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3.
Acta Physiol (Oxf) ; 210(2): 239-56, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24279703

ABSTRACT

The purpose of this review, based upon 40 years of research, is to clear old controversies. The gastric juice is a strong acid with active enzymes (pepsin and lipase); ideal for killing swallowed microorganisms. Totally isolated rat stomach and histamine determination. Human gastric carcinomas were examined for ECL cell differentiation because tumours found in rodents after dosing with inhibitors of acid secretion were reclassified to be of ECL cell origin. The gastrin receptor is localized to the ECL cell only, where gastrin stimulates the function and growth. Drug-induced hypo-acidity induces hypergastrinaemia and ECL cell hyperplasia responsible for rebound acid hypersecretion. Every condition with long-term hypergastrinaemia disposes to ECL cell neoplasia. In man, both atrophic gastritis and gastrinoma lead to ECL cell carcinoids. Proton pump inhibitors induce hypergastrinaemia with ECL cell hyperplasia and ECL cell carcinoids that disappear when stopping treatment. The gastrin antagonist netazepide induces regression of ECL cell carcinoids due to atrophic gastritis. Human gastric carcinomas of diffuse type, particularly the signet-ring subtype, show ECL cell differentiation, suggesting involvement of gastrin in the carcinogenesis. Helicobacter pylori (Hp) causes gastritis and peptic ulcer, and when infecting the antrum only gives a slight hypergastrinaemia with acid hypersecretion predisposing to duodenal ulcer, but protecting from gastric cancer. When Hp infection spreads to oxyntic mucosa, it induces atrophy, reduced acid secretion and marked hypergastrinaemia and cancer.It is remarkable that the interaction between Hp and gastrin may explain the pathogenesis of most diseases in the upper gastrointestinal tract.


Subject(s)
Gastric Acid/metabolism , Animals , Gastrins/metabolism , Humans , Stomach Neoplasms/metabolism
4.
Clin Exp Immunol ; 173(3): 502-11, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23668802

ABSTRACT

Anti-microbial peptides might influence the pathogenesis and course of inflammatory bowel disease (IBD). We sought to clarify the role of the anti-microbial glycoprotein lipocalin 2 (LCN2) in the colon by determining its localization and regulation in IBD. Following a microarray gene expression study of colonic biopsies from a large IBD population (n = 133), LCN2 was localized using immunohistochemistry and in-situ hybridization. Moreover, we examined the regulation of LCN2 in HT-29 cells with a panel of pattern recognition receptors (PRRs) and sought evidence by immunohistochemistry that the most relevant PRR, the Toll-like receptor (TLR)-3, was indeed expressed in colonic epithelium in IBD. LCN2 was among the 10 most up-regulated genes in both active ulcerative colitis (UCa) and active Crohn's disease (CDa) versus healthy controls. LCN2 protein was found in both epithelial cells and infiltrating neutrophils, while mRNA synthesis was located solely to epithelial cells, indicating that de-novo synthesis and thus regulation of LCN2 as measured in the gene expression analysis takes place in the mucosal epithelial cells. LCN2 is a putative biomarker in faeces for intestinal inflammation, different from calprotectin due to its epithelial site of synthesis. LCN2 release from the colonic epithelial cell line HT-29 was enhanced by both interleukin (IL)-1ß and the TLR-3 ligand poly(I:C), and TLR-3 was shown to be expressed constitutively in colonic epithelial cells and markedly increased during inflammation.


