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Distribution and structure of vagal afferent intraganglionic laminar endings (IGLEs) in the rat gastrointestinal tract.

Intraganglionic laminar endings (IGLEs) are special terminal structures of vagal afferent fibers and have been demonstrated in the myenteric plexus of esophagus and stomach. In order to quantitatively map their presence and distribution over the entire gastrointestinal tract, including the small and large intestines, vagal afferents were anterogradely labeled in vivo by microinjections of the fluorescent carbocyanine dye DiI into the left or right nodose ganglion of adult male rats. In the most successfully labeled cases the highest density of IGLEs was found in the stomach, with about half to one-third of the myenteric ganglia receiving at least one IGLE. The proportion of myenteric ganglia innervated by IGLEs decreased in the small intestine; however, because of its large surface area this gut segment was estimated to contain the highest total number of IGLEs. Both the cecum and colon also contained significant numbers of IGLEs. In the stomach, this vagal afferent innervation by IGLEs was more or less lateralized, with less than 20% of labeled IGLEs found on the contralateral side with respect to the injection. The left/ventral vagus contributed a larger proportion of IGLEs to the proximal duodenum, while the right/dorsal vagus contributed a larger proportion of IGLEs to the distal duodenum and jejunum. Laser scanning confocal microscopy on select specimens revealed further structural details. The parent axon typically formed two or more branches that flanked the ganglia laterally, and in turn produced numerous highly arborizing laminar terminal branches that covered one or both flat sides of the ganglion in a dome-like fashion. The similar distribution patterns and structural details suggest a uniform function for the IGLEs throughout the gastrointestinal tract, but there is as yet no clear proof for any of the hypothesized roles as specialized mechanosensors or local effector terminals.

Animals↗

Expression of p53-related protein p63 in the gastrointestinal tract and in esophageal metaplastic and neoplastic disorders.

p63 is a p53-related DNA-binding protein that helps regulate differentiation and proliferation in epithelial progenitor cells. Its expression has never been evaluated in the human gastrointestinal tract. The aim of this study was to evaluate the expression of p63 in the esophagus and related metaplastic and neoplastic disorders to gain insight into the pathogenesis of these processes. Of particular interest was the expression of p63 in Barrett esophagus (BE) and in BE-associated multilayered epithelium. Multilayered epithelium has been postulated to represent an early precursor to the development of BE primarily because it shares morphologic and immunophenotypic features of both squamous and columnar epithelium, and has been shown prospectively to be highly associated with BE. Routinely processed mucosal biopsy or resection specimens that contained normal esophageal squamous epithelium (n = 20), squamous dysplasia (n = 4), squamous cell carcinoma (n = 7), BE (n = 10), BE-associated multilayered epithelium (n = 13), esophageal mucosal gland ducts (n = 10), BE-associated dysplasia (n = 12), and BE-associated adenocarcinoma (n = 7) were immunostained for p63 to determine the extent and location of staining. p63 staining was compared with the staining patterns observed for p53, Ki 67 (proliferation marker), and cytokeratins (CKs) 13 (squamous marker), 14 (basal squamous marker), 8/18 (columnar marker), and 19 (basal/columnar marker). Expression of p63 messenger RNA (mRNA) isoforms was also analyzed by reverse-transcription polymerase chain reaction of freshly isolated tissues. In the normal esophagus, p63 was expressed in the basal and suprabasal layers of the squamous epithelium and in basal cells that line the mucosal gland ducts but was negative in all other epithelia of the gastrointestinal tract, including the stomach, small intestine, and colon. Similarly, p63 was not expressed in BE, but it, was present in the basal layer of multilayered epithelium in 9 of 13 cases (69%). p63-positive cells in multilayered epithelium and in the mucosal gland duct epithelium were positive for CK8/18 (100%) and CK13 (67% and 30%, respectively) and negative for CK14 (0%), in contrast to p63-positive cells in squamous epithelium, which were positive for CK14 and CK13 (100%) but negative for CK8/18. In neoplastic tissues, p63 was diffusely expressed in all cases of esophageal squamous cell dysplasia and carcinoma but was negative in all cases of esophageal and colorectal adenocarcinoma. The DeltaN isoform of p63 mRNA predominated in all benign and neoplastic squamous tissues examined. p63 may represent a marker of 2 distinct epithelial progenitor cells (basal squamous epithelium and gland duct epithelium) in the esophagus. P63 is upregulated in squamous neoplastic conditions and in this manner may play a role in squamous carcinogenesis. These data also indicate that multilayered epithelium is phenotypically similar to, and may share a lineage relationship with, mucosal gland duct epithelium.

