Temperature dependence of the [Formula: see text] anomaly in the excitation spectrum of the 2D quantum Heisenberg antiferromagnet.

It is well established that in the low-temperature limit, the two-dimensional quantum Heisenberg antiferromagnet on a square lattice (2DQHAFSL) exhibits an anomaly in its spectrum at short-wavelengths on the zone-boundary. In the vicinity of the [Formula: see text] point the pole in the one-magnon response exhibits a downward dispersion, is heavily damped and attenuated, giving way to an isotropic continuum of excitations extending to high energies. The origin of the anomaly and the presence of the continuum are of current theoretical interest, with suggestions focused around the idea that the latter evidences the existence of spinons in a two-dimensional system. Here we present the results of neutron inelastic scattering experiments and Quantum Monte Carlo calculations on the metallo-organic compound Cu(DCOO)[Formula: see text]D2O (CFTD), an excellent physical realisation of the 2DQHAFSL, designed to investigate how the anomaly at [Formula: see text] evolves up to finite temperatures [Formula: see text]. Our data reveal that on warming the anomaly survives the loss of long-range, three-dimensional order, and that it is thus a robust feature of the two-dimensional system. With further increase of temperature the zone-boundary response gradually softens and broadens, washing out the [Formula: see text] anomaly. This is confirmed by a comparison of our data with the results of finite-temperature Quantum Monte Carlo simulations where the two are found to be in good accord. In the vicinity of the antiferromagnetic zone centre, there was no significant softening of the magnetic excitations over the range of temperatures investigated.

Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver.

BACKGROUND: Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by life-threatening acute neurovisceral attacks due to the induction of hepatic δ-aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency. So far, the treatment of choice is hemin which represses ALAS1. The main issue in the medical care of AIP patients is the occurrence of debilitating recurrent attacks. OBJECTIVE: The aim of this study was to determine whether chronic hemin administration contributes to the recurrence of acute attacks. METHODS: A follow-up study was conducted between 1974 and 2015 and included 602 French AIP patients, of whom 46 had recurrent AIP. Moreover, we studied the hepatic transcriptome, serum proteome, liver macrophage polarization and oxidative and inflammatory profiles of Hmbs-/- mice chronically treated by hemin and extended the investigations to five explanted livers from recurrent AIP patients. RESULTS: The introduction of hemin into the pharmacopeia has coincided with a 4.4-fold increase in the prevalence of chronic patients. Moreover, we showed that both in animal model and in human liver, frequent hemin infusions generate a chronic inflammatory hepatic disease which induces HO1 remotely to hemin treatment and maintains a high ALAS1 level responsible for recurrence. CONCLUSION: Altogether, this study has important impacts on AIP care underlying that hemin needs to be restricted to severe neurovisceral crisis and suggests that alternative treatment targeting the liver such as ALAS1 and HO1 inhibitors, and anti-inflammatory therapies should be considered in patients with recurrent AIP.

BRAF V600E mutation in early-stage multiple myeloma: good response to broad acting drugs and no relation to prognosis.

In this study, we analyzed the prevalence and clone size of BRAF V600E mutation in 209 patients with multiple myeloma and related the results to clinical phenotype, response and survival. Biopsies were screened for BRAF V600E by allele-specific real-time PCR (AS-PCR). Positive results were confirmed by immunohistochemistry, Sanger sequencing and, in three patients from whom we had stored purified myeloma cells, whole-exome sequencing. Eleven patients (5.3%) were BRAF V600E mutation positive by AS-PCR and at least one other method. The fraction of mutated cells varied from 4 to 100%. BRAF V600E-positive patients had no characteristic clinical phenotype except for significantly higher levels of serum creatinine (125 versus 86 µmol/l) Seven of eleven patients responded with at least very good partial response to alkylators, immunomodulatory agents or proteasome inhibitors. Progression-free and overall survival were similar in patients with and without the mutation. By this integrated approach, we found that patients with BRAF V600E mutation responded very well to broad acting drugs and there was no relation to prognosis in early-stage myeloma. In particular, a large mutated cell fraction did not correlate with aggressive disease.

Microscopic theory of non-adiabatic response in real and imaginary time.