Subject(s)
Acute-Phase Proteins/metabolism , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/metabolism , Lipocalins/metabolism , Proto-Oncogene Proteins/metabolism , Toll-Like Receptor 3/genetics , Adult , Aged , Biopsy , Colitis, Ulcerative/genetics , Colitis, Ulcerative/metabolism , Colitis, Ulcerative/pathology , Crohn Disease/genetics , Crohn Disease/metabolism , Crohn Disease/pathology , Female , Gene Expression Regulation , Gene Silencing , HT29 Cells , Humans , Inflammatory Bowel Diseases/pathology , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Lipocalin-2 , Lipocalins/blood , Male , Middle Aged , Poly I-C/pharmacology , Protein Transport , Proto-Oncogene Proteins/blood , RNA, Messenger/genetics , RNA, Messenger/metabolism , Toll-Like Receptor 3/metabolism , Young Adult
5.
Aliment Pharmacol Ther ; 36(11-12): 1067-75, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23072686

ABSTRACT

BACKGROUND: Patients with chronic atrophic gastritis have long-term gastric hypoacidity, and secondary hypergastrinaemia. Some also develop gastric ECL cells carcinoids (type 1 GC). Most type 1 GC remain indolent, but some metastasise. Patients undergo surveillance, and some are treated with somatostatin analogues, endoscopic resection or surgery. Netazepide (YF476) is a highly selective, potent and orally active gastrin receptor antagonist, which has anti-tumour activity in various rodent models of gastric neoplasia driven by hypergastrinaemia. Netazepide has been studied in healthy volunteers. AIM: To assess the effect of netazepide on type 1 GC. METHODS: Eight patients with multiple type 1 GC received oral netazepide once daily for 12 weeks, with follow-up at 12 weeks in an open-label, pilot trial. Upper endoscopy was performed at 0, 6, 12 and 24 weeks, and carcinoids were counted and measured. Fasting serum gastrin and chromogranin A (CgA) and safety and tolerability were assessed at 0, 3, 6, 9, 12 and 24 weeks. RESULTS: Netazepide was well tolerated. All patients had a reduction in the number and size of their largest carcinoid. CgA was reduced to normal levels at 3 weeks and remained so until 12 weeks, but had returned to pre-treatment levels at 24 weeks. Gastrin remained unchanged throughout treatment. CONCLUSIONS: The gastrin receptor antagonist netazepide is a promising new medical treatment for type 1 gastric carcinoids, which appear to be gastrin-dependent. Controlled studies and long-term treatment are justified to find out whether netazepide treatment can eradicate type 1 gastric carcinoids.


Subject(s)
Benzodiazepinones/therapeutic use , Carcinoid Tumor/drug therapy , Chromogranin A/blood , Phenylurea Compounds/therapeutic use , Receptor, Cholecystokinin B/antagonists & inhibitors , Stomach Neoplasms/drug therapy , Aged , Carcinoid Tumor/blood , Female , Gastrins/blood , Humans , Male , Middle Aged , Stomach Neoplasms/blood , Treatment Outcome
6.
Aliment Pharmacol Ther ; 36(7): 644-9, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22861200

ABSTRACT

BACKGROUND: Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion and give hypergastrinemia secondary to gastric hypoacidity. PPI treatment therefore induces enterochromaffin-like (ECL) cell hyperplasia. Long-term hypergastrinemia in rodents and man also leads to ECL cell neoplasia. Whether long-term PPI treatment will induce ECL cell neoplasia in man has been disputed. AIM: To describe gastric carcinoids in two patients with a history of long-term PPI use. RESULTS: Two patients had been taking PPI for 12-13 years due to gastro-oesophageal reflux disease. At routine upper gastrointestinal endoscopy a solitary tumour was found in the oxyntic mucosa of both patients. Histology from the tumours showed in both cases a well-differentiated neuroendocrine tumour. Biopsies from flat oxyntic mucosa showed no signs of atrophic gastritis and a normal presence of parietal cells in both cases, but hyperplasia of ECL cells. The tumour in patient 1 was resected endoscopically. After cessation of PPI treatment the tumour regressed in patient 2 and the ECL cell hyperplasia regressed in both patients. In patient 2 serum gastrin and chromogranin A were elevated during PPI treatment, and normalised after cessation of treatment. In patient 1, unfortunately, we had serum only after treatment, and at that time both parameters were normal. CONCLUSION: These cases show that hypergastrinemia secondary to proton pump inhibitors treatment, like other causes of hypergastrinemia, may induce enterochromaffin-like cell carcinoids in man.