Adenocarcinoma↗

Bacterial adhesion in human upper gastrointestinal tract.

Small bowel biopsy specimens were taken from 21 patients undergoing gastrointestinal endoscopy to detect a possible adhesion of bacteria to the mucous layer of the upper gastrointestinal tract. In 30 control biopsy specimens taken from 10 patients free from gastrointestinal pathology, no associated bacteria were found, whereas in 23 biopsy specimens taken from eight gastrectomized patients an associated bacterial flora including E. coli or Pseudomonas was grown. Bacterial adhesion was confirmed by means of transmission electron microscopy of the eight patients yielding positive cultures. Bacterial adhesion induced local alterations of the brush border membrane. These results suggest that adherent bacteria may be present in hypochlorhydric patients. Pathophysiologic consequences require further studies.

Bacterial Adhesion↗

Utility of colour Doppler endoscopic ultrasound evaluation and guided therapy of submucosal tumours of the upper gastrointestinal tract.

BACKGROUND AND AIMS: Endoscopic ultrasound is considered the method of choice for evaluation of submucosal tumours. Endoscopic therapy of selected lesions represents a useful mini-invasive approach. The aim of this study was to assess the endoscopic management of submucosal tumours of the upper gastrointestinal tract (GIST), with emphasis on the use of colour and power Doppler endoscopic ultrasound. METHODS: The study included 35 consecutive patients referred to endoscopic ultrasound with submucosal tumours of the upper gastrointestinal tract. Colour and power Doppler imaging were performed with radial or linear instruments in all patients and allowed a better characterisation of the submucosal lesions. Histology was obtained in 22 patients and permitted a correct diagnosis, as well as confirmation or exclusion of malignancy. RESULTS: In 18 patients (51.4%) there was discrepancy between the suspected endoscopic diagnosis and the diagnosis made by endoscopic ultrasound. Most of the malignant GISTs had significant intratumoural vessels detected by colour or power Doppler EUS (5 out of 6 patients, 83.3%), as compared with the benign GISTs (2 out of 7 patients, 28.6%). Colour Doppler EUS was essential, both to diagnose and to direct therapy in vascular submucosal lesions (two haemangiomas). The same technique was useful to better characterise lipomas or cysts. CONCLUSIONS: Endoscopic ultrasound management of submucosal tumours was enhanced by the use of colour and power Doppler imaging. A precise management plan, supported by colour and power Doppler findings improved the diagnostic options and increased the feasibility and safety of endoscopic ultrasound guided therapeutic interventions.

Duodenal Neoplasms↗

Self-expanding metallic stents for continuous dilatation of benign stenoses in gastrointestinal tract - first results of long-term follow-up in interim stent application in pyloric and colonic obstructions.

The use of self-expandable metallic stents (SEMS) is an established palliative treatment of malignant stenosis in the gastrointestinal tract. There is wide experience with the palliation of malignant esophageal obstruction and fistulae, but the application of stents in benign stenosis is rarely reported and exclusively deals with obstruction of the esophagus. No data has been available for benign gastric outlet and rectosigmoid obstruction until now. For the first time we report about 4 cases, in which we temporarily implanted a SEMS (Ultraflex(R) stent, Boston Scientific Microvasive(R)) in benign stenosis of the pylorus or rectosigmoid between 09.97-07.98. The indications for stent implantation were failure of established dilatation therapy and/or refusal of surgical treatment, and/or surgical high-risk patients. Our idea was to prolong the duration of the dilatation by interim implantation (range 8 days - 12 weeks) of a SEMS. There where no peri-interventional complications or dislocations. In one case endoscopic removal was not possible, peranal surgical approach allowed the removal of the stent. During follow-up (range 34-39 months) 2 patients needed one bougienage directly after stent removal. Endoscopic examinations showed no recurrence of any stenosis in all patients. We conclude that interim application of SEMS in benign stenosis of the gastrointestinal tract may be a possible therapeutic tool in selected patients. Further trials with greater numbers of patients dealing with the questions of duration of stay of SEMS and choice of stent type are needed.

