverse experiences were reported in each treatment group. None of these experiences were serious enough to warrant discontinuation of treatment. These results suggest tha sucralfate is as effective as cimetidine in the short-term treatment of duodenal ulcer.

The most comfortable gas for peritoneoscopy has been the subject of debate. We subjected 46 patients to double-blind comparison of carbon dioxide and nitrous oxide during initial pneumoperitoneum. The discomfort from local anesthesia was similar in both patient groups. The patient's and the physician's assessment of discomfort during gas insufflation showed that carbon dioxide was more uncomfortable as perceived by the patient (p = 0.02), the physician (p = 0.0006), and objectively assessed by degree of abdominal splinting (p = 0.006). The presence of intraabdominal adhesions had no relationship to discomfort. We conclude that nitrous oxide is more comfortable for institution of pneumoperitoneum during peritoneoscopy under local anesthesia.

The effect of estrogen treatment on risk for cholecystectomy, cholelithiasis, peptic ulcer, and other disorders was investigated using autopsy data from a study of patients randomized to hormonal therapy for prostatic cancer. Treatment with diethylstilbestrol, a nonsteroidal estrogen, was associated with an increased number of cholecystectomies but was unrelated to the presence of cholelithiasis at autopsy. These findings support previous reports of an association between steroidal estrogen use and cholecystectomy, but the risk estimate was more than three times that previously reported. Despite this risk and ample experimental evidence demonstrating that estrogen increases bile lithogenicity, no relationship between estrogen use and cholelithiasis was observed. The absence of such a relationship could not be readily explained by the study size, dose, or duration of estrogen treatment, treatment after leaving the study, or the frequency of preexisting stones. Given these findings the increases cholecystectomy risk may have resulted from estrogen related symptomatology mimicking gallbladder disease or an actual pathophysiologic effect of estrogen on the gallbladder, perhaps involving impaired emptying. In addition, estrogens, orchiectomy, or both were associated with a decreased frequency of peptic ulcer, supporting reports of the efficacy of estrogen in the treatment of peptic ulcer.

The effect of wine on gastric emptying of meals was studied in 10 healthy male subjects. A dual radioisotopic method was employed utilizing isotope tracers added to the liquid (111In-diethyltriamine pentaacetic acid) and solid phases (99mT-tagged chicken liver) of the meal. In a random design subjects were fed two standardized 900-g meals containing 450 g of solid food ingredients and 450 g of either Cabernet Sauvignon (mean ethanol concentration = 9500 mg/dl) or low-alcohol Cabernet Sauvignon (mean ethanol concentration = 1312 mg/dl). In addition, 7 of the 10 subjects were fed wine and low-alcohol wine without solid food. Wine, when compared with low-alcohol wine, did not significantly alter gastric emptying of either liquid or solid food components.