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Lectins are proteins that bind glycoproteins; binding patterns are altered with changes in glycoprotein expression accompanying maturation or disease. Binding of two lectins, wheat germ agglutinin (WGA) and peanut agglutinin (PNA), in human and rodent colon were previously examined. Normal tissue showed intense WGA binding; PNA binding was minimal. Diseased tissues showed increased PNA binding. We hypothesized that N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-lectin-drug conjugates could deliver therapeutic agents to diseased tissues by targeting colonic glycoproteins. We examined biorecognition of free and HPMA copolymer-conjugated WGA and PNA and anti-Thomsen-Friedenreich (TF) antigen antibody binding in normal neonatal, adult, and diseased rodent tissues, human specimens of inflammation, and Barrett's esophagus. Neonatal WGA binding was comparable to the adult, with additional luminal columnar cell binding. PNA binding was more prevalent; luminal columnar cell binding existed during the first 2.5 weeks of life. WGA binding was strong in both normal and diseased adult tissues; a slight decrease was noted in disease. PNA binding was minimal in normal tissues; increases were seen in disease. Anti-TF antigen antibody studies showed that PNA did not bind to the antigen. The results suggest that HPMA copolymer-lectin-drug conjugates may provide site-specific treatment of conditions such as colitis and Barrett's esophagus.

New types of biodegradable and pH-sensitive hydrogels were synthesized by the crosslinking of polymeric precursors. They contained both acidic comonomer and enzymatically degradable azoaromatic crosslinks. Such hydrogels are suitable for colon-specific drug delivery. In the low pH range of the stomach, the swelling of the gel is low and the drug is protected against digestion by enzymes. In the small intestine, the swelling increases. Upon arrival in the colon, a degree of swelling is reached that makes the crosslinks accessible to azoreductase activity. The gel is degraded and drug released. The hydrogels were characterized by the network structure (i.e., content of crosslinks, unreacted pendent groups, and cycles), the equilibrium and dynamic swelling as a function of pH, modulus of elasticity, and in vitro/in vivo degradation. The results indicated that the hydrogel network structure strongly depends on the reaction conditions such as polymer concentration, and the ratio of the reactive groups during the crosslinking reaction. The swelling and mechanical properties of hydrogels can be controlled by the modification of polymer backbone structure and/or the crosslinking density. Depending on the network structure, the degradation of hydrogels followed either a surface erosion or a bulk-degradation-like process. In vivo degradation rate of hydrogels was three to five times faster than that in vitro. The effect of a penetration enhancer, CapMul MCM (a medium chain glyceride), on physiological properties of rabbit intestinal epithelium was investigated in vitro using the Ussing chamber technique. It was shown that CapMul MCM affected tissue ion transport, permeability, and morphology in a concentration- and time-dependent manner. It was found that with minimal epithelial disruption and moderate change in ion transport in the colon, the increase in marker molecule permeabilities ranged between 7 and 25 times depending upon their molecular weight.

The mechanism(s) by which bile acids increase biliary protoporphyrin excretion was characterized using perfused rat livers. We determined 1) relationships between biliary bile acids, phospholipid, and protoporphyrin, using rapid kinetic analyses; 2) protoporphyrin excretion in livers with defective canalicular multispecific organic anion transport; 3) effects of intracellular vesicular transport inhibition with colchicine and monensin; and 4) the role of luminal bile acids, using retrograde intrabiliary taurocholate injections. Biliary protoporphyrin excretion peaked with phospholipid excretion 14-18 min after loading. Protoporphyrin excretion induced by taurocholate was not related to effects on intracellular transport, including colchicine- and monensin-inhibitable vesicular systems. Eisai hyperbilirubinemic rat livers excreted protoporphyrin similarly to controls. Retrograde intrabiliary taurocholate injections increased protoporphyrin output. Collectively, these data suggest that 1) intracellular protoporphyrin transport is mediated by nonvesicular carriers targeted to the canalicular membrane, and 2) bile acid facilitates protoporphyrin translocation into bile in the same manner it effects phospholipid excretion.

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymers were evaluated as colon-specific drug carriers. Their design was based on the concept of site-specific binding of carbohydrate moieties complementary to colonie mucosal lectins and on the concept of site-specific drug (5-aminosalicylic acid) release by the microbial azoreductase activity present in the colon. A new 5-aminosalicylic acid-containing monomer was synthesized and incorporated into the copolymer together with the fucosylamine (bioadhesive moiety )-containing comonomer by radical copolymerization. The in vitro release rate of 5-ASA from HPMA copolymers by azoreductase activity in guinea pig cecum was approx. 2.5 times lower than from a low molecular weight analog. The azoreductase activities in cecum contents of guinea pig, rat, and rabbit as well as in human feces were determined. The relative activities for rat:guinea pig:human:rabbit were 100:65:50:28. Both in vitro and in vivo HPMA copolymer-containing side-chains terminated in fucosylamine showed a higher adherence to guinea pig colon when compared to HPMA copolymer without fucosylamine moieties. The incorporation of 5-ASA-containing aromatic side-chains into HPMA copolymers further increased their adherence probably by combination of nonpecific hydrophobic binding with specific recognition.

