Search PubMed⌕ Search

Biomedical subjects

Mitchell L Schubert

Publications and source records attributed to Mitchell L Schubert.

12 recordsLinked to original sources
PubMed2006

Gastrointestinal stromal tumor (GIST).

Gastrointestinal stromal tumors (GISTs), the most common nonepithelial neoplasms of the gastrointestinal (GI) tract, occur most commonly in the stomach. These neoplasms were previously classified as smooth muscle tumors, but it has become apparent that they represent distinct clinicopathologic entities. All GISTs should be considered as having malignant potential, although they display varying degrees of aggressiveness. Although usually asymptomatic, large GISTs may present with pain or bleeding. Definitive diagnosis is made by immunohistochemical staining of the tissue for CD117, also known as KIT protein, a cell membrane receptor with tyrosine kinase activity. Size and mitotic activity are predictive of malignant behavior. Primary treatment for GISTs with high malignant potential is surgical resection. Specific therapy targeting the KIT receptor with imatinib has resulted in improved outcomes for patients with unresectable, metastatic, and recurrent disease.

Journal Article↗
PubMed2006

Gastric secretion.

PURPOSE OF REVIEW: To summarize the literature over the past year on the regulation of gastric exocrine and endocrine secretion. RECENT FINDINGS: Gastric acid secretion by parietal cells is precisely regulated by overlapping neural, hormonal, and paracrine pathways, both centrally and peripherally. Too much acid can induce gastroduodenal injury. Too little acid can interfere with the absorption of iron, calcium, vitamin B12, and certain drugs as well as predispose the patient to enteric infection. A number of peptides implicated in the central control of food intake such as ghrelin, orexin, and leptin are present in the stomach and are capable of modulating acid secretion. The precise mechanisms whereby Helicobacter pylori produces perturbations in acid secretion are not precisely known but appear to involve changes in somatostatin and perhaps ghrelin secretion. Both gastrin and gastrin-receptor knockout mice as well as gastrin-overexpressing and cAMP-overexpressing mice develop gastric atrophy; gastric atrophy is associated with antiparietal cell antibodies and may be a model for autoimmune gastritis. SUMMARY: A better understanding of the pathways and mechanisms regulating acid secretion as well as the development of genetically engineered mouse models should lead to new strategies to prevent and treat a variety of gastric disorders, including peptic ulcer disease, neoplasia, and autoimmune gastritis.

Animals↗
PubMed2005

Gastric and Postpyloric Total Enteral Nutrition.

The provision and maintenance of good nutrition in patients with acute and chronic illness is a fundamental part of standard medical and surgical care. Recently, there is great interest in using enteral nutritional support to reverse the morbidity and mortality associated with malnutrition. Enteral nutrition is preferred over parenteral nutrition because it is more physiologic, maintains intestinal structure and function, limits bacterial translocation, has less morbidity, has fewer complications, and is less expensive. However, the decision to feed into the stomach or into the small bowel (postpyloric) continues to be a matter of some debate and continued clinical investigation. Although the gastric route of enteral feeding is easier and less expensive, some physicians worry that gastric feeding may predispose to aspiration and pneumonia, especially in critically ill patients who frequently have delayed gastric transit. In these critically ill patients, small bowel function usually remains relatively intact and placement of a postpyloric feeding tube may permit more effective delivery of nutrients. However, it should be noted that placement of postpyloric feeding tubes can be challenging, and this may lead to a delay in initiation of nutritional support.

Journal Article↗
PubMed2005

Gastric secretion.