We present a general approach to describe slowly driven quantum systems both in real and imaginary time. We highlight many similarities, qualitative and quantitative, between real and imaginary time evolution. We discuss how the metric tensor and the Berry curvature can be extracted from both real and imaginary time simulations as a response of physical observables. For quenches ending at or near the quantum critical point, we show the utility of the scaling theory for detecting the location of the quantum critical point by comparing sweeps at different velocities. We briefly discuss the universal relaxation to equilibrium of systems after a quench. We finally review recent developments of quantum Monte Carlo methods for studying imaginary time evolution. We illustrate our findings with explicit calculations using the transverse-field Ising model in one dimension.

Expression of Toll-like receptor-3 is enhanced in active inflammatory bowel disease and mediates the excessive release of lipocalin 2.

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.

Mode of delivery and postpartum emotional distress: a cohort study of 55,814 women.

OBJECTIVE: To assess the association between mode of delivery and maternal postpartum emotional distress. DESIGN: A prospective study of women from 30 weeks of gestation to 6 months postpartum. SETTING: Pregnant women in Norway during the period 1998-2008. POPULATION: A total of 55,814 women from the Norwegian Mother and Child Cohort Study. METHODS: Emotional distress was reported in a short form of the Hopkins Symptom Checklist-25 (SCL-8) at 30 weeks of gestation and at 6 months postpartum. Information on mode of delivery was obtained from the Medical Birth Registry of Norway. MAIN OUTCOME MEASURES: Changes in SCL-8 score from 30 weeks of gestation to 6 months postpartum and presence of emotional distress at 6 months postpartum. RESULTS: Women with instrumental vaginal, emergency caesarean or elective caesarean deliveries had similar changes in SCL-8 score between 30 weeks of gestation and 6 months postpartum, as compared with women with unassisted vaginal delivery (adjusted regression coefficient, 0.00, 95% CI -0.01 to 0.01; 0.01, 95% CI 0.00-0.02; and -0.01, 95% CI -0.02 to 0.00, respectively). The corresponding odds ratios (ORs) associated with the presence of emotional distress at 6 months postpartum (SCL-8 ≥ 2.0) were: OR 1.01, 95% CI 0.86-1.18; OR 1.13, 95% CI 0.97-1.32; and OR 0.96, 95% CI 0.79-1.16, respectively. These estimates were adjusted for emotional distress during pregnancy and other potential confounding factors. Emotional distress during pregnancy showed the strongest association with the presence of emotional distress at 6 months postpartum (adjusted OR 14.09, 95% CI 12.77-15.55). CONCLUSIONS: Mode of delivery was not associated with a change in SCL-8 score from 30 weeks of gestation to 6 months postpartum or with the presence of emotional distress postpartum.

The role of mechanical forces and adenosine in the regulation of intestinal enterochromaffin cell serotonin secretion.

Enterochromaffin (EC) cells of the diffuse neuroendocrine cell system secrete serotonin (5-HT) with activation of gut motility, secretion, and pain. These cells express adenosine (ADORA) receptors and are considered to function as mechanosensors. Physiological pathways mediating mechanosensitivity and adenosine responsiveness remain to be fully elucidated, as do their roles in inflammatory bowel disease (IBD) and neoplasia. Pure (98-99%) FACS-sorted normal and IBD human EC cells and neoplastic EC cells (KRJ-I) were studied. IBD-EC cells and KRJ-I overexpressed ADORA2B. NECA, a general ADORA receptor agonist, stimulated, whereas the A2B receptor antagonist MRS1754 inhibited, 5-HT release (EC50 = 1.8 × 10-6 M; IC50 = 3.7 × 10-8 M), which was associated with corresponding alterations in intracellular cAMP levels and pCREB (Ser133). Mechanical stimulation using a rhythmic flex model induced transcription and activation of Tph1 (tryptophan hydroxylase) and VMAT1 (vesicular monoamine transporter 1) and the release of 5-HT, which could be inhibited by MRS1754 and amplified by NECA. Secretion was also inhibited by H-89 (PKA inhibitor) while Tph1 and VMAT1 transcription was regulated by PKA/MAPK and PI3K-mediated signaling. Normal and IBD-EC cells also responded to NECA and mechanical stimulation with PKA activation, cAMP production, and 5-HT release, effects reversible by MRS1754. EC cells express stimulatory ADORA2B, and rhythmic stretch induces A2B activation, PKA/MAPK/IP3-dependent transcription, and PKA-dependent secretion of 5-HT synthesis and secretion. Receptor expression is amplified in IBD and neoplasia, and 5-HT release is increased. Determination of factors that regulate EC cell function are necessary for understanding its role as a mechanosensory cell and to facilitate the development of agents that can selectively target cell function in EC cell-associated disease.

