Papular acrodermatitis of childhood (PAC) is characterized by papular eruption of skin, lymphadenopathy, and acute hepatitis B surface antigen (HBsAg)-positive anicteric hepatitis. To study the course of hepatitis B virus infection we followed 16 patients with PAC, 2 to 7 years of age, for periods ranging from 6 to 46 months. All patients tested developed hepatitis B surface antigenemia subtype ay, and produced antibody to hepatitis B core antigen with the highest incidence after 3 to 5 months. Half of the children investigated developed antibody to hepatitis B surface antigen 4 to 18 months (mean, 6.5) after the onset of PAC. At the end of the investigation, 31% of the children were still HBsAg-positive, 50% were antibody to hepatitis B core antigen-positive, and in 43% the activity of serum aminotransferases was abnormal. Liver biopsy repeated in 2 children showed chronic aggressive hepatitis. The pattern of antibody response to hepatitis B virus is similar in both HBsAg-positive hepatitis and PAC. The frequent development of HBSAg carrier state and the high proportion of children with liver abnormalities at the end of the investigation suggest an impaired clearance of hepatitis B virus and a tendency to chronicity.

A new ferromagnetic method for the measurement of gastric emptying is described. An inert tracer, magnesium ferrite, is added to a test meal. Its amount in the stomach is then measured at regular intervals by an external transducer using its ferromagnetic properties. The method is noninvasive and devoid of radiation exposure. The magnetic fields used are harmless. The feasibility, reliability, and reproducibility of the method are described. Gastric emptying was studied in 61 subjects. The shape of the gastric emptying curve conformed best to an exponential function. The mean half-time of gastric emptying was 49 +/- 17.4 min. In this limited series age and sex did not affect gastric emptying.

Esophageal function was determined in 50 unselected patients with diabetes mellitus (DM). Fourteen age-matched healthy subjects served as controls. The presence of peripheral neuropathy (PN) was determined by a neurological examination and by nerve conduction studies. An intraluminal transducer assembly placed in the distal esophagus measured pressure in the lower esophageal sphincter and body of the esophagus. Esophageal function was studied both before and after edrophonium chloride, 80 microgram per kg intravenously. There was no significant difference in peristaltic amplitude between the controls and diabetics. There was also no difference in amplitude when DM was divided into presence or absence of PN. However, there was a significant decrease in velocity of peristalsis in DM with PN when compared to DM without PN and to controls. Resting lower esophageal sphincter pressure in DM was similar to controls, with no difference with or without PN. Twenty-eight patients (56%) with DM had abnormal motility, characterized by frequent spontaneous contractions, and decreased prevalence of peristalsis. Abnormal motility in DM was associated with PN and was characterized by a dysfunction of esophageal innervation with intact smooth muscle function.

Students attending a Mexican university who developed diarrhea were randomly treated with bismuth subsalicylate or a placebo. One hundred and eleven were given 30 ml each 1/2 hr until eight doses (total dose of active drug 4.2 g) were given and 58 students received twice this dose (8.2 g of active drug) over the 3 1/2-hr treatment period. The number of unformed stools was significantly decreased in both bismuth subsalicylate treatment groups compared to the placebo controls for the period 4 to 24 hr after therapy. A reduction in diarrhea was additionally noted for the duration of the 48-hr surveillance period for the students receiving the higher dose of active drug. Subjective relief within 24 hr of therapy of the symptoms of diarrhea, nausea, and abdominal pain or cramps was reported with a significantly increased frequency in the bismuth subsalicylate group. The most pronounced effect of the treatment occurred in the United States students with diarrhea who had recently arrived in Mexico. This appeared to be related to the favorable effect of bismut subsalicylate on the course of toxigenic Escherichia coli infection. Students with shigellosis did not experience a prolonged illness in either treatment group.

Forty-three patients with decompensated alcoholic liver disease and ascites of recent onset were randomized to salt and water restriction alone (control group) or to salt and water restriction plus diuretics (diuresis group). The two treatment groups were comparable in clinical findings and laboratory results. Seven patients in the control group and 5 patients in the diuresis group died during the acute illness. Weight loss was more marked and the disappearance of ascites more common in those given diuretics. A modest decrease in serum sodium and increase in serum potassium, and readily reversible elevations of blood urea nitrogen were noted in the diuresis group. Eight patients in each treatment group developed either the hepatorenal syndrome, marked electrolyte abnormalities, or encephalopathy. Diuresis can be accomplished in these critically ill patients without serious complications that can be attributed to the diuretic treatment.