Two hundred thirty patients with reflux symptoms and endoscopically proven erosive esophagitis were enrolled from 15 U.S. centers into a randomized, double-blind, dose-ranging study comparing placebo with omeprazole, 20 or 40 mg given once daily in the morning. Esophagitis grade 2 was present in 44% of patients, grade 3 in 37% of patients, and grade 4 in 19% of patients. Endpoints, defined as complete relief of heartburn and complete esophageal mucosal healing, were assessed after 4 and 8 weeks of treatment. Both omeprazole doses were significantly superior to placebo in complete endoscopic healing. After 8 weeks of treatment, 73.5% of patients in the 20-mg omeprazole group and 74.7% in the 40-mg omeprazole group, compared with 14.0% in the placebo group, had complete healing of the esophageal mucosa. At the end of the study, complete relief of daytime heartburn was obtained in 79.5% of patients in the 20-mg omeprazole group, 81.6% in the 40-mg omeprazole group, and 37.2% in the placebo group (P less than or equal to 0.05). Complete relief of nighttime heartburn was noted by 79.5% of patients in the 20-mg omeprazole group, 85.1% in the 40-mg omeprazole group, and 34.9% in the placebo group (P less than or equal to 0.05). The median time to complete relief of daytime and nighttime heartburn occurred earlier in the 40-mg group than in the 20-mg group (9 vs. 17 days and 9 vs. 20 days, respectively); however, these differences were not statistically significant. Relief of acid regurgitation and dysphagia also occurred earlier in the 40-mg group. Omeprazole was well tolerated in this group of patients. No unexpected adverse experiences occurred. The results of this study confirm those of six multicenter, international trials in which omeprazole in doses of 20-60 mg provided a degree of esophageal mucosal healing and complete relief of reflux symptoms superior to any other medical treatment.

N-(2-Hydroxypropyl)methacrylamide (HPMA)-lectin (wheat germ agglutinin (WGA), peanut agglutinin (PNA)) drug conjugates for treatment of the pre-cancerous conditions ulcerative colitis and Barrett's esophagus are being developed. Cell-surface glycoproteins that are altered in disease and development bind lectins. PNA binds alpha-lactose and the Thomsen-Friedenreich (TF) antigen, a disease- and development-associated glycoprotein. PNA incorporation in conjugates may allow for preferential delivery to diseased over healthy tissues. Conjugates were prepared by attaching lectins to HPMA copolymers via an amide linkage. Frontal affinity chromatography was used to measure dissociation constants (K(d)) of free and conjugated lectins. Animal models of colitis (DSS, TNBS/EtOH) were developed. Human biopsy specimens were obtained. Free and HPMA copolymer-conjugated FITC-labeled lectin and anti-TF antigen antibody binding patterns were examined in normal neonatal, adult and diseased rodent tissues and normal and diseased human tissues. K(d) values of free and conjugated lectins were similar ( approximately 10(-5) M(-1)). Free and conjugated lectins had comparable binding patterns. In health, strong WGA binding was seen in goblet cells; PNA binding was minimal, occurring only in the supranuclear goblet cell region. In disease, WGA binding was not altered, but PNA binding was increased in both human and rodent tissues; entire goblets bound the lectin. Anti-TF antigen antibody binding was minimal, but did overlap with PNA binding patterns both in normal and diseased tissues. Conjugation of lectins to HPMA copolymers does not affect binding affinity. Alterations in glycoprotein structures in development and disease resulted in modified lectin binding patterns. In development and disease, the PNA binding seen was to the TF antigen and other lactose-containing glycoproteins. The results suggest that site-specific delivery of therapeutic agents such as cyclosporin A (CsA) for ulcerative colitis and mesochlorin e(6) for Barrett's esophagus may be achieved. P(HPMA)-lectin-CsA conjugates have been prepared and preliminary in vivo studies are underway.

A 50-year-old woman with acute onset of right lower quadrant pain and hematochezia proved to have segmental ischemic colitis associated with methamphetamine abuse. The diagnosis was established by colonoscopy with biopsy, and abdominal angiography revealed no thrombosis, vasculitis, or vasospasm. The condition resolved within 10 days. Since methamphetamine abuse is increasing, physicians should be aware of its potential to produce intestinal ischemia.