Oral and systemic administration of beta-glucan protects against lipopolysaccharide-induced shock and organ injury in rats.

beta-Glucans are glucose polymers with a variety of stimulatory effects on the immune system. The objective of this study was to determine the effect of prophylactic oral administration of soluble Saccharomyces cerevisiae-derived beta-1,3/1,6-glucan (SBG) on the outcome of experimental endotoxaemia and shock-associated organ injury. Male Wistar rats were pretreated with SBG orally (SBGpo, 20 mg/kg/day) for 14 days, subcutaneously (SBGsc, 2 mg/kg/day) for 3 days, or vehicle (placebo). Rats were anaesthetized and subjected to endotoxaemia by intravenous infusion of Escherichia coli lipopolysaccharide (LPS) (6 mg/kg) or saline infusion (sham). We observed significant levels of plasma beta-glucan in the SBGpo group (P<0 x 5), although the SBGsc group had levels approximately 40-fold higher despite a 10-fold lower dose. SBG prophylaxis caused enhanced blood pressure recovery following LPS-induced blood pressure collapse. Oral treatment with SBG attenuated the LPS-induced rise in plasma creatinine levels (P<0 x 05), indicating protection against renal injury. SBG also attenuated the plasma levels of aspartate aminotransferase and alanine aminotransferase (SBGpo, P<0 x 01; SBGsc, P<0 x 01), indicating protection against LPS-induced hepatic injury. A moderate increase in baseline interleukin (IL)-1beta levels was observed in the SBGsc group (P< 0 x 05). In the LPS-challenged rats, plasma levels of proinflammatory cytokines was moderately reduced in both SBG-treated groups compared to placebo. SBG treatment, particularly oral administration, had a striking effect on the haemodynamics of LPS-treated rats, although only a minute fraction of the orally administered beta-glucan translocated to the circulation. Enhanced organ perfusion may thus be responsible for the attenuated levels of indicators of kidney and liver injury seen in SBG-treated rats.

Variational quantum Monte Carlo simulations with tensor-network states.

We show that the formalism of tensor-network states, such as the matrix-product states (MPS), can be used as a basis for variational quantum Monte Carlo simulations. Using a stochastic optimization method, we demonstrate the potential of this approach by explicit MPS calculations for the transverse Ising chain with up to N=256 spins at criticality, using periodic boundary conditions and D x D matrices with D up to 48. The computational cost of our scheme formally scales as ND3, whereas standard MPS approaches and the related density matrix renormalization group method scale as ND5 and ND6, respectively, for periodic systems.

ECL cell histamine mobilization and parietal cell stimulation in the rat stomach studied by microdialysis and electron microscopy.

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.

Gene expression analysis and clinical diagnosis.

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.

Identification of novel growth factor-responsive genes in neuroendocrine gastrointestinal tumour cells.

Targeting growth-regulatory pathways is a promising approach in cancer treatment. A prerequisite to the development of such therapies is characterisation of tumour growth regulation in the particular tumour cell type of interest. In order to gain insight into molecular mechanisms underlying proliferative responses in neuroendocrine (NE) gastrointestinal (GI) tumours, we investigated gene expression in human carcinoid BON cells after exposure to gastrin, hepatocyte growth factor (HGF), pituitary adenylate cyclase-activating polypeptide or epidermal growth factor. We particularly focused on gastrin- and HGF-induced gene expression, and identified 95 gastrin- and 101 HGF-responsive genes. The majority of these genes are known mediators of processes central in tumour biology, and a number of them have been associated with poor prognosis and metastasis in cancer patients. Furthermore, we identified 12 genes that were regulated by all four factors, indicating that they may be universally regulated during NE GI tumour cell proliferation. Our findings provide useful hypotheses for further studies aimed to search for new therapeutic targets as well as tumour markers in NE GI tumours.

Treatment of ECL cell carcinoids with octreotide LAR.

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.

Spontaneous enterochromaffin-like cell carcinomas in cotton rats (Sigmodon hispidus) are prevented by a somatostatin analogue.