Subject(s)
Carcinoid Tumor/chemically induced , Enterochromaffin-like Cells/drug effects , Gastroesophageal Reflux/drug therapy , Proton Pump Inhibitors/adverse effects , Stomach Neoplasms/chemically induced , Aged , Biopsy , Carcinoid Tumor/pathology , Female , Gastric Mucosa/drug effects , Humans , Male , Middle Aged , Stomach Neoplasms/pathology , Time Factors
7.
Diabetes Obes Metab ; 13(6): 551-8, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21320265

ABSTRACT

AIMS: Serotonergic pathways in the central nervous system (CNS) are activated in the regulation of food intake and body weight. We hypothesized that adipocytes, like other cells of mesenchymal origin, possess serotonin receptors and thus could be regulated by peripherally circulating serotonin. METHODS: In vivo studies: four Sprague-Dawley rats were given daily serotonin (5HT) injections subcutaneously (s.c., 25 mg/kg) for 5 days; four controls received saline. In a long-term study, 12 rats were given serotonin s.c. for 4 months, 10 controls received saline. Body weight was registered throughout the studies, and visceral adipose tissue and plasma were collected and analysed. Adipocytes were isolated from normal rat visceral abdominal adipose tissue and analysed for the expression of serotonin receptors, the serotonin transporter (5HTT/SERT), activation of serotonin synthesis (tryptophan hydroxylase 1, Tph1) and secretion and serotonin-induced leptin regulation by RT-PCR and protein analyses. RESULTS: Hyperserotoninergic rats had significantly lower body weight (-7.4 and -6.8%) and plasma leptin levels (-44 and -38%) than controls, after both short- and long-term serotonin treatment, respectively, whereas plasma ghrelin levels were unaffected. Compared to controls, serotonin induced a 40-fold upregulation of 5HTT mRNA in visceral adipose tissue after 5 days of treatment. In vitro experiments showed that adipocytes express serotonin receptors, Tph1 and 5HTT, synthesize and secrete serotonin and that serotonin regulates leptin in mature adipocytes. CONCLUSIONS: These findings show that serotonin may regulate adipocyte function in a direct manner via the blood circulation and/or paracrine and autocrine mechanisms, and not only indirectly via the CNS as previously assumed.


Subject(s)
Adipocytes/metabolism , RNA, Messenger/biosynthesis , Receptors, Serotonin/metabolism , Serotonin/biosynthesis , Adipocytes/drug effects , Animals , Eating/drug effects , Female , Injections, Subcutaneous , Pilot Projects , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Serotonin/drug effects , Receptors, Serotonin/physiology , Reverse Transcriptase Polymerase Chain Reaction , Up-Regulation
8.
J Comp Pathol ; 139(4): 194-201, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18817920

ABSTRACT

In humans and rodents the association between atrophic gastritis, hypergastrinemia and gastric neoplasia is well-documented. Gastric tumours are rare in dogs, but the Norwegian Lundehund (puffin dog) appears predisposed to the development of gastric neoplasia associated with chronic atrophic gastritis. The present study describes 8 Lundehunds with gastric neoplasia. Seven of these animals had concurrent chronic atrophic gastritis characterized by reduction in parietal cells and hyperplasia of neuroendocrine cells. Four of the tumours displayed neuroendocrine (enterochromaffin-like cell; ECL) differentiation, suggesting that hypergastrinemia secondary to fundic atrophy may be important in carcinogenesis. The Norwegian Lundehund may therefore represent a further animal model for the study of the role of gastrin in the induction of gastric neoplasia.