Aged↗

[Two cases of acute myelogenous leukemia complicated with fatal gastrointestinal tract bleeding after treatment with idarubicin and cytarabine].

We describe herein two newly diagnosed patients with acute myelogenous leukemia (AML), who were treated twice with an idarubicin hydrochloride (IDR)-containing regimen as a response-orientated induction therapy. Both patients had severe gastrointestinal tract hemorrhage complications at their nadir. The two patients were as follows: a 35-year-old male, FAB-M4, and a 47-year-old female, FAB-M0. They received the same induction chemotherapy (IDR 12 mg/m2 for four days and cytarabine 100 mg/m2 for ten days). No response (NR) was obtained in either, so they underwent the same regimen again. During the period of myelosuppression, they developed severe gastrointestinal hemorrhage. One died of sepsis, and the other of acute respiratory distress syndrome without a recovery in bone marrow. The fetal gastrointestinal tract complications may have been due to severe myelosuppression and mucosal damage in these patients. Careful observation will be needed to prevent such severe complications after the treatment with IDR.

Adult↗

Expression of CD34, bcl-2, and kit in inflammatory fibroid polyps of the gastrointestinal tract.

The histogenesis of inflammatory fibroid polyps (IFP) of the gastrointestinal tract, focused on the cell of origin of the stromal cells, is a controversial subject. The reported CD34 reactivity in gastric IFP has implied a histogenetic relationship with a variety of CD34-reactive tumors, including gastrointestinal stromal tumors (GIST). In addition to bcl-2, the majority of GIST has expressed Kit, suggesting an origin in interstitial cells of Cajal (ICC), which are selectively localized around nerve plexuses. Gastric (12) and colonic (two) IFP from 13 patients were studied, using antibodies against CD34, bcl-2, and Kit. IFP expanded muscularis mucosae with prominent vascular channels, inflammatory infiltrates, proliferating stromal cells, and extracellular matrix material. Eleven gastric IFP exhibited concentric stromal proliferations (CP), particularly, around vessels, glands, and muscle bundles. Their stromal cells were CD34 reactive, bcl-2 nonreactive, and Kit nonreactive and showed fibroblast-like appearances with thin, long cytoplasmic processes. In contrast, one gastric and two colonic IFP showed no CP, and their stromal cells were CD34 nonreactive, bcl-2 nonreactive, and Kit nonreactive. IFP with CP may have a different histogenesis from IFP without CP. IFP with CP may originate from a subpopulation of dendritic interstitial cells other than ICC, predominantly localized around blood vessels and muscle fibers in muscularis mucosae of the stomach.

Adult↗

Expression of cytokeratins 7 and 20 in carcinomas of the gastrointestinal tract.

AIMS: The differential expression of cytokeratin (CK) 7 and 20 by carcinomas may help in determining the primary site of a metastatic tumour. The aim of this study was to extend the published data on CK7 and CK20 expression in epithelial neoplasms of the gastrointestinal tract by considering the degree of differentiation and including some unusual neoplasms. METHODS AND RESULTS: Cases referred to the Armed Forces Institute of Pathology were studied prospectively for immunohistochemical expression of CK7 and CK20. Lesions from 105 patients were analysed. Adenocarcinomas of the upper gastrointestinal tract were positive for both CK7 and CK20 in 78% of cases; only poorly differentiated lesions were CK7-. Well-differentiated and moderately differentiated adenocarcinomas of the large intestine, including appendix, were CK7-/CK20+ in the great majority of cases, as were goblet cell carcinoids, but half of the poorly differentiated adenocarcinomas exhibited aberrant expression, as did most of the mixed goblet cell carcinoid/adenocarcinomas. All five high-grade neuroendocrine carcinomas were negative for both CK7 and CK20. CONCLUSIONS: Not only the site but also the grade and histological type of a gastrointestinal carcinoma should be considered when assessing cytokeratin phenotype.

Adenocarcinoma↗

The evaluation of the role of CCK in the opioid modulation of the motility of the gastrointestinal tract in sheep.