Bile acids have been proposed to be important in the pathophysiology of the syndrome of "bile reflux gastritis" after surgery. To examine the role of cholestyramine, an ion exchange resin that binds bile acids, on symptoms of this syndrome, we did a randomized, double-blind crossover study on 16 patients. No differences in frequency of abdominal pain, nausea, vomiting, or bitter taste were observed among cholestyramine (4 g, three times daily for 3 weeks), placebo, and routine (dietary restriction and ad libitum antacid) treatment periods. We conclude that this regimen of cholestyramine was ineffective in symptomatic treatment of bile reflux gastritis.

Relief of duodenal ulcer pain by aluminum hydroxide gel (AG) was compared with that obtained by a dummy gel (DG) in randomized trials. In 44 individual pain episodes, complete relief was obtained by 15-ml doses of AG in 79% and by DG in 45% (P less than 0.05). In 48 identical blind trials replicated at another hospital the difference was not significant. The gels were also tested against ulcer pain induced by intragastric acid instillation (Palmer test) in 35 patients; pain was relieved by AG in 63% and by DG in 62%. Presumed effectiveness in terminating ulcer episodes was studied in 65 patients admitted for pain; 37 received milk and cream hourly and 28 did not. All were treated with 15 ml of AG or DG during waking hours. Median time for complete disappearance of spontaneous pain was 3 days for AG and 7 days for DG, the same in both groups. In all patients the acid instillation test was repeated every few days. For the milk and cream group it became negative after 4 days with AG and after 6 days with DG. In 18 patients with gastric ulcer treated for 4 weeks AG led to greater reductions in size than did DG. A number of these trials indicate AG to be more effective than DG, but sampling and other methodological problems limit the certainty of any conclusions.

An improved catheter infusion system is needed for esophageal intraluminal manometry. Using conventional syringe-pump infusion systems undesirably rapid infusion rates of 6 ml per min or more are often needed to achieve accurate recording of esophageal peristaltic pressure. These rapid base line infusion rates are necessitated by the high compliance of syringe-pump systems which causes substantial reduction in the infusion rate during dynamic pressure transients. In this study we tested a hydraulic-capillary infusion system designed to have low compliance. This minimally compliant system yields accurate recording of esophageal peristaltic pressure at infusion rates of 0.6 ml per min or less. We believe that the hydraulic-capillary infusion system is a useful tool for performing both clinical and investigative studies of esophageal motor function.

Measurement of the postprandial rate of acid delivery into the duodenum directly assessed the efficacy of two radically different acid-reducing therapies for duodenal ulcer disease. Cimetidine, 400 mg, with an ordinary solid meal decreased the 4-hr delivery of titratable acid and hydrogen ion into the duodenum by 63 and 86%, respectively (P less than 0.01 versus control). Liquid Maalox, 30 ml, 1 and 3 hr after an identical meal reduced 4-hr delivery of acid by 47 and 74%, respectively (P less than 0.01 versus control). During the study period, the H2 receptor antagonist effected a continuous reduction in gastric acidity and the delivery of acid into the duodenum. The liquid neutralizing antacid produced a more fluctuating decrease in these parameters. However, given in these dosages, the magnitude and duration of the acid-reducing effect were similar for both treatments.

To determine whether laxatives alter the proctoscopic and morphological appearances of the human rectum, 10 normal subjects were studied prospectively, and the following manipulations were assessed in a randomized, blinded manner: no treatment; oral mannitol to induce diarrhea; isotonic saline enema; Fleet's Phospho-Soda enema; and bisacodyl (Dulcolax), 10 mg, by enema or suppository. The rectal mucosa after mannitol-induced diarrhea, or after saline enema could not be distinguished from untreated rectum by proctoscopy, light microscopy, or scanning electron microscopy. Fleet's enema, and bisacodyl invariably changed proctoscopic appearances, and frequently altered light and scanning microscopic aspects. Both Fleet's enema and bisacodyl caused sloughing of surface epithelium. In addition, bisacodyl decreased the uptake of hematoxylin and eosin by crypt epithelial cells so that the affected cells had a partially erased appearance (16 of 25 biopsies examined by light microscopy). The lamina propria of 3 of these 25 biopsies contained polymorphonuclear cells. Transmission electron microscopy revealed that the abnormal crypt epithelial cells contained fewer cytoplasmic organelles and less nuclear chromatin. All lesions resolved within 7 days. Fleet's enema and bisacodyl by rectum may mislead the proctologist and the pathologist by altering normal rectal mucosa.

