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Aberrant P-cadherin expression is a feature of clonal expansion in the gastrointestinal tract associated with repair and neoplasia.

The recognition of key roles for cadherins in the determination of epithelial cell phenotype, migration, differentiation, and tumour dissemination have stimulated much interest in this family of adhesion molecules. In the gastrointestinal tract, alteration of the expression of classical cadherins with aberrant P-cadherin up-regulation, associated with co-expression or loss of E-cadherin expression, is seen in neoplastic transformation of oral and oesophageal squamous mucosa and in lesions representing early neoplastic transformation of glandular mucosa, such as aberrant crypt foci and metaplastic and adenomatous polyps. This same phenotype is seen in enterocytes adjacent to foci of ulceration in the intestine in colitis, including inflammatory bowel disease, and in colitis-associated dysplasia. In coeliac disease, reversible E-cadherin down-regulation correlates with the degree of villous atrophy, but in contrast with colitis, aberrant P-cadherin expression is not a feature. Aberrant epithelial P-cadherin expression is thus associated with a proliferative phenotype related to ulceration and neoplastic transformation in the gastrointestinal tract, which may confer a survival advantage on these cells, but the relative functional roles of P-cadherin and E-cadherin and the molecular mechanisms underlyingP-cadherin/catenin interactions have yet to be elucidated.

Cadherins↗

Perioperative erythropoietin administration in patients with gastrointestinal tract cancer: prospective randomized double-blind study.

OBJECTIVE: To investigate the effect of recombinant human erythropoietin (r-HuEPO) administration on perioperative hemoglobin concentrations and on the number of blood transfusions in patients undergoing surgery for gastrointestinal tract malignancies. SUMMARY BACKGROUND DATA: Erythropoietin has been shown to improve the yield of autologously predonated blood and to reduce the subsequent requirements for homologous blood transfusions in cancer patients. METHODS: In this double-blind placebo-controlled study, 31 cancer patients received subcutaneous r-HuEPO in a dose of 300 IU/kg body weight plus 100 mg iron intravenously (study group) and 32 patients received placebo medication and iron (control group). All patients received the medications daily for at least 7 days before and 7 days after the operation. RESULTS: Patients who received erythropoietin received significantly fewer transfusions intraoperatively and postoperatively. Postoperatively, the study group had significantly higher hematocrit, hemoglobin, and reticulocyte count values compared to the control group. The use of erythropoietin was also associated with a reduced number of postoperative complications and improved 1-year survival. CONCLUSIONS: Patients with gastrointestinal tract cancer and mild anemia benefit from perioperative erythropoietin administration in terms of stimulated erythropoiesis, reduction in the number of blood transfusions, and a favorable outcome.

Aged↗

Molecular monitoring of the developmental bacterial community in the gastrointestinal tract of Japanese infants.

The dynamics of the developmental bacterial community in the Japanese neonatal gastrointestinal tract were examined by monitoring 16S ribosomal RNA gene (rDNA) diversity in fecal samples by PCR and denaturing gradient gel electrophoresis (DGGE). The results showed a certain pattern common in infants without antibiotic treatment, in which aerobes, e.g., Pseudomonas, appeared first and were then immediately replaced by facultative anaerobe, Enterococcus, Streptococcus, and Enterobacteriaceae through the first month, and finally strictly anaerobic Bifidobactrerium appeared.

Base Sequence↗

Effect of ingested toxic bean lectins on the gastrointestinal tract in the rat.

The present study was undertaken to provide further evidence for the mechanisms proposed for the toxicity of ingested bean lectins in animals: to show the stability of concanavalin A (Con A) in the gastrointestinal tract so that it has enough time to interact with some enzymes localized in the intestinal membrane and to find its effect on the activities of those enzymes that have been adopted as criteria for adaptive changes in response to altered diets, namely intestinal sucrase, alkaline phosphatase and leucine aminopeptidase. Significant amounts of ingested Con A were recovered unaltered (as seen from affinity chromatography and electrophoresis) from the cecal content of rats 4 h after its oral administration and from feces (90% recovery) 4 d later. This indicated that Con A is quite stable during its passage through the gastrointestinal tract. Con A, given at a level of 0.3 or 0.5% in the diet, completely prevented adaptive changes in the activities of those enzymes. These results substantiate the mechanisms proposed earlier by other investigators that the toxicity of ingested bean lectins involves their binding to the luminal surface of the small intestine, where they disturb the function of the brush border membrane.