PURPOSE OF REVIEW: The purpose of this review is to summarize the pertinent literature published in the past year regarding the regulation of gastric exocrine and endocrine secretion. RECENT FINDINGS: Gastric acid aids protein digestion; facilitates the absorption of iron, calcium, and vitamin B12; thwarts enteric infection; and prevents bacterial overgrowth. When levels of acid and proteolytic enzymes overwhelm the mucosal defense mechanisms, ulcers occur. To avoid damage under these harsh conditions, gastric acid must be finely regulated by overlapping neural (e.g. orexin, pituitary adenylate cyclase-activating polypeptide, nitric oxide, and galanin), hormonal (e.g. gastrin, cholecystokinin, and ghrelin), paracrine (e.g. histamine and somatostatin), and autocrine (e.g. transforming growth factor-alpha) pathways. The precise mechanisms whereby Helicobacter pylori induces perturbations in acid secretion are not known, but they seem to involve changes in somatostatin and perhaps ghrelin secretion. Acid secretion by parietal cells involves intracellular elevation of calcium and/or cyclic AMP, followed by a cascade that triggers translocation of the proton pump, HK-adenosine triphosphatase, from cytoplasmic tubulovesicles to the secretory canaliculi. SUMMARY: An improved understanding of the pathways and mechanisms regulating gastric acid secretion may lead to the development of new strategies to prevent and treat acid peptic disorders as well as circumvent the adverse effects of currently prescribed antisecretory medications.

Gastric Acid↗
PubMed2004

Gastric secretion.

PURPOSE OF REVIEW: The purpose of this chapter is to summarize and place into perspective the past year's literature regarding the regulation of gastric exocrine and endocrine secretion. RECENT FINDINGS: To prevent acid and pepsin from overwhelming mucosal defense mechanisms and causing injury, the secretion of gastric acid is precisely regulated by a variety of central (eg, neuropeptide Y, corticotropin-releasing factor, and neuromedin U) and peripheral (eg, gastrin, histamine, acetylcholine, somatostatin, cholecystokinin, calcitonin gene-related peptide, leptin, and parietal cell) pathways. These pathways regulate the acid-producing parietal cell directly and/or indirectly by regulating the secretion of histamine from enterochromaffin-like cells, gastrin from G cells, and somatostatin from D cells. Recently, genetically engineered mouse models have been used to reevaluate the neural, hormonal, and paracrine pathways that physiologically regulate acid secretion. SUMMARY: An improved understanding of the pathways and mechanisms regulating gastric acid secretion should lead to the development of novel therapies to prevent and treat acid-peptic disorders as well as circumvent the adverse effects of currently used antisecretory medications such as the acid rebound observed after discontinuation of proton pump inhibitors.

Journal Article↗
PubMed2003

Adrenomedullin stimulates somatostatin and thus inhibits histamine and acid secretion in the fundus of the stomach.

Adrenomedullin has recently been localized to enterochromaffin-like (ECL) and chief cells in the gastric fundus. It has been proposed that adrenomedullin may play a role in gastric mucosal defense and repair. In the present study, we have used the isolated, luminally perfused mouse stomach and superfused rat fundic segments to examine the effect of adrenomedullin on exocrine and endocrine secretion in this region of the stomach. Addition of adrenomedullin (1 pM to 1 microM) to the isolated mouse stomach caused a concentration-dependent decrease in acid secretion. The EC(50) value was 1.4 x 10(-9) and maximal inhibition of acid secretion was obtained at a concentration of 1 microM (31+/-4% below basal level, P<0.001). In rat fundic segments, superfusion with adrenomedullin (0.1 pM to 0.1 microM) caused a concentration-dependent increase in somatostatin secretion (EC(50), 1 x 10(-10)) that was accompanied by a reciprocal decrease in histamine secretion (EC(50), 1.2 x 10(-11)). Maximal stimulation of somatostatin secretion (60+/-5% above basal level, P<0.001) and inhibition of histamine secretion (50+/-5% below basal level, P<0.01) was obtained at a concentration of 0.1 microM. Changes in acid and histamine secretion induced by adrenomedullin reflected changes in somatostatin secretion and could be abolished by addition of somatostatin antibody. The axonal blocker, tetrodotoxin, also abolished the somatostatin and, consequently, the acid and histamine responses to adrenomedullin, implying that the effect of adrenomedullin on somatostatin secretion was mediated via activation of intramural neurons. We conclude that adrenomedullin, acting via intramural fundic neurons, stimulates somatostatin and thus inhibits histamine and acid secretion. This represents one mechanism by which adrenomedullin might enhance mucosal defense and repair.