SUMMARY Methods: this US multicentre, randomized, double-blind, placebo-controlled, parallel group study determined the effects of two twice daily oral famotidine regimens on symptom relief and healing of erosive oesophagitis in patients with gastro-oesophageal reflux disease. Three hundred and eighteen patients were enrolled: 66 received placebo, 125 received famotidine 20 mg b.d., and 127 received famotidine 40 mg b.d. Patients maintained diaries of their symptoms. Endoscopy was performed at weeks 0 and 6, and again at week 12 if healing had not occurred. Results: healing at 6 and 12 weeks was (respectively) 48% (P < 0.01 vs. placebo) and 69% (P≫ 0.01 vs.placebo) for famotidine 40 mg b.d.; 32% and 54% (P≫ 0.01 vs. placebo) for famotidine 20 mg b.d., and 18% and 29% for placebo. At both 6 and 12 weeks the healing rates of famotidine 40 mg b.d. were significantly greater than placebo and famotidine 20 mg b.d. Compared to placebo, famotidine produced more frequent global symptom improvement and more rapid heartburn relief. There were no significant differences among treatment groups in the incidence of clinical or laboratory adverse events. Conclusions: famotidine 40 mg b.d. was a better regimen than famotidine 20 mg b.d. or placebo. The clinical efficacy paralleled the previously documented effect of the famotidine regimens on decrease of oesophageal acid exposure.

Background: Antireflux therapy has generally failed to induce regression of Barrett's epithelium. It was hypothesized that squamous epithelium could be restored if the columnar tissue was ablated while gastric acid secretion was suppressed. Methods: Ten white men with Barrett's esophagus received 40 mg of omeprazole daily. Thereafter, every 2–5 weeks they underwent videotaped endoscopies to argon laser photoablate columnar tissue, obtain biopsy specimens, and assess results. Squamous re-epithelialization was assessed by correlation of videotapes and directed biopsies. Results: Patients had one to eight areas ablated, totaling 0.5–12.0 cm 2 . Videotape assessments were corroborated by biopsy in all but one instance. Thirty-eight of 40 treatment locations partially or completely re-epithelialized with squamous tissue. Squamous regrowth appeared to occur by spread from contiguous squamous borders and de novo from glandular tissue. Regrowth was influenced by the extent of squamous borders and completeness of ablations. Nonablated glandular tissue persisted beneath squamous epithelium. Conclusions: Ablation of Barrett's epithelium and suppression of acid secretion facilitated squamous re-epithelialization. A progenitor cell within the metaplastic tissue has the potential to differentiate normally.

The effect of bile acids on the formation of biliary thrombi in protoporphyrin-induced cholestasis was determined by perfusing isolated rat livers with taurocholate, chenodeoxycholate and ursodeoxycholate with and without protoporphyrin. Protoporphyrin-induced reduction of bile flow was similar in the presence of each bile acid. The cholestasis was greater at high doses (2,000 to 10,885 nmol) than at low doses (1,500 nmol) of protoporphyrin, unrelated to the amount of lactate dehydrogenase released into the perfusate, and it was not altered by increasing bile acid infusions. Bile acid excretion was inhibited by high protoporphyrin doses. Periportal birefringent pigment deposits were seen in canaliculi and ductules when the biliary protoporphyrin concentration exceeded 161 nmol/ml, 345 nmol/ml and 1,036 nmol/ml for ursodeoxycholate, chenodeoxycholate and taurocholate, respectively; or, when the protoporphyrin (nanomole) to bile acid (micromole) ratio exceeded 3.23, 7.03 and 23.43, respectively. The maximal ratio of ductular deposits to portal tract deposits examined was 0.9. Electron microscopy showed these deposits were associated with canalicular thrombi. Thus, biliary thrombi were produced by infusion of bile acids and protoporphyrin. The occurrence of thrombi varied with bile acid structure. Explanations for this finding are speculative. The presence of periportal thrombi, however, did not influence the degree of functional cholestasis.(HEPATOLOGY 1990; 11:757-763.)

The case of a woman with intermittent upper gastrointestinal hemorrhage beginning 1 month after cholecystectomy is presented. Celiac arteriography demonstrated an intrahepatic arterial aneurysm, and laparotomy confirmed the presence of hemobilia. Ligation of the common hepatic artery was performed, and bleeding has not recurred.