Alkaline Phosphatase↗

Biopsy pathology of the gastrointestinal tract in human immunodeficiency virus-associated disease: a 5 year experience in Zürich.

Patients with human immunodeficiency virus (HIV)-associated disease are subject to a wide variety of unusual opportunistic infections and to the development of malignant tumours. These complications frequently manifest themselves within the gastrointestinal tract and endoscopic biopsies may contribute to their diagnosis. The results of 63 such biopsies from 28 patients are reviewed in this study. The diagnoses made included: upper gastrointestinal tract candidiasis (n = 6); cytomegalovirus infection of large intestine (n = 2); cryptosporidiosis (n = 1); spirochaetosis (n = 2); Kaposi's sarcoma (n = 4); malignant lymphoma (n = 3); and anal carcinoma (n = 2). Many of the specimens also showed inflammatory changes with no demonstrable aetiological agent. No specific pattern could be recognized for HIV infection per se.

Acquired Immunodeficiency Syndrome↗

PAF and CD18 mediate neutrophil infiltration in upper gastrointestinal tract during intra-abdominal sepsis.

Neutrophil infiltration is a critical event in the development of multiple organ failure during sepsis. We hypothesized that platelet-activating factor (PAF) release contributes to neutrophil infiltration in the gastrointestinal tract during sepsis. In the first experiments we administered exogenous PAF (1.56, 6.25, 25, and 100 ng . kg-1 . min-1 for 30 min) to urethan-anesthetized Sprague-Dawley rats. PAF was administered alone or in combination with either the PAF antagonist WEB-2086 (250 microg . kg-1 . min-1), a monoclonal antibody (MAb) to CD18, or a MAb to intercellular adhesion molecule 1 (ICAM-1). In separate groups of rats, cecal ligation and incision (CLI) was performed to create intra-abdominal sepsis, which we hypothesized would stimulate the release of endogenous PAF. CLI was performed in rats given either saline, WEB-2086, anti-CD18, or anti-ICAM-1 MAb. After these experiments, tissue myeloperoxidase (MPO) levels were determined as a marker of neutrophil infiltration. Both exogenous PAF and CLI induced significant increases in MPO activity in the stomach and duodenum. These increases were significantly attenuated by WEB-2086, anti-CD18 MAb, and anti-ICAM-1 MAb in both PAF- and CLI-treated rats. These results suggest that both the inflammatory mediator PAF and the CD18 integrins play a major role in neutrophil infiltration in the upper gastrointestinal tract during sepsis.

Abdomen↗

In vitro fermentation pattern of D-tagatose is affected by adaptation of the microbiota from the gastrointestinal tract of pigs.

Knowledge of the fermentation pattern of D-tagatose is important for the assessment of energy value and compliance of D-tagatose. In vitro fermentation experiments with pig intestinal contents and bacteria harvested from the gastrointestinal tract of pigs were used to investigate the degradation of D-tagatose and the formation of fermentation products. Two groups of eight pigs were fed either a control diet containing 150 g/kg sucrose or a diet which had 100 g/kg of the sucrose replaced by D-tagatose. After 18 d the pigs were killed and the gastrointestinal contents collected for in vitro studies. No microbial fermentation of D-tagatose occurred in the stomach or in the small intestine, whereas the sugar was fermented in the cecum and colon. Formate, acetate, propionate, butyrate, valerate, caproate and some heptanoate were produced by the microbial fermentation of D-tagatose by gut microbiota. Hydrogen and methane were also produced. The population of D-tagatose-degrading bacteria in fecal samples and the capacity of bacteria from the hindgut to degrade D-tagatose were higher in the pigs adapted to D-tagatose compared with unadapted pigs. In unadapted pigs, the major fermentation product from D-tagatose was acetic acid. Much more butyric and valeric acids were produced from D-tagatose by bacterial slurries of tagatose-adapted pigs compared with unadapted pigs; this was especially the case for samples from the colon. We conclude that D-tagatose is not fermented in the upper gastrointestinal tract, and the ability of the large intestinal microbiota to ferment D-tagatose is dependent on adaptation.

Acetic Acid↗

Expression of neuropilin-1 in high-grade dysplasia, invasive cancer, and metastases of the human gastrointestinal tract.