Among inbred female cotton rats (Sigmodon hispidus) 25-50% of the animals develop spontaneous gastric carcinomas; the corresponding figure for male cotton rats is approximately 1%. Animals with carcinomas have hypergastrinaemia and gastric hypo-anacidity and the tumours are derived from enterochromaffin-like (ECL) cells. The mechanism behind the hypo-anacidity is unknown. Carcinomas are found in all female cotton rats with hypergastrinaemia lasting more than 4 months and this represents an excellent animal model for studying gastric carcinogenesis. In this study, the somatostatin analogue octreotide was given to female cotton rats to prevent carcinoma development caused by hypergastrinaemia. Twelve female cotton rats were given monthly injections of long-acting octreotide (5 mg i.m.) for 6 months. A control group of 20 animals was not given injections. Of the 20 control animals, 13 developed hypergastrinaemia and histologically invasive carcinomas or dysplasia. Of the 12 animals in the octreotide group, five developed hypergastrinaemia. None of these five animals developed histological cancer (P<0.05), whereas three had dysplasia. However, octreotide did not affect plasma gastrin concentration or antral gastrin mRNA abundance significantly. Dysplasia of the oxyntic mucosa in hypergastrinaemic animals was accompanied by a marked increase in chromogranin A-immunoreactive cells and cells positive for Sevier-Munger staining. The malignant tissue also contained groups of cells with Sevier-Munger staining. In conclusion, octreotide prevented ECL cell carcinomas in hypergastrinaemic cotton rats without lowering the gastrin concentration.

Identification and regulation of the gastric H+/K+-ATPase in the rat heart.

UNLABELLED: Previous reports indicate that H+/K+-adenosine triphosphatase (ATPase) might be expressed in the heart. AIMS: The objectives of the present study were to explore the presence of H+/K+-ATPase protein and gene expression in the rat heart and to investigate whether the enzyme could contribute to potassium transport across the sarcolemma. METHODS AND RESULTS: We performed reverse transcription-polymerase chain reaction (RT-PCR) on mRNA from myocardium and isolated cardiomyocytes using primers specific for the gastric H+/K+-ATPase alpha-subunit. The PCR products were sequenced and the predicted gastric H+/K+-ATPase sequence was verified. Western blots from myocardium detected a 34-kDa band and a 94-kDa band, indicating the beta-subunit and alpha-subunit of the gastric H+/K+-ATPase, respectively. Immunocytochemistry detected significant immunoreactivity of the beta-subunit in cardiomyocytes. H+/K+-ATPase-dependent potassium transport was assessed by 86Rb+-uptake in isolated cardiomyocytes. Both ouabain and the selective H+/K+-ATPase inhibitor Schering 28080 reduced 86Rb+-uptake at maximum specific inhibition, by 70 and 25%, respectively; the effects were additive. Competitive RT-PCR analysis indicated a significant upregulation of the myocardial H+/K+-ATPase in heart failure after myocardial infarction. CONCLUSION: The gastric isoform of H+/K+-ATPase is expressed in rat cardiac myocytes, both at transcript and protein levels. Functional studies indicate that the enzyme could contribute to potassium and pHi regulation in cardiomyocytes.

Striped phase in a quantum XY model with ring exchange.

We present quantum Monte Carlo results for a square-lattice S=1/2 XY model with a standard nearest-neighbor coupling J and a four-spin ring exchange term K. Increasing K/J, we find that the ground state spin stiffness vanishes at a critical point at which a spin gap opens and a striped bond-plaquette order emerges. At still higher K/J, this phase becomes unstable and the system develops a staggered magnetization. We discuss the quantum phase transitions between these phases.

Effects of anaesthetic agents on gastrin-stimulated and histamine-stimulated gastric acid secretion in the totally isolated vascularly perfused rat stomach.

BACKGROUND: Anaesthetic agents affect gastric acid secretion, but the mechanisms behind this action have not been fully evaluated. The enterochromaffin-like (ECL) cell plays a key role in the regulation of gastric acid secretion, and anaesthetic agents have recently been described as inhibiting histamine release from the ECL cell. The present study examines the effect of anaesthetic agents on the ECL cell and on parietal cell functions. METHODS: Different concentrations of urethane, pentobarbital and a mixture of fluanisone/fantanyl/midazolam (FFM) were examined for the effect on gastrin-stimulated histamine release and acid secretion and on histamine-stimulated acid secretion in the totally isolated vascularly perfused rat stomach. The luminal acid output and histamine concentrations in venous effluents were measured by titration and radioimmunoassay, respectively. RESULTS: Pentobarbital caused an inhibition on both histamine release and acid output in gastrin-stimulated stomachs in a concentration-dependent way. The mixture of FFM at higher concentrations inhibited histamine release from the ECL cell and luminal H+ output in gastrin-stimulated acid secretion. Urethane exerted a slight inhibitory effect on histamine release only at the lowest concentration. Pentobarbital also reduced histamine-stimulated gastric acid secretion, while the mixture of FFM did not. CONCLUSIONS: pentobarbital inhibits acid secretion both by reducing ECL cell histamine release and parietal cell H+ secretion, whereas FFM inhibits acid secretion by interaction with the ECL cell only. Urethane also had a slight inhibitory effect on the ECL cell histamine release at the lowest concentration.