The participation of central cholecystokinin-8 (CCK-8) receptors in the modulatory effect of D-Ala2, N-Me-Phe4, Gly5-ol enkephalin (DAGO), a selective mu-opioid receptor agonist, on the spike burst activity of the gastrointestinal tract (rumen, reticulum, antrum, duodenum, colon and caecum) in sheep was investigated. DAGO was infused intracerebroventricularly (i.c.v.) at doses of 0.1-1 microg/kg body weight (BW). It was shown that DAGO significantly inhibited myoelectrical activity of the wall of the forestomachs, abomasum and colon but stimulated this activity in the duodenum (rate of myoelectrical migrant complex-MMC). The effects of DAGO were prevented by CCK-8 antagonists (L-364.718 and L-365.260) previously infused at doses of 5-20 microg/kg BW. The results of this present study indicate that central receptors of CCK-8 participated in the modulatory action of an opioid on myoelectrical activity of the gastrointestinal tract in sheep. Furthermore, this result suggests that CCK-8 is released in response to mu-receptor stimulation, because CCK-8 antagonists (L-364.718 and L-365.260) prevented the modulatory action of DAGO on the gastrointestinal motility in sheep.

Animals↗

Phase II trial of docetaxel (Taxotere) in patients with adenocarcinoma of the upper gastrointestinal tract previously untreated with cytotoxic chemotherapy: the Eastern Cooperative Oncology Group (ECOG) results of protocol E1293.

The aim of this study was to evaluate the clinical efficacy and safety of docetaxel (Taxotere) in patients with adenocarcinoma of the upper gastrointestinal tract previously untreated with cytotoxic chemotherapy. Docetaxel 100 mg m-2 was administered as a 1 hour intravenous (IV) infusion every 3 weeks to 41 patients. Patients were premedicated prior to each course with dexamethasone, diphenhydramine and cimetidine. Clinical response and toxicity were determined. Objective responses were seen in seven of 41 eligible patients (two complete responses [CRs] and five partial responses [PRs], for an objective response rate of 17% (90% confidence interval [CI], 8% to 30%). The most common toxicity was grade 4 neutropenia, which occurred in 88% of patients; 46% of patients required a dose reduction following an episode of neutropenic fever requiring antibiotic therapy. Additional patients have had reversible grade 3-4 toxicities including nausea, vomiting, stomatitis, diarrhea, fatigue and peripheral neuropathy. Ten patients have had grade 1-3 hypersensitivity reactions. Alopecia has been seen in the majority of patients. Fluid retention grade 1-3 has been observed in patients. Docetaxel administered on this schedule is an active agent in adenocarcinomas of the upper gastrointestinal tract. Further investigation of this drug should be conducted in multi-drug combination programs.

Adenocarcinoma↗

Survival of a probiotic, Lactobacillus casei strain Shirota, in the gastrointestinal tract: selective isolation from faeces and identification using monoclonal antibodies.

Lactobacillus casei strain Shirota (LCS) is a probiotic bacterium used in the production of fermented milk products and lactic acid bacteria preparations. To investigate the survival of LCS in the gastrointestinal tract, we have developed a selective medium and specific monoclonal antibodies to isolate and identify this strain. Selective LLV agar medium was prepared by modifying LBS medium, a selective medium for lactobacilli, through the replacement of glucose with lactitol as a carbon source and vancomycin as a selective antibiotic. Culture in LLV agar medium followed by ELISA using monoclonal antibodies specific for LCS was able to detect the organism in faeces. Using this method, we studied the faecal recovery of LCS in individuals who drank 125 ml of fermented milk which contained 10(10) live LCS for 3 days. The mean recovery was about 10(7) live bacteria per gram of faeces, indicating that LCS survived transit through the gastrointestinal tract after ingestion of the fermented milk.

Adult↗

[Lymphadenectomy in tumors of the upper gastrointestinal tract].