A unique columnar epithelium with elaborate microvilli, secretory granules, and the inability to absorb lipid lines the distal esophagus in many patients with midesophageal stricture. We studied this epithelium, obtained from 3 patients with midesophageal stricture and 1 with an esophageal (Barrett's) ulcer, by electron microscopy, enzyme histochemistry, and specific disaccharidase assay in an attempt to clarify its nature and derivation. Our findings show that the tissue has uniform ultrastructural characteristics, lacks disaccharidase activity, and is histochemically dissimilar from small-intestinal and gastric fundic epithelium. The dissociation of structural and functional characteristics suggests a metaplastic derivation of this tissue.

The pathogenesis of liver disease in protoporphyria has been presumed to result from the hepatic deposition of protoporphyrin. To examine the effects of protoporphyrin on hepatic bile flow and histopathology, studies were performed employing an isolated, in situ, rat liver perfusion system. Rat livers in the control group were perfused with 0-80 μmol sodium taurocholate/h. Rat livers in the experimental group were perfused with sodium taurocholate and (a) sufficient quantities of protoporphyrin to produce maximal canalicular secretion and (b) perfusate protoporphyrin concentrations of 0.01, 0.1, and 1 μM. The administration of protoporphyrin sufficient to achieve maximal canalicular secretion was found to significantly reduce bile flow in rats infused with 0, 40, and 80 μmol sodium taurocholate/h. Linear regression analysis defined the relationship between bile flow and biliary bile acid secretion and showed that the bile acid-independent fraction of bile flow was reduced (P < 0.01). Bile acid-dependent flow was unaffected and there was no significant difference in biliary bile acid secretion rates between control and protoporphyrin-perfused livers. Perfusion of rat livers with varying concentrations of protoporphyrin demonstrated the reduction of bile flow was dose-related. Analysis of perfusate enzyme activity did not reveal abnormalities that could account for the cholestasis. Studies to evaluate the effect of protoporphyrin on regional hepatic hemodynamics were inconclusive. Histopathological studies of control and protoporphyrin-perfused rat livers did not show abnormalities on light microscopy. However, canalicular dilatation, distortion, and loss of microvilli were present in the protoporphyrin-perfused livers examined by transmission electron microscopy. Although ultraviolet microscopy showed diffuse fluorescence of the hepatocytes and canaliculi of protoporphyrin-perfused livers, the deposition of protoporphyrin in amorphous or crystalline forms was notably absent in studies with polarizing and transmission electron microscopy. These studies provide evidence that protoporphyrin has hepatotoxic properties that affect the canalicular secretory apparatus. The mechanism(s) responsible for the injury require further clarification.

Determination of the efficacy and safety of endoscopic laser photocoagulation to control upper gastrointestinal bleeding is prerequisite to the general application of this treatment in humans. We studied photocoagulation hemostasis, penetration, and perforation produced by a 55-W neodymium-yag (Nd:YAG) laser to control standardized experimental gastric bleeding lesions in a heparinized canine model. Photocoagulation of bleeding lesions was 100% successful with an application time of 3.56 +/- 1.65 sec (mean +/- SD). Histologic examintion of the gastric wall revealed a depth of injury to the muscularis externa of 40-100% with greater than 2 sec photocoagulation. Continuous photocoagulation exceeding 4 sec produced an 80-100% depth of muscle injury. Perforation of the gastric wall occurred after 9.6 +/- 1.5 sec, and all dogs studied after perforation survived. These studies indicate that Nd:YAG photocoagulation is an effective method to control experimental gastric bleeding lesions with a ratio between mean photocoagulation hemostasis and perforation times of approximatley 1:3. Further studies are required to define the implications of photocoagulation injury to muscle and the role of the gastric serosa in laser applications.

1. In order to gain information on the effect of protoporphyrin IX on changes in the properties of the canalicular plasma membrane, we studied the release of canalicular membrane constituents, namely phospholipids, cholesterol and 5′-nucleotidase, into bile in anaesthetized rats receiving saline or taurocholate (0.5 μmol min−1 100 g−1 body weight) with or without protoporphyrin IX infusion (10 or 20 μg min−1 100 g−1 body weight). 2. Protoporphyrin IX induced an impairment of spontaneous bile flow and of biliary secretion of cholesterol, phospholipids and bile acids. The taurocholate-induced increase in bile acid output was not significantly reduced by protoporphyrin IX at either of the doses used. However, when a cholestatic dose of protoporphyrin IX was infused, the taurocholate-induced bile flow and secretion of lecithin and cholesterol were significantly reduced. 3. Biliary output of phospholipid species other than lecithin did not counterbalance the protoporphyrin IX-induced reduction in biliary lecithin secretion. Biliary outputs of both total phospholipid and lecithin were inhibited by protoporphyrin IX to similar extents. 4. Protoporphyrin IX alone had no effect on the biliary release of 5′-nucleotidase, whereas when it was given with taurocholate, it increased the bile acid-induced biliary output of this enzyme markedly. 5. In summary, these results indicate that protoporphyrin IX impairs the biliary secretion of phospholipids and cholesterol but not that of bile acid. The release of canalicular membrane constituents other than lipids was also modified by protoporphyrin IX.