As part of a double blind, randomized trial evaluating D-penicillamine in primary biliary cirrhosis, we monitored urinary copper excretion and hepatic copper concentration during the 1st year of therapy in 46 patients with this disease. The retention of copper in primary biliary cirrhosis was confirmed by finding abnormally high levels of standard copper measurements in almost all patients before treatment. The hepatic copper was elevated in 43 of 45 patients, the urinary copper in 42 of 46, and the ceruloplasmin in 46 of 46. Urinary copper excretion correlated with the hepatic copper concentration (r = 0.68, P less than or equal to 0.001). No significant correlation occurred between hepatic copper and ceruloplasmin. Hepatic copper concentrations greater than 400 microng per g of dry weight were found almost exclusively in patients with advanced histological disease (P less than or equal to 0.01). Therapy with D-penicillamine and a low copper diet sustained increased urinary copper excretion for 1 year in almost all patients (P less than or equal to 0.001). Among patients taking placebo, the median hepatic copper concentration increased 13 microng per g of dry weight after 1 year. In contrast, among the patients taking D-penicillamine, the median hepatic copper concentration decreased 99 microng per g of dry weight (P less than or equal to 0.02). Continued observation of this therapeutic trial may help to clarify the relationship of copper retention and liver injury in primary biliary cirrhosis.

Progression of acute type B hepatitis to chronic liver disease and cirrhosis is well recognized, whereas no progression of acute type A hepatitis has as yet been documented. The natural history of acute non-A, non-B hepatitis has not been previously characterized. Ten cases of chronic liver disease were identified in 44 cases of acute non-A, non-B post-transfusion hepatitis. Age, sex, severity of acute illness, and prevalence of preoperative antibodies to known hepatitis-producing agents did not differ between the group whose hepatitis progressed to chronicity and the group whose hepatitis resolved. Less progression of acute hepatitis to chronic liver disease was seen in those patients receiving immune serum globulin preoperatively than in those receiving an albumin placebo (P = 0.009). Only 3 patients had clinical symptoms of hepatitis at the time of liver biopsy, and elevations of liver enzymes and gamma-globulin were mild. However, liver biopsy specimens in 8 of 10 patients showed chronic active hepatitis and an additional biopsy specimen showed cirrhosis. Acute non-A, non-B post-transfusion hepatitis often progresses to chronic active hepatitis. Preoperative gamma-globulin prophylaxis significantly reduces this progression. Identification and characterization of this viral agent(s) will further aid in the prevention of this undesirable complication of blood transfusion.

A randomized double blind clinical comparison of neomycin and lactulose was performed in 33 cirrhotic patients with chronic portal-systemic encephalopathy (PSE) at seven cooperating hospitals. In order to maintain double blindness, sorbitol syrup was used as a control solution along with neomycin and was compared with lactulose syrup and placebo tablets in a double drug protocol. Twenty-nine patients were studied in a crossover investigation in which each received both therapeutic regimens preceded and followed by control periods. Four additional patients received one or the other agent, but did not receive both. Serial, semiquantitative assessments were made in all patients of mental status, asterixis, and the trailmaking test (TMT) and electroencephalograms (EEG) and arterial ammonia levels. Both neomycin-sorbitol and lactulose were effective in the majority of patients (83 and 90%, respectively). Each of these parameters (mental state, asterixis, TMT, EEG, and NH3) was improved significantly by neomycin-sorbitol and lactulose. The post-treatment levels for each of these measures were similar in the neomycin and lactulose-treated groups. Mean stool pH was reduced by neomycinsorbitol to 6.1 and by lactulose to 5.5. This difference was highly significant statistically. Bowel activity was similar in the two groups. Both drugs were free of toxicity. These investigations demonstrate that both lactulose and neomycin-sorbitol are effective in the treatment of chronic portal-systemic encephalopathy.

The effect of nitroglycerine and long acting nitrites was studied in a group of 8 normal control subjects and 12 patients with esophageal spasm. The objective response of the esophagus to these drugs was recorded by obtaining esophageal manometric studies and was correlated with response in clinical symptoms. In 7 patients who had significant gastroesophageal reflux associated with spasm, the response to nitroglycerine was unpredictable. But in the group of 5 patients with diffuse esophageal spasm without gastroesophageal reflux, the response was uniformly good. All of the patients who responded to nitroglycerine also responded to long acting nitrites. These 5 patients, who were placed on long term management with long acting nitrites, remained symptom-free from 6 months to 4 years. None of them had recurrence of symptoms while they were on long acting nitrite therapy. The study suggests that if esophageal spasm is associated with reflux, the use of nitrites is less effective in controlling spasm than it is in those who do not show this association, and that diffuse esophageal spasm can be effectively managed with long acting nitrites on a long term basis in the absence of reflux. If there is esophageal spasm associated with reflux esophagitis, nitrites may be beneficial as an adjunct to antireflux therapy.

