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PubMed2005

The role of TGF-beta and Wnt signaling in gastrointestinal stem cells and cancer.

The past three decades have seen an unremitting quest to identify and understand gastrointestinal stem cells, their plasticity in differentiating across cell types, as well as their role in normal, regenerative, and cancer cells. A fascinating hallmark of stem cells is their ability to undergo assymetric cell division, which entails replication of the DNA followed by division of the nucleus and partitioning of the cytoplasm to yield two different daughter cells: a stem cell as well as a committed progenitor cell, the latter proliferating into differentiated progeny. We are only just beginning to understand how normally quiescent, tissue-specific stem cells interpret a vast array of signals to develop into the gastrointestinal system. These signaling pathways include the transforming growth factor-beta (TGF-beta) superfamily, Wnt, FGFs, Hedgehog, Hox proteins that originate from surrounding mesodermal/stromal tissue as well as endodermal/epithelial tissue. TGF-beta and wnt proteins are key morphogens that ultimately influence cell division and cell fate, so that gut endodermal stem cells enter the cell cycle, and undergo cell division that ultimately leads to differentiated cells such as functional hepatocytes, gastric parietal cells, or gut epithelial cells. Disruptions and errors in this process usually lead to tissue-specific gastrointestinal cancers such as hepatocellular cancers, gastric adenocarcinomas, and colonic adenocarcinomas. An increasingly complex and coherent view of stem/progenitor cell signaling networks, which coordinate cell growth, proliferation, stress management, and survival, is helping to define the fragile areas where malignancies are likely to develop and shows promise for the development of better cancer therapies.

Animals↗
PubMed2003

Cancer risks in naval divers with multiple exposures to carcinogens.

We investigated risks for cancer and the case for a cause-effect relationship in five successive cohorts of naval commando divers (n = 682) with prolonged underwater exposures (skin, gastrointestinal tract, and airways) to many toxic compounds in the Kishon River, Israel's most polluted waterway, from 1948 to 1995. Releases of industrial, ship, and agricultural effluents in the river increased substantially, fish yields decreased, and toxic damage to marine organisms increased. Among the divers (16,343 person-years follow-up from 18 years of age to year 2000), the observed/expected ratio for all tumors was 2.29 (p<0.01). Risks increased in cohorts first diving after 1960 compared to risks in earlier cohorts, notably for hematolymphopoietic, central nervous system, gastrointestinal, and skin cancer; induction periods were often brief. The findings suggest that the increases in risk for cancer and short induction periods resulted from direct contact with and absorption of multiple toxic compounds. Early toxic effects in marine life predicted later risks for cancer in divers.

Adult↗
PubMedDate not supplied

Review of naltrexone, a long-acting opiate antagonist.

The basis for using narcotic antagonists for the treatment of opiate addiction is discussed briefly, and the chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of naltrexone hydrochloride, an opiate antagonist drug, are reviewed. Naltrexone is rapidly and completely absorbed after oral administration but undergoes substantial first-pass extraction and metabolism by the liver. Naltrexone has a half-life of 3.9-10.3 hours and a slow terminal elimination-phase half-life of 96 hours. The major metabolite of naltrexone is 6-beta-naltrexol, which is present in plasma in greater concentrations than the parent drug. Problems in study design and patient adherence to treatment have made assessment of naltrexone's clinical efficacy difficult; however, studies have consistently demonstrated that patients who remained off opiates longer were those who took naltrexone longer. Factors associated with successful treatment outcomes include sustained therapy with naltrexone, participation in multidisciplinary programs of behavioral therapy and psychotherapy, and good family and social support systems. Gastrointestinal irritation and, in some studies, clinically insignificant increases in blood pressure, have been the most common adverse effects. Currently available data suggest that naltrexone is a very safe drug. The usual dosage of naltrexone hydrochloride is 50 mg orally once daily or 350 mg orally per week in three divided doses. Patients should be detoxified and opiate free for two to five days before initiation of naltrexone therapy. Naltrexone appears to be a useful adjunct to therapy in opiate addicts who are well motivated and who have strong psychological support systems.

Animals↗
PubMedDate not supplied

[A selective antimuscarinic agent: pirenzepine. Review of its pharmacologic and clinical properties].