This report describes two patients with esophageal columnar epithelium (Barrett's esophagus) in which microinvasive adenocarcinoma developed. Case 1 had multiple foci of carcinoma in situ contiguous with epithelium resembling gastric and intestinal mucosa. Case 2 had signet-ring type adenocarcinoma. Surveillance for malignant transformation in columnar esophageal epithelium should be routinely performed, and because of its focal nature, multiple biopsies and cytologic examination should be carried out. The presence of carcinoma in situ should lead to consideration of excision of the affected esophagus.

We have compared the activity of the lysosomal enzymes, β-galactosidase and β-glucuronidase, in esophageal columnar, gastric fundic, and small intestinal epithelia. β-Galactosidase activity in esophageal columnar epithelium was less than that in intestinal tissue. β-Glucuronidase activity in the esophageal columnar epithelium was greater than that in gastric fundic tissue. Thus, this unique epithelium has enzyme characteristics which are dissimilar to both intestinal and gastric fundic tissue. This tends to support previous findings that suggested a metaplastic derivation.

In order to correlate histopathology and cell turnover in esophageal tissue in patients with esophageal columnar epithelium, biopsy specimens from 11 patients were studied. Two of the patients had adenocarcinoma of the esophagus not present in the specimens studied. In the heterogeneous esophageal columnar epithelium, the DNA synthesis phase averaged 10.4 ± 0.3 hr; labeling index of cells in the crypt-like structures was 23.3 ± 0.3%; generation time was 44.6 ± 1.2 hr, and the mitotic index was 1.82 ± 0.07%. Significant differences were not present among specimens with columnar epithelium but they differed from cell proliferation in adjacent squamous epithelium where S phase was similar but labeling and mitotic indexes were lower and generation time increased to 105 ± 6 hr. In the 2 patients with adenocarcinoma of the esophagus, and in 1 of 9 without adenocarcinoma, labeling of surface columnar cells after brief exposure to [3H]thymidine was present and suggests that this may be a manifestation of early malignant change.

The relationships between bile acid structure, protoporphyrin load, and biliary protoporphyrin excretion were studied in rat livers perfused with 0 or 0.7 mumol/min taurocholate and protoporphyrin loads between 350 and 35,525 nmol. Bile acid treatment increased the excretion of extracted protoporphyrin from 0.4 to 28%, the maximal biliary protoporphyrin concentration 32-fold, the protoporphyrin excretion rate approximately 150-fold, and the coupling of excreted protoporphyrin to bile acid. Infusions (0.7 mumol/min) of bile acids differing in structure with 1,500 nmol protoporphyrin all significantly increased protoporphyrin excretion but ursodeoxycholate and tauroursodeoxycholate did so less than others. Infusions (0.175-1.4 mumol/min) of taurocholate, deoxycholate, ursodeoxycholate, and chenodeoxycholate confirmed that protoporphyrin excretion increased significantly more with taurocholate or deoxycholate than chenodeoxycholate and chenodeoxycholate more than ursodeoxycholate. The relative ineffectiveness of dihydroxylated bile acids with a hydroxy group at the seven position (alpha- or beta-configuration) was not correlated with physicochemical parameters of the bile acids and remains unexplained. The findings suggest that ursodeoxycholate is the least acceptable bile acid to consider as a potential treatment for protoporphyria.

To determine the effect of bile acids on hepatic protoporphyrin metabolism, balance studies were performed in isolated perfused rat livers. Hepatic protoporphyrin metabolism was found to increase linearly as a function of protoporphyrin dose in livers infused with and without taurocholate (0.7 μmol/min), but their rates differed significantly. Employing a standard 1500-nmol protoporphyrin bolus dose, infusions (0.7 μmol/min) of taurocholate, glycocholate, deoxycholate, and chenodeoxycholate, but not tauroursodeoxycholate or ursodeoxycholate, increased protoporphyrin metabolism 1.7-to 2.7-fold over control (0 bile acid) values. Bile acid infusion ranging from 0.175 to 1.4 μmol/min confirmed that both taurocholate and chenodeoxycholate increased protoporphyrin disposal significantly more than ursodeoxycholate. For all bile acids, the increase of protoporphyrin metabolism was most pronounced between biliary bile acid excretion rates of 10–50 nmol/min · g liver. These data indicate that (a) bile acids facilitated protoporphyrin metabolism, (b) bile acid structure influenced the effect, and (c) ursodeoxycholate may not be a prime candidate to study the role of bile acids in the treatment of protoporphyria.