Subject(s)
Carcinoma, Neuroendocrine/veterinary , Dog Diseases/pathology , Gastritis/veterinary , Stomach Neoplasms/veterinary , Animals , Carcinoma, Neuroendocrine/complications , Carcinoma, Neuroendocrine/pathology , Dogs , Female , Gastritis/complications , Gastritis/pathology , Immunohistochemistry , Male , Stomach Neoplasms/complications , Stomach Neoplasms/pathology
9.
J Neuroendocrinol ; 19(9): 739-42, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17680890

ABSTRACT

We have recently developed a new method for visualisation of gut mucosal cells and demonstrated that enterochromaffin (EC) and enterochromaffin-like (ECL) cells possess cytoplasmic extensions. The aim of the present study was to characterise the morphology of D- and G-cells. The D-cells in the stomach differed morphologically from intestinal D-cells, suggesting two distinct subpopulations of D-cells. Some D-cells appeared to be interconnected. No cell-to-cell contact between parietal and D-cells was found. Both D- and G-cells possessed long cytoplasmic extensions corresponding with our previous descriptions of EC and ECL cells. We propose that all neuroendocrine cells have the ability to develop cytoplasmic extensions, enabling them to signal to their target cells in a neurocrine manner.


Subject(s)
Cell Shape , Enterochromaffin Cells/cytology , Enterochromaffin-like Cells/cytology , Animals , Female , Gastric Mucosa/cytology , Humans , Intestinal Mucosa/cytology , Rats , Rats, Sprague-Dawley , Somatostatin/metabolism
10.
J Exp Clin Cancer Res ; 25(2): 213-21, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16918133

ABSTRACT

Pancreatic ductal adenocarcinomas can display disseminated neuroendocrine (NE) cells. Controversies exist as to their relative incidence, histogenesis, hormone production, and the prognostic implications of their presence. These issues were elucidated by means of a broad immunohistochemical (IHC) investigation of the resected specimens from 47 patients. Chromogranin A (CgA) was chosen as the major NE marker. In addition, the sensitivity of the conventional IHC procedure was increased by means of the TSA (Tyramide Signal Amplification) technique. In tumours with CgA immunoreactive (IR) cells, detected by the conventional or the TSA methods, these NE cells were further IHC analyzed, using antisera raised against a broad spectrum of neurohormonal peptides, serotonin, and IGF-1. The IHC observations were correlated with clinical and histopathological data, the nuclear IR for the Ki67 antigen (proliferation) of the neoplastic cells, and their IR against the p53 protein. Distinct CgA IR cells were found in 5 out of 47 (11%) tumours when studied by the conventional method, and in 9 out of 47 (19%) when examined by the TSA technique. Corresponding figures, if tumours with only questionable IR against CgA were also included, were 14 (30%) and 23 (50%), respectively. Out of the 9 cases with unequivocal CgA IR, only 3 displayed an IR to an additional hormone or growth factor; this hormone turned out to be somatostatin (only minimal foci). Insulin and glucagon cells also appeared exceptionally. The NE differentiation was found to be unrelated to proliferation, p53 protein expression, and to the survival of the patients. It occurred mainly (7 out of 9) in poorly differentiated adenocarcinomas. Thus, the plain NE immunoprofile of the CgA IR cells, together with the increased IR observed when the TSA technique was used, indicates that the NE cells in these adenocarcinomas are only poorly differentiated. When the CgA IR cells exceptionally become highly differentiated, they can express islet hormones. Using strict structural and IHC criteria, a NE differentiation occurs in less than 20 % of cases; its clinico-pathological significance seems to be non relevant.


Subject(s)
Carcinoma, Pancreatic Ductal/pathology , Neurosecretory Systems/pathology , Pancreatic Neoplasms/pathology , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Carcinoma, Pancreatic Ductal/metabolism , Cell Differentiation , Cell Proliferation , Chromogranin A , Chromogranins/metabolism , Female , Humans , Immunoenzyme Techniques , Ki-67 Antigen/metabolism , Male , Middle Aged , Neurosecretory Systems/metabolism , Pancreatic Neoplasms/metabolism , Prognosis , Tumor Suppressor Protein p53/metabolism
12.
Eur Respir J ; 28(3): 542-8, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16707514