The heterogeneity of muscarinic receptors has been well supported by differential characteristics between pirenzepine and atropine both in receptor binding and in whole tissue pharmacology studies. Under these conditions pirenzepine has been classified as a selective receptor antagonist with high affinity for M1 receptors. The antisecretory properties of pirenzepine on gastric acid and pepsin secretion may be attributed to the antagonistic activity of the drug on muscarinic M1 receptors of gastric intramural plexuses, whereas the effect on parietal muscarinic M2 receptors seems of less importance. Additional inhibitory mechanisms on gastric secretion may be represented by pirenzepine-induced increase in somatostatin release from gastrointestinal system. Significant cytoprotective properties of pirenzepine have been observed on a variety of experimentally induced peptic ulcerations. This protective activity may be due to pirenzepine-induced increase in gastric mucosal blood flow as well as to the increase in gastric transmural electric potential difference. In accordance with this pharmacodynamic profile of pirenzepine, numerous clinical studies have revealed its efficacy in the treatment of both duodenal and gastric ulcerations. In addition to this, the clinical usefulness of the drug has been demonstrated in Zollinger-Ellison syndrome, in stress ulceration, in acute gastrointestinal bleeding as well as in gastritis, duodenitis and non-ulcer dyspepsia. In most of the studies pirenzepine has been found to be well tolerated with a low incidence of antimuscarinic effects which may occur at salivary, ocular, cardiac and urinary sites. The clinical use of pirenzepine alone or in association with H2 blockers is recommended in the treatment of peptic ulcer patients, in the case of acute gastrointestinal haemorrhage and in patients non responders to H2 antagonists.

Animals↗
PubMed1986

Suppression of natural killer cell activity by surgical stress in cancer patients and the underlying mechanisms.

The influence of surgical stress on the natural killer (NK) activity of peripheral blood lymphocytes in patients with carcinoma of the lung or gastrointestinal system was studied. The peripheral blood lymphocytes of the patients showed a marked decrease in NK activity against K-562 cells as target cells 1-2 days after surgery. The activity remained lowered for 2 weeks after thoractomy and for 1 week after laparotomy. No appreciable suppression of NK activity was observed with normal human peripheral blood lymphocytes preincubated with postoperative patient sera. Peripheral blood mononuclear cells obtained postoperatively from patients lost NK activity after ultraviolet irradiation, without any detectable loss of viability. Such irradiated mononuclear cells showed inhibition of NK activity after a 24-hour preincubation with peripheral blood lymphocytes from normal subjects. Similar suppressive activity was demonstrable in a fraction of mononuclear cells with adhesiveness to plastic petri dishes, while non-adherent cells had no such activity. When added immediately to the cytotoxicity assay system without the 24-hour preincubation, patient mononuclear cells caused no inhibition of NK activity, whereas adherent cells from normal subjects enhanced NK activity. The findings seems to indicate that, following surgical stress, plastic dish-adherent peripheral blood mononuclear cells become deprived of NK helper activity and exert suppression, thus causing postoperative depression of NK activity.

Gastrointestinal Neoplasms↗
PubMedDate not supplied

Furosemide vasodilates the canine gastrointestinal tract.

The ability of furosemide to induce vasodilation in the canine gastrointestinal system was studied by quantitative flowmetry. Blood flow and conductance increased maximally by 60 per cent in the stomach and duodenum and by 80 per cent in the small and large intestine. Vasodilation was evident at 2.4 mg/kg furosemide and higher. The onset of vasodilation occurred at 24 to 30 seconds and was maximal at 36 seconds in the stomach, at 66 seconds in the duodenum, at 78 to 84 seconds in the small intestine, and at 90 seconds in the large intestine. Hepatic arterial, splenic, and renal blood flows were unchanged. Simultaneous arteriovenous sampling from the small intestine indicated that the increased blood flow was not associated with increased O2 consumption. However, CO2 addition to the venous effluent decreased by 70 per cent. These data indicate that furosemide has a vasodilatory action on the gastrointestinal tract due either to a delayed effect on the vascular smooth muscle cell or on anaerobic bowel wall metabolism. The CO2 data are compatible with, but do not prove, stimulation of secretion of HCO3- by the intestinal mucosa.