Glycine-extended gastrin-17 stimulates acid secretion only via CCK-2 receptor-induced histamine release in the totally isolated vascularly perfused rat stomach.

The effects of gastrin precursors have been discussed during recent years. However, the mechanism for their action, whether through a novel receptor on the parietal cell or a cholecystokinin-2 (CCK-2) receptor on the enterochromaffin like (ECL) cells, is still not settled. This study examines the effect of glycine-extended gastrin-17 (Gly-G-17), the main non-amidated gastrin precursor, on gastric acid secretion and histamine release in the totally isolated vascularly perfused rat stomach. Glycine-extended gastrin-17 at the concentrations from 0.52 to 520 nmol L(-1) was administered to the totally isolated vascularly perfused rat stomach. Glycine-extended gastrin-17 at 52 or 520 nmol L(-1), and gastrin-17 at 0.52 nmol L(-1)were co-administered to examine whether glycine-extended gastrin augmented maximal gastrin stimulated acid secretion and histamine release. Both Gly-G-17 at 52 nmol L(-1) and gastrin-17 (G-17) at 0.52 nmol L(-1) were administered together with the histamine-2 receptor antagonist ranitidine at 10 micromol L(-1). Gastric acid and venous histamine output were measured. Glycine-extended gastrin-17 at lower concentrations from 0.52 to 5.2 nmol L(-1) did not stimulate gastric acid output or histamine release, whereas higher concentrations from 52 to 520 nmol L(-1) elicited a concentration-dependent increase in acid secretion and histamine release. The outputs of acid and histamine at 520 nmol L(-1) Gly-G-17 were at the same level as those found for G-17 at its maximally effective concentration of 0.52 nmol L(-1). Glycine-extended gastrin-17 at maximally effective concentration of 520 nmol L(-1) did not augment maximal gastrin stimulated acid secretion or histamine release. Ranitidine inhibited G-17 and Gly-G-17 stimulated acid secretion to a similar degree. This study confirms that the stimulatory effect of Gly-G-17 on gastric acid secretion is via a CCK-2 receptor on the ECL cell.

The CCK-2 receptor is located on the ECL cell, but not on the parietal cell.

BACKGROUND: The interrelationship between histamine and gastrin in the physiological regulation of gastric acid secretion is still a matter of dispute. CCK-2 receptors are located on enterochromaffin-like (ECL) cells in corpus mucosa and gastrin stimulates acid production by releasing histamine from the ECL cells, which in turn stimulates the parietal cells. Whether parietal cells also possess gastrin receptors of physiological significance is unclear. The aim of the present study was to localize the CCK-2 receptor cellularly and concomitantly demonstrate a gastrin receptor response (histamine release). METHODS: Fluorescein labelled cholecystokinin-8 (Fluo-CCK-8) was added to the arterial infusion to totally isolated, vascularly perfused rat stomachs to a final concentration of 130 pmol L(-1) for 1 min, either alone or along with 520 nmol(-1) CCK-8 after 10-min pre-perfusion with CCK-8. Immediately after the Fluo-CCK-8 had reached the oxyntic mucosa, biopsies were taken and the binding sites were localized by double immunohistochemistry combined with the tyramide signal amplification (TSA) technique. Venous histamine was measured before and during stimulation. RESULTS: Fluo-CCK-8 (130 pM) evoked histamine release, and binding sites were found in the basal part of corpus mucosa, co-localized with histidine decarbocylase (HDC) immunoreactive ECL cells. No binding of Fluo-CCK was found in the mid-glandular region of corpus, dominated by parietal cells. Binding of Fluo-CCK-8 was abolished by concomitant perfusion with excess CCK-8. CONCLUSION: Fluo-CCK-8 given to isolated rat stomachs in a physiological concentration binds to CCK-2 receptors on ECL cells and causes histamine release, whereas no binding of Fluo-CCK-8 to parietal cells was found.