ABSTRACT

The neuroendocrine (NE) system may play an important role in smoking-induced airway diseases. The aim of the present study was to examine the relationship between serum levels of the general NE marker chromogranin A (CgA) and smoking habits, respiratory symptoms and lung function. The study population consisted of never-smokers with normal lung function, smokers with normal lung function and smokers with airway obstruction who were randomly selected from the lung study of the Nord-Trøndelag Health Study (HUNT). Serum CgA was determined in 151, 138 and 116 subjects, respectively. All subjects were seronegative for Helicobacter pylori. Male smokers with airway obstruction had significantly higher serum CgA levels (median 3.70 nmol x L(-1) (interquartile range 3.10-5.15)) than both smokers with normal lung function (3.00 nmol x L(-1) (2.50-3.67)) and never-smokers with normal lung function (2.90 nmol x L(-1) (2.57-3.30)). The elevated levels of CgA correlated with the degree of airway obstruction. Moreover, the presence of respiratory symptoms and chronic bronchitis among male smokers were associated with increased serum CgA levels. Females had CgA levels similar to male smokers independent of smoking status and lung function. Elevated serum chromogranin A levels in subjects with airway obstruction and respiratory symptoms may represent neuroendocrine activation in inflammatory or remodelling processes in the lung.


Subject(s)
Airway Obstruction/diagnosis , Chromogranin A/blood , Neurosecretory Systems/metabolism , Smoking/blood , Adult , Airway Obstruction/metabolism , Chromogranin A/metabolism , Female , Humans , Male , Middle Aged
13.
Acta Physiol (Oxf) ; 186(1): 37-43, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16497178

ABSTRACT

AIM: Gastrin stimulates acid secretion by mobilizing histamine from enterochromaffin-like (ECL) cells that occur predominantly at the base of the gastric glands. The parietal cells occur higher up in the glands nearer to the gastric lumen. The present study was performed to assess whether histamine is transported from the ECL cell via the microcirculation (endocrine route) or local diffusion (paracrine route). METHODS: Totally isolated, vascularly perfused, rat stomachs were examined both in basal and gastrin-stimulated state. Histamine concentrations, determined by radioimmunoassay in venous effluent and microdialysate from an indwelling probe in the submucosa, were monitored over a period of 240 min. Gastrin-17 was infused through an arterial catheter for 120 min. The parietal cells were examined by electron microscopy, and the percentage of actively secreting parietal cells (displaying secretory canaliculi) in four regions along the glands (basal to surface, zones I-IV) was determined. RESULTS: Gastrin stimulated acid secretion and histamine release as well as parietal cell activation. Upon gastrin stimulation, histamine concentration in the microdialysate was 2.5-fold higher than in the venous effluent (P = 0.008). The parietal cells in the upper part of the gland (zone III) were found to be activated the most. CONCLUSION: As the histamine concentrations were higher in the tissue (microdialysate) than in blood, histamine seems to reach the parietal cells via the paracrine route. The fraction of active parietal cells seems to depend more on the age of the parietal cells than on the distance from the ECL cell.


Subject(s)
Enterochromaffin-like Cells/metabolism , Gastric Mucosa/metabolism , Histamine Release/drug effects , Parietal Cells, Gastric/metabolism , Animals , Biological Transport/physiology , Enterochromaffin-like Cells/drug effects , Enterochromaffin-like Cells/ultrastructure , Gastric Acid/metabolism , Gastrins/pharmacology , Histamine/analysis , Histamine/metabolism , Hormones/pharmacology , Immunohistochemistry/methods , Male , Microcirculation/physiology , Microdialysis/methods , Microscopy, Electron/methods , Parietal Cells, Gastric/drug effects , Parietal Cells, Gastric/ultrastructure , Rats , Rats, Wistar , Stomach/drug effects
14.
J Cell Biochem ; 98(1): 139-51, 2006 May 01.
Article in English | MEDLINE | ID: mdl-16408289