Animals↗
PubMed2005

Insights into cGMP signalling derived from cGMP kinase knockout mice.

cGMP signalling plays an important physiological role in diverse organs including the vasculature, the GI-tract and the nervous system. Furthermore, cGMP-elevating substances such as glyceryl trinitrate are important drugs used in cardiovascular diseases. Physiologically, cGMP synthesis is induced by nitric oxide (NO) and natriuretic peptides through the stimulation of guanylyl cyclases. Major mediators of cGMP signalling are the cGMP-dependent protein kinases type I and II (cGKI and cGKII). The functional significance of each kinase type in diverse organs was determined using total and tissue-specific cGKI- and cGKII-deficient mice. These studies established that cGKI plays a major role in the regulation of the cardiovascular and the gastrointestinal system, hippocampal and cerebellar learning and pain perception. cGKII is involved in intestinal water secretion, bone growth and circardian rhythmicity. The cGK mutant mice are important tools to obtain detailed insights into cGMP-mediated signalling pathways in health and disease.

Animals↗
PubMed2000

Gastrointestinal glutathione peroxidase prevents transport of lipid hydroperoxides in CaCo-2 cells.

BACKGROUND & AIMS: Gastrointestinal glutathione peroxidase (GI-GPx), 1 of the 4 types of selenium-dependent glutathione peroxidases, is expressed exclusively in the gastrointestinal system and has therefore been suggested to function as a barrier against the absorption of dietary hydroperoxides. METHODS: The selenium-dependent expression of GI-GPx and cytosolic GPx (cGPx) was analyzed by Western blotting. Transport of 13-hydroperoxy octadecadienoic acid (13-HPODE) was investigated in a CaCo-2 cell monolayer modulated in GI-GPx and cGPx by selenium restriction or repletion. Localization of GI-GPx in rat intestine was visualized by immunohistochemistry. RESULTS: Low but significant GI-GPx levels were detected in selenium-deficient CaCo-2 cells and in the gastrointestinal tract of selenium-deficient rats, whereas cGPx was completely absent. Selenium supplementation of CaCo-2 cells resulted in a 5-fold increase of GI-GPx protein, whereas total GPx activity increased by a factor of 13, with most of the GPx activity under selenium-adequate conditions being cGPx. Irrespective of the selenium status, 13-HPODE did not reach the basolateral side of an intact CaCo-2 cell monolayer. Depending on the selenium status, hydroperoxides damaged the monolayer as evidenced by loss of transepithelial resistance and paracellular diffusion of lucifer yellow. Only under these conditions was unmetabolized 13-HPODE detectable at the basolateral side. CONCLUSIONS: Low GI-GPx levels, as present in selenium deficiency, suffice to prevent transport of 13-HPODE. GI-GPx may thus function as a barrier against hydroperoxide absorption. cGPx contributes to balance major oxidative challenge.

Animals↗
PubMed2006

Effect of soil properties on arsenic fractionation and bioaccessibility in cattle and sheep dipping vat sites.

Historical use of high arsenic (As) concentrations in cattle/sheep dipping vat sites to treat ticks has resulted in severe contamination of soil and groundwater with this Group-A human carcinogen. In the absence of a universally applicable soil As bioaccessibility model, baseline risk assessment studies have traditionally used the extremely conservative estimate of 100% soil As bioaccessibility. Several in-vitro, as well as, in-vivo animal studies suggest that As bioaccessibility in soil can be lower than that in water. Arsenic in soils exists in several geochemical forms with varying degree of dissolution in the human digestive system, and thus, with highly varying As bioaccessibility. Earlier batch incubation studies with As-spiked soils have shown that As bioaccessibility is a function of soil physicochemical properties. We selected 12 dipping vat soils collected from USA and Australia to test the hypothesis that soil properties exert a significant effect on As bioaccessibility in As-contaminated sites. The 12 soils varied widely in terms of soil physico-chemical properties. They were subject to an As sequential fractionation scheme and two in-vitro tests (IVGS and IVGIA) to simulate soil As bioavailability in the human gastrointestinal system. Sequential As fractionation results showed that the majority of the As measured in the dipping vat soils resided either in the Fe/Al hydroxide fraction, or the Ca/Mg fractions, or in the residual fraction. Water-extractable As fraction of the 12 soils was typically <10% of the total, reaching values up to 23%, indicating minimal leaching potential, and hence, lower risk of As-contamination from exposure to groundwater, typically used as drinking water in many parts of the world. Partial individual correlations and subsequent multiple regression analyses suggested that the most significant soil factors influencing As bioaccessibility were total Ca+Mg, total P, clay content and EC. Collectively, these soil properties were able to explain 85 and 86% of the variability associated with the prediction of bioaccessible As, using IVGS and IVGIA in-vitro tests, respectively. This study showed that specific soil properties influenced the magnitude of soil As bioaccessibility, which was typically much lower than total soil-As concentrations, challenging the traditional risk assessment guideline, which assumes that soil As is 100% bioaccessible. Our study showed that total soil As concentration is unlikely to provide an accurate estimate of human health risk from exposure to dipping vat site soils.