At 12 weeks of age, the patient whom we report underwent cholangioduodenostomy for treatment of complete atresia of the common bile duct. After surgery, her course was punctuated by episodes of cholangitis and jaundice. When she was 25 years of age, a liver biopsy showed biliary cirrhosis. Percutaneous cholangiography revealed dilated and deformed intrahepatic biliary ducts containing stones. Surgical removal of the stones and revision of the cholangioduodenal anastomosis was performed. Intrahepatic cholelithiasis has not previously been reported as a complication of this disorder. Her survival is the longest reported in the world literature for this condition, and emphasizes the need to vigorously pursue potentially operable cases.

The effects of acute intravenous alcohol infusion or sham treatment with normal saline on rectosigmoid motility was determined in healthy adult volunteer subjects. A significant reduction of rectosigmoid wave frequency, amplitude, percent activity and motility index occurred in subjects infused with alcohol when compared to their basal period or corresponding periods in the sham-treated group. Chemical intoxication was achieved in all subjects given alcohol and the percent of the basal motility index varied inversely with the blood alcohol level.

Upper gastrointestinal polyps have been considered an uncommon finding in patients with Gardner's syndrome and familial polyposis coli. Investigators from Japan, however, have recently reported finding gastric and duodenal polyps in a high percentage of Japanese patients with these conditions. We endoscopically examined 11 affected members of the originally described Gardner's syndrome kindred to determine if upper gastrointestinal polyps also occurred in patients with Gardner's syndrome living in the United States. Six of the patients were found to have numerous small polyps of the gastric fundus and body. Polyp histology in 5 of the 6 patients was consistent with fundic gland hyperplasia. Biopsy specimens from the remaining patient demonstrated normal mucosa only. Another patient with no fundic polyps had a single antral polyp that was an adenoma. Eight patients exhibited small polyps of the duodenum. Biopsy specimens were obtained in 7 of the 8. All polyps biopsied were adenomas. The terminal ileum was examined by endoscopy in 9 of the 11 study patients. All 9 had ileal polyps, but the polyps were adenomas in 6 patients and lymphoid aggregates in 3 patients. The results indicate that upper gastrointestinal polyps are a common pleiotropic manifestation of the genetic defect responsible for Gardner's syndrome.

1. It is known that the perfusion of rat livers with solutions containing protoporphyrin IX induces a decrease in bile flow which is not due to inhibition of bile acid secretion but rather to decreased electrolyte transport into bile. By contrast, ursodeoxycholate induces hypercholeresis, partly due to a marked stimulation of biliary bicarbonate secretion. The aim of the present work was to investigate the effect of protoporphyrin IX on ursodeoxycholate-induced choleresis in anaesthetized male Wistar rats. 2. Protoporphyrin IX infusion at rates of 10, 20 and 40 μg min−1 100 g−1 body weight into the jugular vein induced a dose-dependent inhibitory effect on bile flow as well as on bile acid and electrolyte secretion. The lowest infused rate only induced slight and non-significant changes in spontaneous bile formation and functional variables such as glycaemia, packed cell volume, blood pH, Pco2, Po2 and bicarbonate concentration, and in hepatic carbonic anhydrase activity. It was thus considered as a subtoxic dose. 3. Sodium taurocholate was infused (0.5 μmol min−1 100 g−1 body weight) over the second hour of the lowest dose of protoporphyrin IX infusion. In these rats, no significant changes in bile flow or bile acid and electrolyte secretion were observed as compared with animals receiving sodium taurocholate plus saline solution. 4. Bile acid secretion induced by ursodeoxycholate infusion (1 μmol min−1 100 g−1 body weight) was similar both in rats receiving ursodeoxycholate plus saline solution and in animals infused with this bile acid over the second hour of the lowest dose of protoporphyrin IX infusion. However, bile flow and biliary bicarbonate secretion induced by ursodeoxycholate were markedly impaired (− 43% and − 56%, respectively) by protoporphyrin IX. 5. These results indicate that in the rat, in vivo, protoporphyrin IX impairs bile formation in a dose-dependent manner. They suggest that the mechanism(s) involved in ursodeoxycholate-induced bicarbonate secretion, and hence hypercholeresis, are particularly sensitive to the inhibitory effect of protoporphyrin IX.