ABSTRACT

Recent studies have proposed a role for serotonin and its transporter in regulation of bone cell function. In the present study, we examined the in vitro effects of serotonin and the serotonin transporter inhibitor fluoxetine "Prozac" on osteoblasts and osteoclasts. Human mononuclear cells were differentiated into osteoclasts in the presence of serotonin or fluoxetine. Both compounds affected the total number of differentiated osteoclasts as well as bone resorption in a bell-shaped manner. RT-PCR on the human osteoclasts demonstrated several serotonin receptors, the serotonin transporter, and the rate-limiting enzyme in serotonin synthesis, tryptophan hydroxylase 1 (Tph1). Tph1 expression was also found in murine osteoblasts and osteoclasts, indicating an ability to produce serotonin. In murine pre-osteoclasts (RAW264.7), serotonin as well as fluoxetine affected proliferation and NFkappaB activity in a biphasic manner. Proliferation of human mesenchymal stem cells (MSC) and primary osteoblasts (NHO), and 5-HT2A receptor expression was enhanced by serotonin. Fluoxetine stimulated proliferation of MSC and murine preosteoblasts (MC3T3-E1) in nM concentrations, microM concentrations were inhibitory. The effect of fluoxetine seemed direct, probably through 5-HT2 receptors. Serotonin-induced proliferation of MC3T3-E1 cells was inhibited by the PKC inhibitor (GF109203) and was also markedly reduced when antagonists of the serotonin receptors 5-HT2B/C or 5-HT2A/C were added. Serotonin increased osteoprotegerin (OPG) and decreased receptor activator of NF-kappaB ligand (RANKL) secretion from osteoblasts, suggesting a role in osteoblast-induced inhibition of osteoclast differentiation, whereas fluoxetine had the opposite effect. This study further describes possible mechanisms by which serotonin and the serotonin transporter can affect bone cell function.


Subject(s)
Fluoxetine/pharmacology , Osteoblasts/drug effects , Osteoblasts/physiology , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin/physiology , 3T3 Cells , Animals , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cell Line , Cell Proliferation/drug effects , Humans , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/physiology , Mice , Osteoblasts/metabolism , Osteoclasts/drug effects , Osteoclasts/metabolism , Osteoclasts/physiology , Osteoprotegerin/metabolism , RANK Ligand/metabolism
15.
Clin Chim Acta ; 363(1-2): 157-64, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16168978

ABSTRACT

BACKGROUND: A new basis for diagnostic tests is being provided by the vast amount of data on gene expression that are now becoming available through large-scale measurement of mRNA abundance. The insights gained from these resources are most likely going to provide both a better basic understanding of disease mechanisms, and to identify molecular markers for more precise diagnoses and for prediction of prognosis and treatment response. METHODS: Some quantitative RT-PCR assays are utilized today for diagnosis of both malignant and non-malignant disease, but the use of gene expression measurements in clinical medicine can be expected to increase dramatically. CONCLUSIONS: There are important technical issues that must be adequately solved in order to obtain robust assays, such as standardized protocols with appropriate quality controls that ensure reliable data for the specific samples being analysed and good inter-laboratory reproducibility.


Subject(s)
Clinical Chemistry Tests/methods , Gene Expression Profiling/methods , Lymphoma/diagnosis , Biomarkers, Tumor/analysis , Genetic Markers , Humans , Lymphoma/genetics , Lymphoma/mortality , Microarray Analysis/methods , Quality Control , Reproducibility of Results , Reverse Transcriptase Polymerase Chain Reaction/methods , Sensitivity and Specificity
17.
Aliment Pharmacol Ther ; 21(2): 149-54, 2005 Jan 15.
Article in English | MEDLINE | ID: mdl-15679764