Animals↗
PubMedDate not supplied

Gastrointestinal carcinoid tumors in rare locations: imaging findings.

In this article, we present radiological findings in three patients with mesenteric, gastric, and rectal carcinoid tumors. More than 90% of the carcinoid tumors arise in the gastrointestinal system (GIS). They comprise 2% of all GIS tumors and are usually located in the small intestine and the appendix. On the other hand, gastric, rectal, and mesenteric carcinoids are rare. Better knowledge of radiological features of carcinoid tumors in rare locations will prevent diagnostic delays and development of carcinoid syndrome.

Adult↗
PubMed1999

Colonization and tissue tropism of Helicobacter pylori and a novel urease-negative Helicobacter species in ICR mice are independent of route of exposure.

BACKGROUND: In humans, Helicobacter pylori is known to colonize the stomach and to induce persistent gastritis; selected reports also suggest it causes extragastric disease, including hepatitis. H. pylori and a novel urease-negative Helicobacter sp. induce gastritis and typhlocolitis, respectively, when inoculated orally into mice. Experimental typhlocolitis and hepatitis have been caused by intraperitoneal (i.p.) injection of H. hepaticus, H. bilis, and the novel Helicobacter spp. However, the route by which i.p.-inoculated organisms localize to specific areas of the gastrointestinal system is unknown. MATERIALS AND METHODS: To determine whether Helicobacter spp. can be isolated from blood, can preferentially colonize specific tissues, and can cause pathological changes, we inoculated 6-week-old outbred mice orally or intraperitoneally with H. pylori or a novel Helicobacter sp. RESULTS: When these mice were inoculated by the i.p. route, H. pylori was cultured from lungs, spleen, liver, cecum, and stomach on day 1 after inoculation, from liver and stomach mucosa on day 3 after inoculation, and from the stomach on day 30 after inoculation, suggesting preferential colonization of the stomach. After inoculation by the i.p. route, the novel intestinal Helicobacter sp. was cultured from the blood, lungs, spleen, liver, kidneys, cecum, and feces but not from stomach mucosa on day 1 after inoculation. By day 30 after inoculation, the novel Helicobacter sp. was cultured from cecum and feces only, suggesting that it had preferentially colonized the lower bowel. By the i.p. route, the novel Helicobacter sp. induced hepatitis that persisted for 30 days after inoculation. Though mice inoculated intraperitoneally with H. pylori developed an acute hepatitis, the liver lesion began to resolve 30 days after inoculation. Mice inoculated orally with either H. pylori or the novel Helicobacter sp. did not have hepatitis on day 30 after inoculation but developed 100% colonization of stomach and cecum, respectively. CONCLUSION: The isolation of H. pylori and the novel Helicobacter sp. from multiple tissues infers that a transient helicobacter bacteremia occurs when Helicobacter spp. are injected intraperitoneally, but organisms are cleared rapidly from nontarget tissues and preferentially colonize specific regions of the gastrointestinal tract.

Animals↗
PubMedDate not supplied

Interoception: the inside story--a model for psychosomatic processes.

