Decreased life expectancy may occur after remote peptic ulcer surgery, but the cause of shortened survival is unclear. A 50-year follow-up study of an Amsterdam cohort of postgastrectomy patients who underwent ulcer surgery between 1931 and 1960 showed a statistically significant decrease in survival after a postoperative interval of 12 years or more compared with the general population. The shortened life expectancy mainly reflected decreased survival in men. In women, no significant difference in survival compared with the general population was observed. The excess mortality in men was predominantly due to a statistically significant increase in cancer-related deaths. Carcinoma of the lung accounted for the majority of excess mortality. No time relationship between lung cancer death and interval since surgery was observed. Thus, smoking, primarily in men who had undergone surgery for gastric ulcers, seems an important factor contributing to excess mortality and shortened life expectancy. Excess mortality due to tobacco use has also been observed in postmarketing surveillance of H2-receptor antagonists. Therefore, smoking cessation may provide the greatest improvement in the long-term prognosis of peptic ulcer patients, regardless of the treatment.

To evaluate the cost-effectiveness of extracorporeal shock-wave lithotripsy vs. cholecystectomy for symptomatic gallstones, a model was constructed that projects charges and survival for both treatments. For a 45-year-old woman with one small stone, treatment with extracorporeal shock-wave lithotripsy rather than cholecystectomy is projected to result in an average gain of only 3 days of life and an average increase in direct medical charges of $1729 over 5 years of follow-up. The resulting marginal cost-effectiveness of extracorporeal shock-wave lithotripsy vs. cholecystectomy is $216,000 of extra charges per year of life gained with extracorporeal shock-wave lithotripsy. Extracorporeal shock-wave lithotripsy is projected to be much more cost-effective for elderly than for young patients (10-20-fold difference), but considerably less cost-effective for multiple stones than a single stone (2-4-fold difference), and less cost-effective for women than men (twofold difference). Adjusting for effects of morbidity on quality of life, extracorporeal shock-wave lithotripsy is projected to have slightly better quality-adjusted survival than cholecystectomy for the small subset of patients with one stone (by 8 to 43 days at 5 years) but not for young patients with multiple stones. It is concluded that decisions about appropriate use of extracorporeal shock-wave lithotripsy should consider the effects of patient characteristics on clinical and economic outcomes.

While it is generally accepted that cholesterol supersaturation of bile is of key importance in the rapid formation of cholesterol crystals, the role of total biliary protein and pH in the pathogenesis of cholesterol gallstones is less well understood. The relation of cholesterol saturation, total protein, and pH was studied in 73 gallbladder bile samples with and 35 gallbladder bile samples without cholesterol crystals. In samples containing crystals, a trend to higher values of cholesterol and to a higher cholesterol saturation index was observed. However, significantly (P = 0.02) higher concentrations of total protein were found in samples with crystals [0.80 +/- 0.40 g/dL (8.0 +/- 4.0 g/L)] than in samples without crystals [0.63 +/- 0.26 g/dL (6.3 +/- 2.6 g/L)]. Moreover, of 22 bile samples with total protein concentrations greater than 10.0 g/L, cholesterol crystals were detected in all but 2. Total lipids, bile acids, phospholipids, and pH values were not significantly different in the two groups of bile samples. It was concluded that high biliary protein concentrations are frequently associated with cholesterol crystals and may, therefore, be a possible risk factor in the pathogenesis of cholesterol gallstones.

A cholestatic syndrome caused by sclerosing cholangitis and papillary stenosis has been described in patients with the acquired immunodeficiency syndrome and hepatobiliary cryptosporidiosis and cytomegalovirus infection. The case of a 41-year-old homosexual man with the acquired immunodeficiency syndrome who presented with abdominal pain, diarrhea, fever, and cholestasis is reported. A percutaneous transhepatic cholangiogram showed that the extrahepatic and right-sided intrahepatic ducts were normal. Computerized tomography of the abdomen showed multiple hypodense lesions in the liver. Guided needle biopsies of several of these lesions showed severe confluent necrotizing pericholangitis with cytomegalovirus-infected cells. Numerous cryptosporidia were seen attached to biliary epithelium. The unique histopathologic and radiographic features of this case should be added to the spectrum of hepatobiliary manifestations of the acquired immunodeficiency syndrome.

Autoradiography was used to localize and quantify substance P receptors in the feline gastrointestinal tract. The specific binding of 125I-Bolton Hunter substance P was determined in the esophagus, lower esophageal sphincter, antrum, pylorus, duodenum, jejunum, ileum, ileocecal sphincter, and colon. Competitive binding studies indicated that substance P binding sites or NK-1 receptor sites were demonstrated. The concentration of NK-1 receptors was greatest in the distal half of the gastrointestinal tract, with the highest concentrations in the proximal colon. The circular muscle layer contained the greatest amount of substance P binding. The location and density of binding sites for substance P may be important in understanding the relative importance of both the pharmacological responses to this neuropeptide and the immunohistochemical evidence of the peptide at different sites in the intestine.