ABSTRACT

BACKGROUND: Rebound acid hypersecretion develops after the use of acid inhibitors. AIM: To estimate the duration of hypersecretion and to elucidate the role of the enterochromaffin-like (ECL) cell in rebound acid hypersecretion. METHODS: Patients waiting for anti-reflux surgery who had used a proton pump inhibitor daily > 1 year were included. All patients discontinued taking acid inhibiting drugs after the operation. Basal and pentagastrin stimulated acid output was measured at 4, 8, 16 and 26 weeks postoperatively. Oxyntic mucosal biopsies were collected before and 26 weeks after the operation for counting of histidine decarboxylase (HDC) immunoreactive cells. Serum chromogranin A (CgA) and gastrin were measured before and at 4, 8, 16 and 26 weeks after the operation. RESULTS: Pentagastrin stimulated acid secretion was higher at 4 and 8 weeks than at 26 weeks after the operation. Gastrin and CgA were significantly reduced at 4 and 8 weeks, respectively. The number of HDC immunoreactive cells was reduced by 60% at 26 weeks postoperative. DISCUSSION: Rebound acid hypersecretion lasts more than 8 weeks, but less than 26 weeks after long-term proton pump inhibition. CONCLUSION: The findings indicate that not only the parietal cell mass, but also ECL cell mass and activity are involved in the mechanism of acid hypersecretion.


Subject(s)
Antacids/therapeutic use , Enterochromaffin-like Cells/metabolism , Gastric Acid/metabolism , Gastroesophageal Reflux/drug therapy , 2-Pyridinylmethylsulfinylbenzimidazoles , Adult , Aged , Anti-Ulcer Agents/therapeutic use , Esophagitis/drug therapy , Esophagitis/metabolism , Female , Gastroesophageal Reflux/metabolism , Humans , Immunohistochemistry , Lansoprazole , Long-Term Care , Male , Middle Aged , Omeprazole/analogs & derivatives , Omeprazole/therapeutic use , Pentagastrin/pharmacology , Proton Pump Inhibitors
18.
Scand J Gastroenterol ; 39(10): 919-26, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15513328

ABSTRACT

BACKGROUND: Among inbred female cotton rats (Sigmodon hispidus) 25%-50% of the animals develop spontaneous gastric carcinomas, whereas males have an incidence of less than 1%. The carcinomas are enterochromaffin-like (ECL)-cell derived. Animals with gastric carcinomas also have hypergastrinaemia and gastric hypoacidity, but the mechanism behind the hypoacidity is unknown. Carcinomas have been found in all female cotton rats with spontaneous hypergastrinaemia lasting more than 4 months, and a gastrin receptor antagonist prevents the development of carcinoma. The purpose of the present study was to investigate whether induced hypergastrinaemia in male cotton rats would also result in carcinomas. METHODS: Hypergastrinaemia was induced by partial corpectomy of male cotton rats, aiming at removal of 80%-90% of the corpus. A control group was sham-operated. RESULTS: All partially corpectomized animals developed persistent hypergastrinaemia. Six months after the operation, 9 out of 13 partially corpectomized animals developed gastric cancer. In the dysplastic mucosa surrounding the tumours there was an increase in chromogranin A immunoreactive cells, where numerous cells also were stained using the Sevier-Munger technique. Tumour tissue also contained cells that were chromogranin A positive and stained by Sevier-Munger. CONCLUSIONS: ECL-cell carcinomas can be induced in male cotton rats by partial corpectomy. This supports a previous statement that spontaneous carcinomas in female cotton rats are caused by gastric hypoacidity and hypergastrinaemia. In hypergastrinaemic animals, ECL-cell carcinomas develop independently of gender within a relatively short period of time, and cotton rats therefore represent an interesting model for studying gastric carcinogenesis.


Subject(s)
Carcinoma/pathology , Enterochromaffin-like Cells/pathology , Gastrins/metabolism , Stomach Neoplasms/pathology , Animals , Biopsy, Needle , Disease Models, Animal , Gastrectomy/methods , Gastrins/blood , Hydrogen-Ion Concentration , Immunohistochemistry , Male , Probability , Rats , Sensitivity and Specificity , Sigmodontinae , Statistics, Nonparametric
19.
Scand J Gastroenterol ; 39(10): 969-73, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15513336