Adrenomedullin↗
PubMed2003

Gastric secretion.

PURPOSE OF REVIEW: Gastric acid facilitates the digestion of protein and the absorption of iron, calcium, and vitamin B12. It also protects against bacterial overgrowth and enteric infection, including prion disease. When homeostatic mechanisms malfunction, the volume and concentration of acid may overwhelm mucosal defense mechanisms, leading to duodenal ulcer, gastric ulcer, and gastroesophageal reflux disease. This article reviews recent knowledge contributing to understanding of the regulation of gastric acid secretion at the central, peripheral, and intracellular levels. RECENT FINDINGS: The vagus nerve contains afferent fibers that transmit sensory information from the stomach to the nucleus of the solitary tract. Input from the nucleus of the solitary tract is relayed to vagal efferent neurons that originate from two brain stem nuclei: the nucleus ambiguus and the dorsal motor nucleus of the vagus. The latter is also influenced by thyrotropin-releasing hormone neurons that act centrally to stimulate acid secretion. The main peripheral stimulants of acid secretion are the hormone gastrin and the paracrine amine histamine. Gastrin stimulates acid secretion directly and, more importantly, indirectly by releasing histamine from fundic enterochromaffin-like cells. Gastrin also exerts trophic effects on various tissues, including the gastric and intestinal mucosa. The main inhibitor of acid secretion is somatostatin. Somatostatin, acting via ssTR2 receptors, exerts a tonic paracrine inhibitory influence on the secretion of gastrin, histamine, and acid secretion. Calcitonin gene-related peptide, adrenomedullin, amylin, atrial natriuretic peptide, and pituitary adenylate cyclase-activating polypeptide all stimulate somatostatin secretion and thus inhibit acid secretion. HK-ATPase, the proton pump of the parietal cell, is stored within cytoplasmic tubulovesicles during the resting state, but during stimulation, it is shuttled to the canalicular membrane by a poorly understood mechanism that probably involves soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins. The proton pump inhibitor, pantoprazole, is unique in that it binds cysteine 822, located deep within the membrane domain of the alpha-subunit. The difficulty that reducing agents, such as glutathione, have in reaching cysteine 822 may be responsible for the longer half-time for acid recovery observed with pantoprazole. Hypergastrinemia, induced by proton pump inhibitors, enhances expression of cyclooxygenase-2 and hence prostaglandins within parietal cells, a feedback pathway that may protect the stomach against acid-induced damage. SUMMARY: In the past year, significant advances have been made in understanding of the regulation of gastric acid secretion. Ultimately, these advances should lead to improved therapies to prevent and treat acid-related disorders. Gastric acid secretion must be precisely controlled at a variety of levels to prevent disease caused by hyperchlorhydria and hypochlorhydria. The mechanisms include neural (central and peripheral), hormonal, paracrine, and intracellular pathways that operate in concert to switch acid secretion on during ingestion of a meal and off during the interdigestive period. A better understanding of the physiology of acid secretion in health and disease should eventually lead to improved therapies to prevent and treat acid-related disorders.

Journal Article↗
PubMed2003

Regulation of atrial natriuretic peptide secretion by cholinergic and PACAP neurons of the gastric antrum.

Atrial natriuretic peptide (ANP) released from enterochromaffin cells helps regulate antral somatostatin secretion, but the mechanisms regulating ANP secretion are not known. We superfused rat antral segments with selective neural agonists/antagonists to identify the neural pathways regulating ANP secretion. The nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP) stimulated ANP secretion; the effect was abolished by hexamethonium but doubled by atropine. Atropine's effect implied that DMPP activated concomitantly cholinergic neurons that inhibit and noncholinergic neurons that stimulate ANP secretion, the latter effect predominating. Methacholine inhibited ANP secretion. Neither bombesin nor vasoactive intestinal polypeptide stimulated ANP secretion, whereas pituitary adenylate cyclase-activating polypeptide (PACAP)-27, PACAP-38, and maxadilan [PACAP type 1 (PAC1) agonist] each stimulated ANP secretion. The PAC1 antagonist M65 1) abolished PACAP-27/38-stimulated ANP secretion; 2) inhibited basal ANP secretion by 28 +/- 5%, implying that endogenous PACAP stimulates ANP secretion; and 3) converted the ANP response to DMPP from 109 +/- 21% above to 40 +/- 5% below basal, unmasking the cholinergic component and indicating that DMPP activated PACAP neurons that stimulate ANP secretion. Combined atropine and M65 restored DMPP-stimulated ANP secretion to basal levels. ANP secretion in the antrum is thus regulated by intramural cholinergic and PACAP neurons; cholinergic neurons inhibit and PACAP neurons stimulate ANP secretion.