An unusual case of an exertional heatstroke in a healthy 25-year-old man is presented. Initially, the patient was deeply comatose and developed severe rhabdomyolysis and massive hepatic necrosis. Subsequently, he received a liver transplant with remarkable improvement in his mental status, although the rhabdomyolysis continued. The patient died 41 days after the transplant due to a complicating infection. Providing that infections can be effectively controlled, liver transplants might be a promising therapeutic alternative for the few patients who survive the initial neurological consequences of this unusual event.

The effect of substance P antagonism on membrane potential responses to transmural nerve stimulation in the presence of atropine was examined in circular smooth muscle of the guinea pig ileum. Intracellular recordings of membrane potential responses recorded 3-5 mm oral to the transmural stimulus consisted of an inhibitory junction potential followed by two distinct depolarizations referred to as early and late excitatory junction potentials. Substance P antagonism was achieved by desensitization with high doses of substance P or use of the antagonist Spantide (Sigma Chemical Co., St. Louis, MO). Substance P antagonism had no effect on the amplitude of the inhibitory junction potential, caused an increase in the latter portion of the early excitatory junction potential, and abolished the late excitatory junction potential. The excitatory junction potential potentiated by substance P receptor antagonism was associated with a decrease in membrane resistance, increased in amplitude with conditioning hyperpolarizations to the estimated equilibrium potential for K+, and was blocked by the Cl-/HCO3- exchange inhibitor DIDS or prolonged perfusion with low-chloride solution. These studies suggest that a noncholinergic, non-substance P neurotransmitter is released from enteric motoneurons that produces excitation through an increase in smooth muscle chloride conductance.

Rotavirus enteritis is the leading cause of diarrhea in infants worldwide. A research priority of the World Health Organization is to develop oral rehydration solutions containing amino acids or other additives that will stimulate intestinal absorption more efficiently than the current glucose-based oral rehydration solutions. Glutamine is the principal metabolic fuel of the small bowel and a putative stimulator of mucosal repair. This report describes the transport response to mucosal L-glutamine following intestinal injury caused by porcine rotavirus. Peak symptoms and mucosal damage were observed 2-7 days after oral rotavirus inoculation. In vitro transport studies of the maximally injured region, the midjejunum (80% reduction in lactase), surprisingly, showed transport responses to L-glutamine (30 mmol/L) and L-alanine (30 mmol/L) that were similar qualitatively and quantitatively to those observed in control tissue. Subsequent application of mucosal D-glucose (30 mmol/L) caused additional stimulation of electrogenic Na+ transport, but the response to glucose was blunted (P less than 0.05) in the infected tissues. Glutamine and alanine enhanced Na+ absorption to a similar degree (2-2.5 muEq.cm-2.h-1), but glutamine stimulated equal amounts of electrogenic and electroneutral NaCl absorption, whereas alanine had no significant effect on net Cl- flux. Glutamine is a potentially useful substrate for investigation in oral rehydration solutions for infant diarrhea.

Immunohistological analysis of the expression of lactase protein in adults with hypolactasia has been carried out using monoclonal antibodies. Eight different antibodies that recognize at least three distinct epitopes on the lactase protein each gave the same result. Strong brush border staining was observed in all the lactase-persistent adults. No staining at all was detected in 9 of the hypolactasic subjects. In the remaining 12 individuals a mosaic pattern of expression was observed: small patches of enterocytes stained strongly, whereas the surrounding areas showed no staining at all. Sucrase-isomaltase, in contrast, showed no such mosaicism in these or in any of the other individuals. The mosaicism observed in the 12 hypolactasic individuals suggests that the differentiation of the columnar cells along the villus is not homogeneous. Furthermore, the existence of two patterns of expression of the lactase protein in the lactase-deficient individuals (i.e., absence of protein and mosaicism), if characteristic of the entire length of the intestine of the individuals tested, would suggest the existence of two phenotypes of adult-type hypolactasia in the population studied.