OBJECTIVE: To comprehend psychosomatic processes, it will be necessary to understand the brain's influences on bodily functions and also the body's afferent sensory input to the central nervous system, including the effects of this input on behavior and cognitive functions, especially emotion. The objective of this Presidential Address is to review what is known circa the year 2000 of the processes and mechanisms of visceral sensory psychobiology, often called interoception. METHODS: Over 1000 publications that have appeared since the 19th century were reviewed to prepare this review, including a group that are specifically cited here. RESULTS: Factors and data were reviewed that were identified as germane to understanding interoception. These included definitional issues, historical roots, the neural basis, studies and results in the cardiovascular-respiratory and alimentary-gastrointestinal systems, studies of emotion, and studies in people with mental disorders. Drug and hormone effects, pain, proprioception, and phantom limb or organ factors, and the role of awareness were briefly described. Methodological issues, methods of study including functional imaging, and possible future directions for study were identified. CONCLUSIONS: Understanding the physical basis of psychosomatic processes, including the so-called mind-body problem, will require a detailed understanding the psychobiology of interoception.

Brain↗
PubMed2007

Gastrointestinal regulation of food intake.

Despite substantial fluctuations in daily food intake, animals maintain a remarkably stable body weight, because overall caloric ingestion and expenditure are exquisitely matched over long periods of time, through the process of energy homeostasis. The brain receives hormonal, neural, and metabolic signals pertaining to body-energy status and, in response to these inputs, coordinates adaptive alterations of energy intake and expenditure. To regulate food consumption, the brain must modulate appetite, and the core of appetite regulation lies in the gut-brain axis. This Review summarizes current knowledge regarding the neuroendocrine regulation of food intake by the gastrointestinal system, focusing on gastric distention, intestinal and pancreatic satiation peptides, and the orexigenic gastric hormone ghrelin. We highlight mechanisms governing nutrient sensing and peptide secretion by enteroendocrine cells, including novel taste-like pathways. The increasingly nuanced understanding of the mechanisms mediating gut-peptide regulation and action provides promising targets for new strategies to combat obesity and diabetes.

Adipose Tissue↗
PubMed2001

Respiratory alkalosis.

Respiratory alkalosis is an extremely common and complicated problem affecting virtually every organ system in the body. This article reviews the various facets of this interesting problem. Respiratory alkalosis produces multiple metabolic abnormalities, from changes in potassium, phosphate, and calcium, to the development of a mild lactic acidosis. Renal handling of the above ions is also affected. The etiologies may be related to pulmonary or extrapulmonary disorders. Hyperventilation syndrome is a common etiology of respiratory alkalosis in the emergency department setting and is a diagnosis by exclusion. There are many cardiac effects of respiratory alkalosis, such as tachycardia, ventricular and atrial arrhythmias, and ischemic and nonischemic chest pain. In the lungs, vasodilation occurs, and in the gastrointestinal system there are changes in perfusion, motility, and electrolyte handling. Therapeutically, respiratory alkalosis is used for treatment of elevated intracranial pressure. Correction of a respiratory alkalosis is best performed by correcting the underlying etiology.

Alkalosis, Respiratory↗
PubMed1999

Effect of preoperative paracetamol on gastric volumes and pH in children.

The effect preoperative paracetamol elixir has on gastric contents is unknown. Children presenting for elective adenotonsillectomy were randomized to receive either paracetamol elixir (40 mg x kg(-1)) 90 min before surgery or paracetamol suppositories (40 mg x kg(-1)) intraoperatively. Following induction of anaesthesia a 16 Fr multiple-oriface orogastric tube was passed into the stomach and measure taken of the residual gastric volume and pH. The children had a mean age of 8.5 years (SD 3.2) with a weight of 35 kg (SD 16.5). Children given elixir (n=41) had a mean residual gastric volume of 0.083 ml x kg(-1) (95% CI; 0.006, 1.24) and a pH of 1.83 (95% CI; 0.75, 4.49), while those given suppositories (n=40) had a mean residual gastric volume of 0.083 ml x kg(-1)(95% CI; 0.008, 0.9) and a pH of 2.07 (95% CI; 0.84, 5.12). There was no significant difference between these two groups. Paracetamol elixir is rapidly absorbed in the gastrointestinal system of children and preoperative administration has no effect on gastric contents. Given paracetamol's slow equilibration rate constant from the central to the effect compartment, children may be given this medication preoperatively for routine surgical procedures.