Animals↗
PubMed2002

Amylin, released from the gastric fundus, stimulates somatostatin and thus inhibits histamine and acid secretion in mice.

BACKGROUND & AIMS: Amylin, a peptide that displays 50% homology with calcitonin gene-related peptide (CGRP), is colocalized with somatostatin in endocrine cells of the gastric fundus. The present study was designed to determine the mechanism of action of amylin on gastric exocrine and endocrine secretion. METHODS: Acid secretion was measured in the isolated mouse stomach by titration. Somatostatin and histamine secretion were measured in rat fundic segments by radioimmunoassay. RESULTS: In isolated mouse stomach, amylin caused a concentration-dependent decrease in acid secretion. In rat fundic segments, amylin and CGRP each caused a concentration-dependent increase in somatostatin and a decrease in histamine secretion. Changes in histamine secretion induced by amylin reflected changes in somatostatin secretion and could be abolished by addition of somatostatin antibody. Both the somatostatin and the histamine responses to amylin were abolished by the selective amylin antagonist AC187 but were unaffected by the CGRP antagonist CGRP8-37. In contrast, the responses to CGRP were abolished by CGRP8-37 but were unaffected by AC187. AC187 alone decreased somatostatin and increased histamine in fundic segments and increased acid secretion in isolated stomach, indicating that endogenous amylin participates in the regulation of gastric endocrine (somatostatin and histamine) and exocrine (acid) secretion. CONCLUSIONS: In gastric fundus, release of amylin from somatostatin cells interacts with distinct amylin receptors to enhance somatostatin secretion via an autocrine pathway that leads to inhibition of histamine and acid secretion.

Amyloid↗
PubMed2002

Gastric secretion.

Overlapping neural, hormonal, and paracrine pathways finely regulate gastric acid secretion. In rats and guinea pigs, most of the intrinsic neural innervation to the gastric mucosa originates in the myenteric plexus. In contrast, human stomachs have a clearly defined submucosal plexus that contains a variety of transmitters including nitric oxide, vasoactive intestinal peptide (VIP), gastrin-releasing peptide (GRP), substance P, and calcitonin gene-related peptide (CGRP). Although GRP is known to participate in meal-stimulated acid secretion by releasing gastrin in a variety of laboratory animals, recent studies were unable to demonstrate a role for endogenous GRP in meal-stimulated gastrin secretion in humans. Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the secretin-glucagon-VIP family, has been localized to gastric mucosal neurons and may participate in vagally mediated acid secretion. Two novel peptides, ghrelin and leptin, have been localized to the stomach. Peripheral administration of ghrelin stimulates and of leptin inhibits acid secretion. The binding of secretagogues to parietal cells generates changes in second messengers that regulate the translocation and activation of the proton pump, HK-ATPase. In resting cells, HK-ATPase is contained within cytoplasmic tubulovesicles in an inactive form. At stimulation, the tubulovesicles fuse with the apical canaliculi and the HK-ATPase is incorporated into the apical membrane where it actively pumps H ions in exchange for K. Acute infection with Helicobacter pylori results in hypochlorhydria, whereas chronic infection can cause either hypo- or hyperchlorhydria, depending on the distribution of the infection and the degree of corpus gastritis. Recent studies suggest that inflammatory cytokines, produced in response to the organism, can play a role in the perturbations in acid and gastrin secretion induced by H. pylori.

Journal Article↗