The Caco-2 cells have been used as a model system to study the pathways of diamine oxidase secretion by the intestinal epithelium. When grown in Transwell filter chamber devices, the polarized cell monolayers released the enzyme preferentially into the basal chamber. Heparin (1-10 USP U/mL) rapidly induced a marked stimulation of enzyme secretion only when in contact with the basolateral cell membrane, where high affinity binding sites for [3H]heparin were also exclusively located. Among the other glycosaminoglycans tested, only heparan sulfate (150 mg/mL) was able to induce enzyme release; chondroitin sulfate (150 mg/mL) and dermatan sulfate (150 mg/mL) were without effect. Four monoclonal antibodies specific for human diamine oxidase were produced and found to immunoprecipitate a single protein with a molecular weight of 95,000 (under reducing conditions) from the culture medium of Caco-2 cells. Immunofluorescence staining of cryostat sections of human small intestine with these four antibodies localized diamine oxidase at the lateral and basal sides of the villus cells. Staining was markedly reduced in specimens obtained from patients who received doses of heparin in vivo. This study concludes that release of diamine oxidase by intestinal cells occurs specifically at the basolateral aspect of the cells, most likely through the constitutive secretory pathway. Heparin may induce its marked stimulation of enzyme release by complexing with diamine oxidase bound to the cell surface or through interaction with specific binding sites also located in the basolateral membrane. In the intestinal mucosa in vivo, the basal aspect of the villus cells represents the main site of diamine oxidase storage in the presence of normal circulating levels of heparin.

The courses of 38 patients with severe, uncomplicated acute colitis (16 with Crohn's colitis and 22 with ulcerative colitis) were analyzed retrospectively. The patients were placed on total parenteral nutrition and treated concomitantly with corticosteroids, antibiotics (often metronidazole), sulfasalazine, and/or azathioprine. Fifteen of the 16 Crohn's colitis patients were initially managed without surgery. Four patients subsequently relapsed, two responded to reinstituted medical therapy, and two underwent colon resection 2 and 4 years later. Of 22 ulcerative colitis patients, 16 required surgery during the initial hospitalization, one patient subsequently had surgery, and one died after refusing surgery. Three of the other four continue in remission on medical therapy. Thus, there were significant differences in this series between the clinical courses of severe ulcerative colitis and severe Crohn's colitis. While most of the ulcerative colitis patients with severe disease underwent colectomy, most of the patients with severe but uncomplicated Crohn's colitis responded to aggressive medical therapy, of which total parenteral nutrition and perhaps bowel rest seemed to be an important part. Afterwards, the majority remained in remission on long-term medical therapy.

Gallbladder mucin is a densely glycosylated macro-molecule that promotes cholesterol gallstone formation in experimental animals and in humans. Bovine gallbladder mucin structure was studied after chemical deglycosylation by treatment with anhydrous hydrogen fluoride at 23 degrees C for 3 hours. Deglycosylated mucin contained less than 5% of the amino sugar and neutral hexose content of native mucin. Electrophoretic and molecular sieve chromatographic analyses indicated that significant cleavage of the mucin polypeptide core had occurred during deglycosylation. Deglycosylated mucin was separated into three major fractions by reverse-phase chromatography, one of which was enriched with respect to threonine and proline. Tryptic peptides prepared from this fraction were purified by molecular sieve and reverse-phase chromatography, and the amino acid sequences (8-20 residues) of the four principal tryptic peptides were determined. These peptides contained 65%-75% threonine and proline residues and demonstrated 80%-100% sequence similarity. These data provide the first information on the primary structure of gallbladder mucin and suggest that repeating amino acid sequences occur in this protein. Comparison of gallbladder mucin peptide structure with the consensus repeat sequence of human intestinal mucin showed approximately 60% sequence similarity. It was concluded that mammalian gastrointestinal mucins may be derived from a common ancestral gene.

This study sought to determine the effects of synthetic human secretin on ionized calcium and carbonate concentrations in human hepatic bile. Five patients with a nasobiliary drain in the right hepatic duct were studied. Three basal samples of bile were collected, each over a 15-minute period. Synthetic human secretin was then infused IV at 0.05 micrograms.kg-1.h-1 for 45 minutes followed by 0.5 micrograms.kg-1.h-1 for 45 minutes. Bile was sampled over 15-minute periods. To document return to baseline conditions, two further samples of bile were obtained over 15-minute periods 2 hours after the infusion was terminated. Bile acid concentration was determined by an enzymatic method; pH and PCO2 were measured with an automated analyzer. Total calcium was determined by inductively coupled plasma emission spectrometry and ionized calcium by an ion-specific electrode. Bicarbonate and carbonate concentrations were calculated using Henry's law and the Henderson-Hasselbalch equation. The fraction of bile sampled by the catheter was determined by Indocyanin Green recovery at the end of the experiment. Secretin caused an increase in bile flow and bicarbonate output. Bicarbonate concentrations increased from 26 +/- 3 mmol/L to 41 +/- 3 mmol/L (P less than 0.05), and chloride concentrations decreased. Mean bile acid concentrations declined significantly from 14.6 +/- 2 mmol/L to 4.7 +/- 1 mmol/L (P less than 0.05). Ionized calcium concentrations decreased from 0.7 +/- 0.005 mmol/L to 0.5 +/- 0.02 mmol/L (P less than 0.05) while pH increased significantly from 7.44 +/- 0.06 to 7.6 +/- 0.04 (P less than 0.05). Carbonate concentrations increased significantly from 0.15 +/- 0.02 mmol/L to 0.26 +/- 0.03 mmol/L, and the ion product for calcium carbonate increased significantly from 0.099 +/- 0.002 (mmol/L)2 to 0.135 +/- 0.015 (mmol/L)2 (P less than 0.05). Synthetic human secretin augments the ion product of calcium and carbonate in human hepatic bile, increasing the tendency for calcium carbonate precipitation.