Neuropilin-1 (NRP-1) functions as an axonal guidance molecule in the developing nervous system, and recent work has identified NRP-1 up-regulation in several cancers, including neuroblastomas and breast carcinoma. We examined for the first time NRP-1 expression in a large variety of gastrointestinal carcinomas and precursor lesions to determine whether NRP-1 up-regulation correlated with invasive growth in this system. Protein expression and localization of NRP-1 were studied by immunolabeling and semiquantification in >300 dysplastic, invasive, and metastatic lesions of the gastrointestinal tract, and confirmation of NRP-1 protein expression was performed by Western blot analysis on pancreatic cancer cell lines. NRP-1 expression was limited within normal tissues of the gastrointestinal tract, with prominent labeling present only in endothelial cells, pancreatic islet cells, and the most apical colonic epithelium. Invasive cancer of the esophagus, gallbladder, ampulla of Vater, pancreas (endocrine and exocrine), and colon, however, all demonstrated striking NRP-1 expression. NRP-1 was also identified in precursor lesions of gastrointestinal adenocarcinomas, such as Barrett esophagus and colorectal adenomas. Within the spectrum of precursor lesions, a progressive increase in both intensity and area of expression was evident during histologic progression from low-grade to high-grade dysplasia. Notably, the most intense up-regulation of NRP-1 was apparent at or around the point of invasion, with focal expression of NRP-1 at levels equivalent to the invasive cancer (2- to 3-fold increase). Prominent labeling for NRP-1 was apparent in primary invasive cancers, liver metastases, and a subset of lymph node metastases, with a 2- to 3-fold increase of NRP-1 over dysplastic lesions. We conclude that increased expression of NRP-1 occurs in gastrointestinal adenocarcinomas and in a subset of high-grade precursor lesions. This up-regulation appears to parallel invasive behavior and may therefore be used as a potential marker for cancer aggressiveness in this system.

Adenocarcinoma↗

99mTc-HMPAO leucocyte scintigraphy fails to detect Crohn's disease in the proximal gastrointestinal tract.

OBJECTIVE: To investigate the use of (99m)Tc-HMPAO (hexamethyl propylene amine oxime) leucocyte scintigraphy as a non-invasive screening test for inflammatory bowel disease. PATIENTS: 10 children with suspected Crohn's disease, in whom routine investigation using barium contrast radiology, upper gastrointestinal endoscopy, colonoscopy, and mucosal biopsies had identified severe gastroduodenal and/or jejunal involvement. DESIGN: (99m)Tc-HMPAO leucocyte scintigraphic studies performed in each of these cases were assessed by a radiologist who was blinded to the disease distribution. RESULTS: In nine cases there was no scintigraphic evidence of inflammation in the proximal gastrointestinal tract. The 10th child had both gastroduodenal and jejunal involvement, but scintigraphy only revealed faint jejunal positivity. CONCLUSIONS: (99m)Tc-HMPAO leucocyte scintigraphy should not be depended upon as a screening test for Crohn's disease. False negative results are likely in cases with Crohn's disease confined to the proximal gastrointestinal tract.

Barium Sulfate↗

Pancreatic polypeptide response to a meal before and after cutting the extrinsic nerves of the upper gastrointestinal tract and the pancreas in the dog.

The role of the sympathetic and parasympathetic innervation in the release of pancreatic polypeptide (PP) basally and in response to a meal was studied after stepwise extrinsic denervation of the pancreas and the upper gastrointestinal tract in conscious dogs with gastric fistulae. One set of seven dogs was fed a meat meal (35 g/kg body weight) before and after truncal vagotomy and after truncal vagotomy plus celiac and superior mesenteric ganglionectomy, ie, extrinsic denervation of the pancreas and the upper gastrointestinal tract. In another set of six dogs, only ganglionectomy was performed. Experiments were repeated in the presence of atropine (50 micrograms/kg body weight, given as an intravenous bolus 60 min prior to the meal). Truncal vagotomy significantly (P less than 0.05) reduced the postprandial 120-min integrated plasma PP response (IPPPR) by 84% as compared to the prevagotomy response. Before truncal vagotomy, atropine significantly reduced the IPPPR by 57%. After truncal vagotomy, atropine completely abolished the residual PP response. Additional celiac and superior mesenteric ganglionectomy did not alter the IPPPR already reduced by truncal vagotomy. With the vagus nerves intact, ganglionectomy alone had no effect on the IPPPR whether or not atropine was given. These findings indicate that (1) the splanchnic nerves do not play a significant role in postprandial PP release and (2) that the vagus nerves are important mediators of the response to a meal. The effect of atropine on postprandial PP release after truncal vagotomy may be due to interruption of short enteropancreatic reflexes, suppression of the intrinsic cholinergic activity of the pancreas, or inhibition of hormonally induced PP release.