Similar to other tumor entities, complete tumor removal with an adequate safety margin in all three dimensions (the oral margin, the aboral margins and the tumor bed) must be the primary aim of any surgical approach to carcinoma of the upper gastrointestinal tract. The same goal has to be achieved in the area of the lymphatic drainage. All positive nodes and nodes with a so-called 'microinvolvement' have to be removed together with the primary tumor. The safety margin of lymphadenectomy can be estimated by the lymph node ratio, i.e., the ratio between the number of removed and positive nodes. Several studies have shown that for carcinoma of the upper gastrointestinal tract the prognosis can be improved markedly if the lymph node ratio is below 0.2. For tumors in the early phase of lymphatic metastasis this can be achieved by extensive lymph node dissection. In practice, this requires as a minimum a lymphadenectomy of compartments I and II of the tumor's lymphatic drainage (D2 lymphadenectomy). The individual compartments are determined by the embryogenesis of the affected organ and defined by the tumor location. In patients with advanced lymphatic metastases, lymphadenectomy does not improve the prognosis and can only result in a reduction of local recurrences. Lymphadenectomy does not increase the risk and morbidity of the surgical procedure, provided it is restricted to the removal of nodes. These basic principles of lymphadenectomy are valid for carcinomas of the esophagus, cardia and stomach.

Cardia↗

Immunohistologic expression of blood-group antigens in normal human gastrointestinal tract and colonic carcinoma.

A panel of 7 mouse monoclonal antibodies and the lectin from Ulex europeus, detecting blood-group-related antigens of the ABH and Lewis systems, have been used to define the distribution of these antigenic structures within the human gastrointestinal tract, and to characterize their expression and modulation in colorectal carcinomas. The reagents employed detect the following blood-group specificities: A (all variants), B, H (type 2), Lewisa, Lewisb, X (Lewisx), Y (Lewisy) and type 1 precursor chain. Immunohistochemical studies demonstrate that these antigens are differentially expressed in various cell types and developmental stages of the human gastrointestinal tract. ABH expression undergoes developmental modulation in the human colorectal tract from positive to negative during embryogenesis, and is lost in adult cells. Colorectal tumors exhibit neosynthesis of ABH specificities that appear in tumor cells, and accumulation of the precursor antigens. They also show increased expression of Lewis antigens, especially Y determinant, which has a restricted pattern of distribution in normal tissues and is not found in normal colonic mucosa. Enhancement of the Lewis antigens is observed in all colorectal tumors analyzed, regardless of blood-group type and secretory status of the individuals studied. Tumor modulation of these antigens may be related to activation of suppressed genes and enhancement of fucosyltransferases.

ABO Blood-Group System↗

sst1 mRNA is the prominent somatostatin receptor mRNA in the rat gastrointestinal tract: reverse transcription polymerase chain reaction and in situ-hybridization study.

The inhibitory peptide hormone somatostatin and its receptors (sst1-sst5) regulate many physiological functions in the gastrointestinal tract. In an attempt to correlate the various effects of somatostatin in gastrointestinal physiology to individual sst subtypes sst1-sst5, mRNAs have been localized by semiquantitative reverse transcription polymerase chain reaction amplification and in situ hybridization of sst1 and sst3 in the rat alimentary tract. sst1-sst4 mRNAs were found throughout the gastrointestinal tract, sst1 mRNA being more abundant than sst2 and much more abundant than sst3 and sst4 mRNAs. sst5 transcripts were at the detection threshold. sst1 and sst3 mRNAs are present in enterocytes and enteric neurons suggesting a role of these subtypes in the somatostatin-mediated inhibition of acetylcholine release from myenteric neurons and of secretomotor neuron activity in the submucous plexus. The presence of sst3 mRNA in smooth muscle cells points to an additional role of this receptor in regulating gut motility.

Animals↗

Association between gastrointestinal tract carriage of Candida, blood group O, and nonsecretion of blood group antigens in patients with peptic ulcer.

Of 112 patients with peptic ulcer disease examined for oral carriage of Candida, 66 (59%) were carriers. Candida carriage was associated with blood group O (P < 0.05) and, independently, with nonsecretion of blood group antigens (P < 0.01). For each subject, the presence or absence of yeasts was found to be a constant characteristic, and only among patients positive for Candida was blood group O or nonsecretion more frequent than expected in the general population. The quantity of yeasts isolated was significantly greater in patients than in normal subjects (P < 0.002), as was the frequency of carriage in the patient population (59% vs 32%). This increase was not associated with treatment with H2-receptor antagonists. The results of paired oral and gastroduodenal aspirate cultures suggested that identifying Candida in the oral cavity was a good indicator of the presence of yeasts elsewhere in the gastrointestinal tract. Mechanisms whereby overgrowth of Candida in the upper gastrointestinal tract might contribute to the inflammatory background of peptic ulcer disease are discussed.