Pancreatic secretory trypsin inhibitor was examined for growth-promoting activity on five cell lines using standard cell culture techniques. One cell line, AR4-2J, derived from a rat pancreatic acinar cell carcinoma, responded with significantly increased incorporation of [3H]thymidine and colony formation. Pancreatic secretory trypsin inhibitor stimulated the incorporation of [3H]thymidine in liquid culture; the maximal increase was 61 +/- 10% above control (P less than 0.001) and was seen at a concentration of 10(-9) mol/L. Using a soft agarose clonogenic assay, pancreatic secretory trypsin inhibitor also consistently stimulated (3 assays) colony formation: the peak activity occurred at a concentration of 10(-10) mol/L which caused a 150 +/- 55% (mean +/- SE, P less than 0.05) increase above control. Aprotinin had no effect on the growth of AR4-2J cells and pancreatic secretory trypsin inhibitor did not bind to the epidermal growth factor receptor. AR4-2J cells were shown to produce pancreatic secretory trypsin inhibitor. The study raises the possibility that pancreatic secretory trypsin inhibitor provides autocrine stimulation of tumor cell growth.

In a double-blind randomized trial, the hemodynamic events following the administration of propranolol (n = 51) or a placebo (n = 51) were prospectively studied in cirrhotic patients with esophageal varices. The hepatic venous pressure gradient, heart rate, and variceal size were determined at the baseline and 3, 12, and 24 months after the beginning of therapy. Baseline values were similar in both groups. At 3 months, the hepatic venous pressure gradient decreased significantly in propranolol-treated patients (from 18.1 +/- 4.2 to 15.7 +/- 3.4 mm Hg; P less than 0.05) but not in patients receiving the placebo (19.6 +/- 6.8 to 17.5 +/- 5.3 mm Hg; NS). At subsequent time intervals this gradient decreased significantly from the baseline value in both groups. Heart rate decreased significantly in the propranolol-treated group at all times (P less than 0.001). Variceal hemorrhage occurred in 13 patients (11 placebo-, 2 propranolol-treated; P less than 0.01), all of whom had a hepatic venous pressure gradient greater than 12 mm Hg. In 21 patients (14 propranolol-, 7 placebo-treated) the hepatic venous pressure gradient decreased to less than or equal to 12 mm Hg; none of them bled from esophageal varices, and their mortality rate also decreased. Because most of the bleeding events occurred during the first year (10 placebo-, 1 propranolol-treated; P less than 0.01), propranolol seems to have its protective effect during the period associated with the largest reduction in the hepatic venous pressure gradient. Because a reduction in the hepatic venous pressure gradient to less than 12 mm Hg protects from variceal bleeding and increases the rate of survival, this should be the aim of the pharmacological therapy of portal hypertension.

The present study compared in vitro the motor responses of human and rabbit distal colonic longitudinal and circular muscle to acetylcholine, histamine, leukotrienes B4 and D4, and prostaglandins E2 and F2 alpha. The active and passive mechanical properties of these muscles were also evaluated. All muscle types were contracted by acetylcholine and histamine. Longitudinal muscle from both species was contracted by prostaglandin E2 and prostaglandin F2 alpha, although rabbit muscle was more sensitive. Prostaglandin E2 relaxed the majority of both human and rabbit circular muscle preparations that were studied. Prostaglandin F2 alpha first relaxed and then contracted circular muscle from both species. Leukotriene B4 had no effect on any tissue studied. Leukotriene D4 caused transient relaxations in a proportion of all muscle types, but the relaxations were not concentration-related. Contractile responses did not differ under isotonic recording conditions, but relaxations were much more clearly defined. Based on experiments using atropine, phentolamine and propranolol, and pyrilamine or tetrodotoxin, it was concluded that the responses of both human and rabbit distal colonic muscles to these inflammatory mediators have a similar pharmacological basis. All muscle types exhibited low passive tension and developed active tension in the range 0.8-1.2 Lo. These data strongly support the belief that after the onset of an induced colitis, the rabbit colon has value as a predictive model for the study of inflammatory mediator-induced colonic motility changes in humans.