Two patients with massive gastrointestinal bleeding are reported. One bled from an aneurysm of a branch of the left hepatic artery, the blood reaching the bowel through communication with the biliary tree. The second had an aneurysm of a branch of the splenic artery which communicated with the pancreatic duct. This type of bleeding is intermittent and, consequently, actual extravasation of contrast media is not always seen. Therefore, if one sees an aneurysm of a visceral artery, even if it does not directly supply the enteric tract, one should consider the possibility that it is the origin of the hemorrhage. Pathogenesis, diagnostic modalities, and therapeutic implications are discussed.

(1975). Detergent Toxicity: Effects on Esophageal and Gastric Mucosa. Clinical Toxicology: Vol. 8, No. 4, pp. 399-404.

Serial morphological, secretory, and serological observations of a patient with Menetrier's disease disclosed hypergastrinemia, antibodies to parietal cells and dietary substances, and an acute reduction of gastrointestinal protein loss after atropine administration. Transformation of the gastric mucosa from hypertrophy to atrophic gastritis was associated with disappearance of the protein-losing gastroenteropathy and serum antibodies and reduction of the serum gastrin concentration.

To clarify the pathogenesis of protoporphyrin-induced cholestasis, liver surface membrane enzyme activities were determined after (a) isolated rat liver perfusion with protoporphyrin administered by bolus (1.0 mumol) or bolus plus constant infusion (1.0 mumol + 0.05 mumol/min) and (b) combination of liver surface membrane with protoporphyrin (0.9-53.4 nmol/ml) in vitro. The perfusion studies showed that protoporphyrin significantly inhibited Na+, K+- and Mg+2-adenosine triphosphatase activities. In vitro, these adenosine triphosphatase activities and the 5'-nucleotidase activity were inhibited linearly by protoporphyrin up to a concentration of approximately 18 mumol/ml; thereafter, enzyme activity was maintained. Greater inhibition of the adenosine triphosphatase activities occurred with protoporphyrin than was reported for chlorpromazine at similar molar concentrations. This effect was independent of the quantity of membrane protein analyzed and was not reversible with a 50:1 dilution. The inhibitory effect of protoporphyrin on surface membrane enzyme activities was also nonselective. Although the hepatotoxic effects of protoporphyrin may be more generalized, the present data underscore protoporphyrin's toxic interaction with liver surface membranes.

Nutrition is an antegral part of medical management and patient care. The goal of nutritional therapy is to provide nutrients in form and amount appropriate to patients' needs. Dietary modification and application of available nutritional supplements in digestive disorders should be based upon an appreciation of the fundamental pathophysiological derangements and tailored to restore optimal gastrointestinal function.

Pemoline, a central nervous system stimulant, has been used extensively in Great Britain and Europe for a variety of conditions including memory failure and depression. In the 10 years that the drug has been used no report of hepatotoxicity has appeared. A prospective study of efficacy and safety of pemoline was started in the United States approximately 3 years ago. This report describes two patients who developed reversible liver abnormalities while receiving pemoline during the study and following rechallenge with the drug.

Analog bile supersaturated with cholesterol was constituted, filtered and divided into equal portions containing no calcium or calcium, 2.5-15 mM. Aliquots were removed over the next 48 h and filtrates analyzed for cholesterol, bile acid and lecithin. Calcium accelerated cholesterol loss from solution in a dose-related fashion.

The effect of detergent treatment of the canine gastric mucosa on transport of drugs from blood to gastric juice was studied using a chamber technique, in vivo. Detergent treatment was found to increase antipyrine and aminopyrine transport. Facilitation of drug transport was associated with disruption of the gastric mucosal barrier and an increase of aminopyrine clearance.

A patient with cirrhosis developed hemoperitoneum, lactic acidosis, and hyperphosphatemia in the absence of shock. At post-mortem examination occult multicentric hepatocellular carcinoma eroding the liver capsule was present. The case emphasizes the central role of the liver in lactic acidosis, indicates that hemoperitoneum may precipitate this complication, and documents the association of lactic acidosis and hyperphosphatemia.

Twenty-eight patients with chronic, incapacitating upper abdominal pain after cholecystectomy had excision of the common wall between the terminal bile duct and duct of Wirsung (ampullary septum). Twenty-two also had a sphincteroplasty: six had had this procedure previously. Pancreatic function studies, scintiscans, ultrasound and pancreatograms were non-diagnositic. Hyperamylasemia was an uncommon finding. Eight patients were found to have evidence of mild pancreatitis at exploration. There was gross scarring of the ampullary septum in 22 cases. Histologic examination revealed inflammation in 12 septa; the degree of fibrosis could not be assessed since 14 control septa from autopsy material free from biliary tract disease revealed a comparable degree of collagen and smooth muscle. There were no deaths, and minimal morbidity. In follow-up from seven to 59 months (mean = 26), 16 patients are relatively free of pain, five have occasional episodes which require non-narcotic analgesics, and seven have gained no relief from the operative procedure. A randomized controlled trial is recommended.