ABO Blood-Group System↗

Gastrointestinal-tract models and techniques for use in safety pharmacology.

The gastrointestinal tract (GI tract), which extracts nutrients, electrolytes, minerals, and water, is prone to injury as a result of oral drug administration. Clinical assessment of the GI tract is often limited to measurements of transit time and observations of vomiting or diarrhoea, despite the existence of methods and techniques capable of assessing specific changes in GI function at the membrane, cell, and whole animal levels. Membrane studies, record the uptake of solutes, and electrolyte transport, assessing the affects of compounds on transepithelial GI transport and flux. Such methods lend themselves to permeability, immunohistochemistry, morphology, and molecular biology techniques. Isolated cells from the GI tract or cultured cell lines provide knowledge of regulation and function at a cellular level, whilst motility patterns, taken in vivo or from biopsies, provide information at a more integrated level. In anesthetised animals, ligated segments of the intestine can be infused with test compounds, providing information about absorptive and secretory processes important for the treatment of diarrhoea. Computer simulations and modelling are used to predict the disposition of a chemical and its metabolite and can, to some extent, replace animal testing, thereby reducing development costs. Indeed, software programs can be used to simulate the dissolution, absorption, distribution, metabolism, and excretion (ADME) properties of potential drugs in the human GI tract. Finally, advances in the field of imaging, combined with endoscopy, have resulted in a wireless capsule, allowing the inspection of the GI tract anatomy and pathology without surgical intervention. It is concluded that the field of safety pharmacology could rapidly, cheaply, and routinely incorporate membrane, isolated tissue, and endoscopy techniques for GI tract testing of drugs.

Administration, Oral↗

Endocannabinoids and the gastrointestinal tract.

In the past centuries, different preparations of marijuana have been used for the treatment of gastrointestinal (GI) disorders, such as GI pain, gastroenteritis and diarrhea. Delta9-tetrahydrocannabinol (THC; the active component of marijuana), as well as endogenous and synthetic cannabinoids, exert their biological functions on the gastrointestinal tract by activating two types of cannabinoid receptors, cannabinoid type 1 receptor (CB1 receptor) and cannabinoid type 2 receptor (CB2 receptor). While CB1 receptors are located in the enteric nervous system and in sensory terminals of vagal and spinal neurons and regulate neurotransmitter release, CB2 receptors are mostly distributed in the immune system, with a role presently still difficult to establish. Under pathophysiological conditions, the endocannabinoid system conveys protection to the GI tract, eg from inflammation and abnormally high gastric and enteric secretion. For such protective activities, the endocannabinoid system may represent a new promising therapeutic target against different GI disorders, including frankly inflammatory bowel diseases (eg, Crohn's disease), functional bowel diseases (eg, irritable bowel syndrome), and secretion- and motility-related disorders.

Animals↗

Ischaemia-sensitive sympathetic afferents innervating the gastrointestinal tract function as nociceptors in cats.

1. Activation of sympathetic visceral afferents during mesenteric ischaemia induces visceral pain and reflexly excites the cardiovascular system. The present study investigated the differential responses of ischaemically sensitive and insensitive sympathetic C fibre afferents to graded distension of the gastrointestinal tract. 2. Single-unit activity of C fibre afferents innervating the stomach, duodenum and jejunum was recorded from the right thoracic sympathetic chain of anaesthetized cats. Ischaemically sensitive and insensitive C fibre afferents were identified according to their response to 5-20 min of ischaemia. The functional characteristics of the stimulus-response relationships of afferents were determined by distension of a balloon placed in the corresponding segment of gastrointestinal tract. 3. The results show that ischaemically insensitive C fibre afferents had a lower threshold in response to distension (13 +/- 5 mmHg, n = 10). The discharge frequency of these afferents was saturated within a low pressure range of distension. However, ischaemically sensitive C fibre afferents had a high threshold (86 +/- 12 mmHg, n = 10) and a larger peak response to mechanical distension in the noxious range (60-180 mmHg). There were no differences between ischaemically sensitive and insensitive C fibre afferents with regard to their testing activity or responses to bradykinin (10 micrograms I.A.). 4. This study demonstrates that the gastrointestinal system is innervated by low and high threshold sympathetic C fibre afferents, the latter having the distinct ability to encode nociceptive information such as excessive distension and ischaemia.

Animals↗