Pancreatic bicarbonate secretion and plasma secretin were measured in response to graded amounts of hydrochloric acid (0.94, 1.88, 3.75, and 7.5 mEq per 5 min) instilled directly into the duodenum in duodenal ulcer patients and in normal subjects. These graded amounts of acid produced graded increases in pancreatic bicarbonate in both groups. Mean bicarbonate secretion was significantly greater in the duodenal ulcer patients than in the normal subjects basally and after the lowest dose of hydrochloric acid. Mean (+/- SE) peak 30-min bicarbonate output (in milliequivalents) after duodenal acidification was 3.0 +/- 1.0 in the duodenal ulcer patients and 2.1 +/- 0.6 in the normal subjects (P less than 0.5). A significant (P less than 0.05) increase in plasma secretin occurred after duodenal acidification, but the increase in the duodenal ulcer and normal subjects was not significantly different (P less than 0.2). These results indicate that pancreatic bicarbonate secretion and increase in plasma secretin in response to graded amounts of duodenal acid are at least as great in patients with duodenal ulcer as in normal subjects.

Crude preparations of hog gastric intrinsic factor or their own previously collected gastric juices administered with labeled vitamin B12 did not enhance vitamin B12 absorption in patients with vitamin B12 malabsorption secondary to pancreatic insufficiency. However, when these sources of gastric intrinsic factor were incubated with three times crystallized preparations of insolubilized bovine trypsin or chymotrypsin, the proteolytic enzymes were removed by centrifugation, and the preparations of gastric intrinsic factor were readministered to these patients, the absorption of vitamin B12 was markedly enhanced. Studies of hog gastric intrinsic factor before and after exposure to proteolytic enzymes failed to show any difference on Sephadex chromatography or polyacrylamide gel electrophoresis or on its affinity for vitamin B12 or the ileal receptor in guinea pigs. These investigations demonstrate that: (1) gastric intrinsic factor as secreted by subjects with pancreatic insufficiency or obtained from hog pyloric mucosal extracts is ineffective in promoting vitamin B12 absorption in patients with pancreatic insufficiency, (2) incubation of crude preparations of gastric intrinsic factor with insolubilized pancreatic proteases modified these preparations of gastric intrinsic factor in an as yet undefined manner, allowing them to enhance vitamin B12 absorption, and (3) in vitro studies using gut sacs or brush border preparations do not reflect the abnormality in vitamin B12 absorption associated with pancreatic dysfunction.

The effect of deoxycholate ingestion, 750 mg per day, on bile acid kinetics, biliary bile acid composition, and biliary lipid secretion was studied in 7 healthy volunteers. Bile acid kinetics were measured by isotope dilution, and hourly outputs of bile acid, cholesterol, and phospholipid were quantitated by a duodenal perfusion technique during a 24-hr period which included three liquid meals and an overnight fast. Biliary bile acid composition was assessed by coupled gas chromatography-mass spectrometry. After deoxycholic acid ingestion, biliary bile acids became composed of predominantly deoxycholyl conjugates, and deoxycholic acid pools increased 4-fold. Both chenodeoxycholic and cholic acid pools decreased, and daily synthesis of each of the primary bile acids was inhibited by 50%. Total bile acid pools did not change in any consistent manner. Daily bile acid secretion increased slightly during deoxycholic acid ingestion, and recycling frequency varied reciprocally with the total bile acid pool both before and during deoxycholic acid treatment. Deoxycholic acid ingestion caused no change in either the daily secretion of cholesterol or lecithin, or the cholesterol saturation of fasting-state bile, which remained unsaturated throughout the study. SGOT levels increased to 4 times the upper limits of normal in 2 of 7 subjects, but these levels promptly returned to normal when deoxycholate feeding was stopped. Serum cholesterol levels decreased in every subject (average 15%) during deoxycholic acid administration. No evidence for a direct role of deoxycholate in the pathogenesis of cholesterol cholelithiasis was obtained in these studies.