Animals↗

Distribution of glucagon-like peptide I in canine and feline pancreas and gastrointestinal tract.

Recently, a putative hormone, glucagon-like peptide I (GLP I), has been identified in the predicted sequences of the precursors to pancreatic glucagon in human, rat, hamster, and ox. The distribution of GLP I immunoreactivity in canine and feline pancreas and gastrointestinal tract was examined immunohistochemically and was compared with that of two other antigenic determinants of pancreatic pro-glucagon, i.e., glucagon and the NH2 terminus of glicentin. All three determinants occurred in the same population of islet cells in normal pancreas and in pancreas consisting predominantly of islet tissue from dogs with canine pancreatic acinar atrophy. Northern blot analysis of mRNA from the latter tissue, using a rat pre-pro-glucagon complementary DNA probe, revealed a single mRNA species similar in size to the pre-pro-glucagon mRNA detected in fetal rat pancreas. The three antigenic determinants of pancreatic pro-glucagon were co-localized also in intestinal L-cells and in canine gastric A-cells. Canine and feline pancreatic pro-glucagons therefore resemble those identified in other mammals and may also occur in gastrointestinal endocrine cells. Although there is evidence that the GLP I sequence is not liberated from pancreatic pro-glucagon, our results raise the possibility that this putative hormone may be a cleavage product of pro-glucagon in the gastrointestinal tract.

Animals↗

Changes in serotonin dynamics in the gastrointestinal tract of colon-26 tumour-bearing mice: effects of cisplatin treatment.

Severe nausea and vomiting are common side effects of anti-cancer chemotherapy. 5-HT3 receptor antagonists have been used for the treatment of these gastrointestinal symptoms. The purpose of this study was to examine whether specific changes in serotonin dynamics occurred in the gastrointestinal tract in mice in which Colon-26 adenocarcinoma cells were injected s.c., especially after treatment with cisplatin. The serotonin content of the small intestine of mice inoculated s.c. with Colon-26 adenocarcinoma increased significantly 2 weeks after the inoculation of the tumor cells; this was associated with an increase in tryptophan hydroxylase activity and the number of enterochromaffin cells as compared with control mice. Intravenous injection of cisplatin significantly reduced the serotonin content in the small intestine of Colon-26 tumour-bearing mice but not in control mice. The spontaneous release of serotonin from isolated intestine was not different between Colon-26 tumour-bearing and control mice; however, pretreatment of mice with cisplatin induced two fold increases in serotonin release from duodenum, jejunum and ileum in Colon-26 tumour-bearing mice but not in control mice. These results indicate that a region-specific increase in the number of enterochromaffin cells is observed in the intestine of Colon-26 tumour-bearing mice, associated with an increase in the serotonin content and tryptophan hydroxylase activity. Cisplatin treatment induced the release of serotonin from affected enterochromaffin cells in the gastrointestinal tract, which may be related to the occurrence of nausea in clinical use.

Animals↗

Measurement of occult upper gastrointestinal tract blood loss: a direct comparison of radiochromium and haem-porphyrin assay techniques.

Faecal haem-porphyrin assay by the HemoQuant method has many practical advantages over the well-validated, radiochromium (51Cr-tagged red cell) method for measuring gastrointestinal blood loss. Because haem may be absorbed but the chronic ion is not, the two measures were directly compared in low-grade bleeding from the proximal gastrointestinal tract. Blood loss was measured by both methods simultaneously in 40 patients with osteoarthritis before and during medication with aspirin preparations. Mean (geometric) daily blood loss before aspirin usage measured 0.60 mL radiochromium (range 0.13-1.62) and 0.47 mL (0.14-1.40) by HemoQuant (P = 0.042). On aspirin, bleeding rose to 1.57 mL/day (0.43-4.85) by radiochromium and to 0.72 mL/day (0.23-3.0) by HemoQuant (P < 0.0001). The two measures correlated well, r = 0.847 (P << 0.0001), but the regression coefficient was 0.417, reflecting the lower estimates of bleeding by HemoQuant. In four normal subjects who ingested 51Cr-labelled red cells (26-41 mL) over 3 days, recovery of 51Cr was complete (103 +/- 2%, +/- s.e.), but recovery of haem-porphyrins was only 63 +/- 13% (P = 0.01), presumably because of absorption of haem. Although faecal haem-porphyrin assay is of considerable clinical utility, it is a quantitative index rather than an absolute measure when low amounts of bleeding originate from the proximal gastrointestinal tract.