Absorption↗
PubMed2006

Comparison of gastrostomy tube replacement verification using air insufflation versus gastrograffin.

OBJECTIVE: To compare the safety of air insufflation as a contrast medium for percutaneous endoscopic gastrostomy (PEG) tube replacement verification with that of the more traditional method using positive contrast material (gastrograffin) under fluoroscopic guidance. DESIGN: Retrospective case series comparing 2 radiographic procedures used for PEG tube verification at a rehabilitation hospital. The first series reviewed studies of patients over 1 year, during which the method of choice for PEG tube replacement verification was with air insufflation. The second series reviewed studies of patients over the subsequent year, during which the method of choice for PEG tube replacement verification was with gastrograffin. SETTING: An inpatient rehabilitation hospital. PARTICIPANTS: Nineteen patients and 29 PEG tube replacements were identified that used air insufflation and 17 patients and 19 PEG tube replacements were identified that used gastrograffin. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Medical complications in a 2-week follow-up period as a result of the verification procedures. RESULTS: There were no cases in either of the replacement procedures in which the PEG tube was found to not be in the gastrointestinal system. There was also no evidence at 2-week follow-up that any of the patients' complications were the result of either procedure. CONCLUSIONS: The air contrast procedure appears to be a relatively safe alternative procedure for PEG tube replacement verification.

Adolescent↗
PubMed1994

[Computerized tomography in the differential diagnosis of non-gynecologic abdomino-pelvic masses].

The female pelvis is an anatomical region where masses can be found originating from pelvic organs, mostly from the genital system or else from abdominal organs and systems, by continuity, by contact or by metastatic spread. The clinician needs to define and characterize a pelvic mass since treatment options can vary greatly. If a malignant pelvic lesion is clinically suspected, ultrasonography is the investigation technique of choice, whose differential diagnosis accuracy is good especially in gynecologic conditions. However, in nongynecologic masses, US diagnostic yield is poorer, which led us to retrospectively review 31 such cases. CT was used to assess the mass origin and tissue characterization to define the clinical role of this method. On the whole, CT yielded good results (80.6% overall diagnostic accuracy, 25/31 cases) which however differed according to the different pathologic conditions. Gastrointestinal system conditions, tumors and inflammations were easy to diagnose with CT (11/15 cases, 73.3%), except for the patients with intestinal cancer spreading to the ovaries, that is, a Krukenberg's lesion, or the cases with an abscess hiding the annexa and thus preventing CT from detecting the mass origin, be it intestinal or annexial. CT diagnostic accuracy was high in extraperitoneal (retro- and properitoneal) masses (8/8 cases, 100%), but much lower (75%, 6/8 cases) in the diagnosis of primary intraperitoneal organs conditions. To conclude, CT is confirmed as an accurate imaging technique in the differential diagnosis of nongynecologic abdominopelvic masses. The mass origin is usually correctly detected and tissue characterization is accurate, which provides the clinician with enough pieces of information for best treatment planning.

Abdominal Neoplasms↗
PubMed1996

Mutations affecting development of zebrafish digestive organs.

The zebrafish gastrointestinal system matures in a manner akin to higher vertebrates. We describe nine mutations that perturb development of these organs. Normally, by the fourth day postfertilization the digestive organs are formed, the epithelial cells of the intestine are polarized and express digestive enzymes, the hepatocytes secrete bile, and the pancreatic islets and acini generate immunoreactive insulin and carboxypeptidase A, respectively. Seven mutations cause arrest of intestinal epithelial development after formation of the tube but before cell polarization is completed. These perturb different regions of the intestine. Six preferentially affect foregut, and one the hindgut. In one of the foregut mutations the esophagus does not form. Two mutations cause hepatic degeneration. The pancreas is affected in four mutants, all of which also perturb anterior intestine. The pancreatic exocrine cells are selectively affected in these four mutations. Exocrine precursor cells appear, as identified by GATA-5 expression, but do not differentiate and acini do not form. The pancreatic islets are spared, and endocrine cells mature and synthesize insulin. These gastrointestinal mutations may be informative with regard to patterning and crucial lineage decisions during organogenesis, and may be relevant to diabetes, congenital dysmorphogenesis and disorders of cell proliferation.

Animals↗