ABSTRACT

BACKGROUND: Chromogranin A (CgA) has been shown to be a useful marker in the diagnosis of neuroendocrine (NE) tumours. The clinical significance of CgA has been studied mostly in patients with known NE tumours. The diagnosis was evaluated in 153 consecutive patients in whom CgA was measured in a given time interval. METHODS: CgA in serum was measured by radioimmunoassay. Immunohistochemistry with an antibody against CgA was performed in tumours from patients with adenocarcinoma and elevated CgA levels using a conventional method and the more sensitive tyramide signal amplification (TSA) technique. RESULTS: Elevated serum CgA levels were found in 44 patients; 19 had NE tumours and 6 had tumours classified as adenocarcinomas. With the TSA technique, a high proportion of CgA-positive cells were disclosed in five of the adenocarcinoma patients. Patients with atrophic gastritis (no. 2) and patients treated with inhibitors of gastric acid secretion (no. 6) also had elevated levels of CgA. A modest increase in CgA levels was observed in 2 patients with renal impairment, and in 9 patients without any obvious cause. CONCLUSION: The current study confirms that serum CgA is a sensitive marker for the detection of NE neoplasia. Elevated levels found in patients with adenocarcinoma may indicate NE differentiation in the tumour. CgA is a useful tool in the monitoring of enterochromaffin-like (ECL) hyperplasia secondary to treatment with acid secretion inhibitors or atrophic gastritis.


Subject(s)
Adenocarcinoma/diagnosis , Biomarkers, Tumor/blood , Chromogranins/blood , Gastrointestinal Neoplasms/diagnosis , Neuroendocrine Tumors/diagnosis , Adenocarcinoma/blood , Adolescent , Adult , Aged , Aged, 80 and over , Biopsy, Needle , Child , Chromogranin A , Chromogranins/metabolism , Cohort Studies , Female , Gastrointestinal Neoplasms/blood , Humans , Immunohistochemistry , Male , Middle Aged , Neuroendocrine Tumors/blood , Probability , Prognosis , Radioimmunoassay , Sensitivity and Specificity , Severity of Illness Index , Statistics, Nonparametric
20.
Scand J Gastroenterol ; 39(7): 621-8, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15370681

ABSTRACT

BACKGROUND: Patients with chronic atrophic gastritis (CAG) and hypergastrinaemia are at risk of developing hyperplasia of the enterochromaffin-like (ECL) cells and ECL-cell-derived tumours. The effect of the somatostatin analogue octreotide on ECL cell carcinoids is examined. METHODS: Five patients with hypergastrinaemia and ECL cell carcinoids were enrolled in a 1-year study of octreotide LAR (long-acting release) 20 mg given at monthly intervals. Biopsies from tumours and from flat oxyntic mucosa were done at the start and 3, 6 and 12 months thereafter. Sections were stained with haematoxylin-erythrosin, immunostained with chromogranin A (CgA) and doublestained with CgA and Ki-67. Serum gastrin and CgA were measured. RESULTS: The number of visible tumours was reduced by more than 50 %. Sections from both tumours and flat mucosa showed a reduced number of CgA immunoreactive cells. Mean serum gastrin decreased from 421 to 186 pM (normal <40 pM); P > 0.05, and serum CgA from 73 to 25 ng/ml (normal < 30 ng/ml); P < 0.001. CONCLUSIONS: During treatment the patients were still markedly hypergastrinaemic, whereas the serum CgA showed normalization. A diminished tumour load and reduced ECL cell density were found, indicating an antiproliferative effect of octreotide directly on the ECL cells.


Subject(s)
Antineoplastic Agents, Hormonal/administration & dosage , Carcinoid Tumor/drug therapy , Enterochromaffin-like Cells/drug effects , Octreotide/administration & dosage , Stomach Neoplasms/drug therapy , Aged , Carcinoid Tumor/pathology , Cell Proliferation/drug effects , Chromogranin A , Chromogranins/blood , Chromogranins/drug effects , Delayed-Action Preparations , Female , Gastric Mucosa/drug effects , Gastric Mucosa/pathology , Gastrins/blood , Gastrins/drug effects , Gastroscopy , Humans , Male , Middle Aged , Stomach Neoplasms/pathology , Time Factors
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