Aged↗

Augmented enhancement of in vitro production of inflammatory cytokines in peripheral blood mononuclear cells in patients undergoing simultaneous resection of the liver and gastrointestinal tract.

OBJECTIVE: To determine changes in the production of inflammatory cytokines and acute-phase proteins, and in the priming of peripheral blood mononuclear cells (PBMC), as mechanisms for the high incidence of postoperative complications in patients who have undergone hepatectomy simultaneously with resection of the gastrointestinal tract. DESIGN: Prospective, clinical study for 3 wks after operation. SETTING: A surgical department in a university hospital. PATIENTS: Twenty-one consecutive adult patients with synchronous and metachronous hepatic metastases from gastrointestinal malignancies, curatively resected by simultaneous resection (group A, n = 9) or by hepatectomy alone (group B, n = 12), and 15 patients with gastrointestinal malignancies undergoing curative resection (group C). INTERVENTION: Peripheral venous blood samples collected before operation and on days 1, 3, 5, 7, 10, 14, and 21 after operation. MEASUREMENTS AND MAIN RESULTS: The serum and plasma levels of acute-phase proteins, interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and endotoxin were measured. The in vitro production of IL-1beta and TNF-alpha by PBMC was also determined by the stimulation of lipopolysaccharide. The incidence of postoperative complications was significantly higher in group A than in groups B and C. The serum levels of IL-6 increased significantly, with a peak at postoperative day 1 in all groups, and the peak levels of IL-6 in groups A and B were significantly higher than that in group C. The serum levels of all acute-phase proteins measured in this study (alpha1-antitrypsin, haptoglobin, and C-reactive protein) increased markedly after operation in group C (p < .05). In group A, only C-reactive protein increased after operation, but its peak level was lower than in groups B and C (p < .05). Although IL-1beta and TNF-alpha in the serum were not detectable in any of the groups during the entire study period, the lipopolysaccharide-induced in vitro production of IL-1beta and TNF-alpha by PBMC in all groups was significantly elevated after operation, with a peak at days 1 and 3 after operation, respectively. In addition, the elevation of the in vitro production of IL-1beta and TNF-alpha in group A was significantly greater than that in group C, lasting until postoperative day 5 (IL-1beta) and postoperative day 10 (TNF-alpha). The levels of plasma endotoxin increased significantly in all groups, with a peak at day 1 after operation, and the peak levels were significantly higher in group A than in groups B and C. There was a significant correlation between the peak levels of in vitro TNF-alpha production and the peak levels of plasma endotoxin (r2 = .331, p< .01). CONCLUSIONS: The augmented enhancement of the priming of PBMC as a result of surgery in patients undergoing simultaneous resection of the liver and gastrointestinal tract, together with the reduced synthesis of the acute-phase reactants and impaired host defense mechanisms, might be responsible for the high incidence of postoperative complications, possibly because subsequent exposure of primed macrophages/monocytes to triggering substances such as endotoxin and bacterial components after operation results in inappropriate production of inflammatory cytokines.

Acute-Phase Proteins↗

Epithelial cell proliferation is promoted by the histamine H(3) receptor agonist (R)-alpha-methylhistamine throughout the rat gastrointestinal tract.

The temporal effect of (R)-alpha-methylhistamine on epithelial cell proliferation throughout the rat gastrointestinal tract was investigated. (R)-alpha-methylhistamine was administered at 100 mg/kg orally and the rats were sacrificed 1, 24, 48, 72 and 144 h later. All the animals received 5-bromo-2'-deoxyuridine, (BrdU), 200 mg/kg i.p., 2 h before sacrifice. Gastrointestinal tissue was processed for histology and immunohistochemistry. (R)-alpha-methylhistamine caused a progressive increase in mucosal thickness of gastric fundus, distal small intestine and distal colon. Statistically significant differences from control values were found between 48 and 72 h after (R)-alpha-methylhistamine. (R)-alpha-methylhistamine significantly increased the number of BrdU-positive cells in the gastric fundus and antrum, intermediate and distal small intestine and distal colon. Peak effects were observed between 1 and 24 h after (R)-alpha-methylhistamine administration. Proliferating cell number and mucosal thickness were comparable to those of control rats at 144 h. (R)-alpha-methylhistamine exerts a long lasting growth-promoting effect on the stomach, distal small intestine and distal colon. Present data support a role of histamine H(3) receptors in the normal regulation of cell cycle in epithelial tissue.

Analysis of Variance↗