To clarify the value of the serum inorganic phosphate concentration in the diagnosis of ischemic bowel disease, a retrospective study of 24 patients with various causes of intestinal ischemia was carried out. Only 25 percent of the patients had elevations of their serum phosphate concentrations. These patients had the combination of extensive bowel injury, acute renal insufficiency, and acidosis. Mortality was significantly increased in these patients. Thus, the serum phosphate concentration was not a sensitive indicator of ischemic bowel disease, but elevations did predict extensive injury and poor prognosis.

Pancreatography is a valuable diagnostic technic to identify structural changes in the pancreatic ductal system. Although specific diagnoses based on ductal changes are not always possible, patients with surgically normal glands and those showing changes of chronic pancreatitis were reliably identified in this series. Patients evaluated for postcholecystectomy pain usually had normal pancreatograms and grossly normal pancreatic glands at the time of surgical exploration. The overall consistency in interpretation of pancreatograms by experienced radiologists was approximately 80 per cent. Pancreatic cancer was poorly predicted due to either minimal changes in the ductal system or inability to distinguish gross changes from those seen with chronic pancreatitis.

The major route of protoporphyrin elimination is biliary secretion. To clarify the nature of the secretory process, maximal canalicular secretion of protoporphyrin was determined under basal conditions and after treatment with various choleretics. The maximal secretion of protoporphyrin under basal conditions was 0.07 +/- 0.01 micrograms.min-1.100 g body wt-1. Infusion of physiological amounts of sodium taurocholate increased protoporphyrin secretion 13-fold (0.90 +/- 0.02), primarily by increasing the biliary protoporphyrin concentration. Biliary protoporphyrin secretion tended to plateau in spite of a continued rise in both biliary bile acid secretion and concentration. Infusion of sodium dehydrocholate increased protoporphyrin secretion, but to only 35% of that achieved by sodium taurocholate. Ethacrynic acid and phenobarbital increased bile flow over controls but failed to enhance protoporphyrin transport. Thus, canalicular secretion of protoporphyrin was maximally enhanced by micelle-forming bile acids and unaffected by nonbile acid choleretics. The observed limitation of protoporphyrin secretion may be related to achievement of a canalicular transport maximum or to a toxic effect of protoporphyrin on the transport process.

Smoking has been shown to be a factor in acid peptic disease. A recent U.S. multicenter trial investigating use of ranitidine in the treatment of gastroesophageal reflux disease provided an opportunity to compare smokers and nonsmokers with regard to demographic features, manifestations of disease, and symptomatic response to treatment. A comparison of characteristics of smokers and nonsmokers revealed similar pretrial clinical findings. No significant differences between groups were found with regard to previous complications or recent symptoms of gastroesophageal reflux disease. There were also no significant differences in the way smokers and nonsmokers responded to treatment. Subjects on ranitidine, regardless of their smoking status, showed significantly greater improvement in heartburn symptoms and consumed less antacid than subjects who received placebo. Results of these analyses indicate that smoking as an independent variable was not related to symptomatic response or esophageal healing and that ranitidine was similarly effective in decreasing heartburn symptoms in smokers and nonsmokers.

Examination of gallbladder bile in the sediment of duodenal drainage obtained after magnesium sulfate stimulation was used to evaluate the presence or absence of gallbladder disease in thirty-four patients with symptoms suggestive of cholecystitis and normal or equivocal oral cholecystography. Ten patients had positive tests and nine of these had cholecystectomy. All nine had pathologically confirmed cholecystitis and seven of nine had cholelithiasis. Three patients with negative test results had laparotomy and normal gallbladders. The remaining twenty-one patients with negative tests have been followed up to three years, and none have returned with evidence of biliary tract disease. The results of this study suggest that duodenal drainage (Meltzer-Lyon test) is a valuable adjunctive diagnostic study in patients with gallbladder disease symptoms in whom normal or equivocal oral cholecystograms are obtained.

Asymptomatic bile leakage developed in a woman following percutaneous liver biopsy. The case is remarkable because features of cholestasis were not present at the time of biopsy, the bile leak occurred through the needle tract in the liver, bilious ascites occurred without signs of acute peritonitis, and the complication was the initial manifestation of extrahepatic biliary obstruction due to encasement of the common bile duct by histiocytic lymphoma. (Arch Intern Med139:245-246, 1979)